IT'S A TERRIFIC HONOR TO BE ABLE
TO INTRODUCE 2 OF NIAIDs MOST
BRILLIANT STARTS D
R. VERONIQUE NUSSENBLATT AND
DR. ELODI GHEDIN WHO WILL TALK
ABOUT WHAT, ELSE?
SO I WILL GIVE A BRIEF
INTRODUCTION AND ELODIIS OUR
CHIEF OF CONSULTATION SERVICES
SO YOU SLEEP APNEA AND OBESITYY
HER ALL OVER AND OUR PROGRAM
DIRECTOR FOR TRAINING AND
INFECTIOUS DISEASE, SHE GREW UP
IN THE REGION, WENT TO
UNIVERSITY OF MARYLAND AND JOHNS
LOP KINS WHERE SHE GOT HER MHS
IN EPIDEMIOLOGY AND INFECTIOUS
DISEASE, YOU SEE THE LINK HERE
AND THEN HER M. D. AT MARYLAND,
HER RESIDENCY ON THE ESTEEMED
[INDISCERNIBLE] SERVICE, I HAVE
A STAKE HERE AND THEN DID
INFECTIOUS DISEASE TRAINING AT
JOHNS HOPKINS FOLLOWED BY
FURTHER TRAINING IN EPIDEMIOLOGY
AND PUBLIC HEALTH.
A SHORT STINT IN [INDISCERNIBLE]
BEFORE COMING BACK TO HOPKINS
WHERE SHE WAS RUNNING PART OF
THE PROGRAM OUT AT THE BAYVIEW
MEDICAL CENTER AND THEN WE WERE
FANTASTICALLY LUCKY TO GET HER
TO COME BACK HERE AND TO RUN OUR
TRAINING PROGRAM.
AND SHE IS A 2021 NIH RECIPIENT
OF THE COVID-19 AWARD FOR THE
OUTBREAK RESPONSE TEAM.
FOLLOWING HER WILL BE
DR. ELODIE GHEDIN, YOU YOU MIGHT
BE SAYING WAIT A MINUTE
COVID-19'S A FASCINATING PROGRAM
BUT IT'S NOT TYPICALLY
CONSIDERED A PARASITIC DISEASE.
THIS WAS AN ERROR, I DON'T KNOW
HOW THIS HAPPENED HERE BUT THE
FACT IS THAT MICROBIAL GENOMICS
IS ALWAYS IMPORTANT.
SO ELODIE COMES TO US FROM
CANADA.
YOU WOULDN'T KNOW IT LOOKING
OUTSIDE RIGHT NOW BUT GOT HER B.
S. AT Mc GILL AND HER MASTERS
AT UNIVERSITY OF QUEBEC AND
Ph.D. AT Mc GILL.
SHE DID HER POST DOC HERE AT THE
LPD DISP WENT FROM LEER TO THE
INSTITUTE FOR IME NATIONAL
LIBRARY OF MEDICINIC RESEARCH
TIGER IN THE YEAR OF ROCKVILLE
AND THEN WENT TO PITTSBURGH
WHERE SHE ROSE THROUGH THE RANKS
TO AN ASSOCIATE PROFESSOR WITH
TENURE BEFORE DECAMPING TO
NEW YORK WHERE SHE WAS THE--
WE WERE FORTUNATE TO THIS AND
SHE'S ALSO THE RECIPIENT TO THE
FOUNDATION FELLOWSHIP.
SO WITH THAT I WILL STOP AND
TURN IT OVER TO
DRS. NUSSENBLATT AND GHEDIN.
>> THANK YOU SO MUCH FOR JUST A
KIND INTRODUCTION.
AND ON BEHALF OF BOTH OF US AS
WELL, THANK THE COVID-19 SIG
LECTURE COMMITTEE FOR THE
INVITATION TO SPEAK TODAY ABOUT
A TOPIC THAT'S OF GREAT INTEREST
TO BOTH OF US WHICH IS WHETHER
THE INABILITY OF SOME IMMUNE O
COMPROMISED INDIVIDUALS TO
EFFECTIVELY CONTROL AND CLEAR
SARS-COV-2 AFTER INFECTION COULD
BE CONTRIBUTING TO A POTENTIAL
VARIANT EMERGENCE.
SO THIS ILLUSTRATION SHOWS US
THE TIMELINE OF THE INNATE AND
THE ADAPTIVE IMMUNE RESPONSES
DURING SARS-COV-2 INFECTION, SO
WE SEE THE INNATE RESPONSE
PRETTY IMMEDIATELY SIMULATING
INTERFERON TO COMBAT THE VIRUS
AND AS THE VIRAL LOAD INCREASES,
WE THEN SEE THE ADAPTIVE IMMUNE
RESPONSE WITH THE B-CELL AND
T-CELL PROLIFERATION, ANTIBODY
PRODUCTION LEADING TO DECREASE
IN VIRAL LOAD, RESOLUTION OF
SYMPTOMS AND ULTIMATELY, THE
CLEARANCE OF THE VIRUS.
NEXT SLIDE, PLEASE.
SO IN THIS ILLUSTRATION THAT YOU
SEE ON THE RIGHT, WE ARE SHOWING
WHAT WE OFTEN SEE IN MANY IMMUNE
O COMPROMISED HOSTS WHICH IS
THAT YOU STILL SEE THIS INNATE
RESPONSE BUT YOU DON'T HAVE THAT
ROBUST ADAPTIVE IMMUNE RESPONSE
LEADING TO PROLONGED VIRAL
PROLIFERATION, PROLONGED
INFECTION AND IN COMBINATION
WITH INFLAMMATION FROM THE
INNATE IMMUNE SYSTEM, WE ALSO
SEE PROLONGED SYMPTOMS AS WELL.
NEXT SLIDE, PLEASE.
SO WHY DOES THAT MATTER, WELL IN
THE UNITED STATES ALONE, WE HAVE
APPROXIMATELY 7 MILLION
INDIVIDUALS WITH SOME TYPE OF
IMMUNE O COMPROMISE, AND WHILE
ALL OF THE CONDITIONS YOU SEE ON
THIS SLIDE TODAY ARE ASSOCIATED
TO SOME DEGREE WITH PROLONGED
INFECTION WITH SARS-COV-2, THE
PATIENTS IN WHICH WE REALLY SEE
THE VERY PROLONGED REPRUITT
DESSENT TYPES OF INFECTIONS ARE
THOSE WHO HAVE SEVERE B-CELL
DEPLETION, USUALLY WITH SOME
T-CELL COMPROMISE AS WELL.
SO THAT CAN BE BECAUSE OF
UNDERLYING HEMEAT O LOGIC
MALIGNANCIES OR FROM
LYMPHO-DEPLETION, SO TODAY WE
WILL FOCUS ON DURATION OF
INFECTION, IT'S IMPORTANT TO
POINT OUT THAT THE ISSUES WE ARE
GOING TO BRING UP TODAY AND THE
CONCERNS ABOUT VIRAL EVOLUTION
CAN BE APPLIED TO ANY INDIVIDUAL
WITH IMPAIRED IMMUNITY.
NEXT SLIDE, PLEASE.
SO WHILE THIS COMES WITH MEDICAL
CONCERNS, IT ALSO BRINGS PUBLIC
HEALTH CONCERNS.
BECAUSE IT RAISES THE QUESTION
COULD PATIENTS WITH IMMUNE O
SUPPRESSION WHO HAVE PERSISTENT
OR PROLONGED INFECTION BE
SERVING A RESERVOIR FOR
MULTIMUTATIONAL VIRUSES THAT MAY
BE ACCUMULATING MORE MUTATIONS
AT A FREQUENCY THAT'S HIGHER
THAN EXPECTED AND COULD THOSE BE
SPILLING OUT INTO THE COMMUNITY.
WE KNOW THAT SOME VARIANTS OF
CONCERN HAVE THESE MUTATIONAL
LEAKS SO THESE SUGGEST AN
EXTENDED OF PERIOD OF HOST
WITHIN WHICH EVOLUTION HAS
OCCURRED.
NEXT SLIDE, PLEASE.
SO THIS TABLE HERE SHOW US US
STUDIES THAT HAVE BEEN PUBLISHED
OF PATIENTS WITH--WHO ARE IMMUNE
O SUPPRESSED WITH A LONG
DURATION OF LONG DURATION OF
ACTIVE SARS-COV-2 INFECTION AND
YOU CAN SEE THAT MOST OF THEM
WHAT THEY HAVE IN COMMON IS
SEVERE B-CELL IMPAIRMENT EITHER
FROM A MEDICATION LIKE
RETUXIMAB, OR A SETTING THR
THERAPY FOR A HEMEAT O LOGIC
MALIGNANCY, ALTHOUGH WE ARE
SEEING REPORTS NOW COME NOTHING
THE LITERATURE OF PATIENTS WITH
UNCONTROLLED HIV FOR EXAMPLE,
HAVING PROLONGED INFECTION AS
WELL.
SOMETIMES THEY'RE IN THE
HOSPITAL THE ENTIRE TIME,
SOMETIMES THEY GET BETTER WITH
THE THERAPIES WE GIVE THEM ONLY
TO REPRUITT DESAND REPRESENT.
SO SOME OF THESE REQUIRE SOME
KIND OF FREQUENT INTERVENTION TO
GET THEM BETTER.
AND SO YOU CAN IMAGINE THAT AN
INFECTION THAT GOES ON FOR THAT
LONG GIVES THE VIRUS AMPLE
OPPORTUNITY TO MUTATE AND IN
FACT, ALL OF THESE CASES REPORT
MUTATIONS IN THE RECEPTOR
BINDING DOMAIN, THE PRIME TARGET
OF THE PROTECTIVE ANTIBODY
RESPONSE AND IMPORTANT FOR VIRAL
ENTRY.
IN ADDITION MANY PATIENTS ARE
ALSO TREATED WITH CONVALESCENT
PLASMA OR ANTIBODIES AND
CONVALESCENT PLASMA IS
RECOMMENDEDDER ON USED ROUTINELY
IN NONIMMUNE O SUPPRESSED
PATIENTS.
BUT, WE DO HAVE EVIDENCE THAT IN
PATIENTS WHO ARE IMMUNE O
SUPPRESSED SPECIFICALLY THOSE
WITH HEMEAT O LOGIC MALIGNANCIES
CONVALESCENT PLASMA CAN LEAD TO
BETTER OUTCOMES AND SO EVENT
THOUGH IT'S NOT USED ROUTINELY
IN THE COMMUNITY, MANY CENTERS
ARE STILL USING THESE TO TREAT
THESE VERY DIFFICULT CASES.
NEXT SLIDE, PLEASE.
SO THIS FIGURE SHOWS US SEQUENCE
POLYMORPHISMS OVER TIME IN A
PATIENT WITH A VERY PROLONGED
INFECTION OF 152 DAYS.
SO THIS IS A PEASHT WHO'S HAD A
SEVERE ANTILIPID
PHOSPHO-INFECTION, THIS PATIENT
REQUIRED MANY ROUNDS OF
REMDESIVIR AND EVENTUALLY AROUND
DAY 140 WAS GIVEN MONOCLONAL
ANTIBODY AS WELL TO HELP HIM TRY
TO CLEAR THE VIRUS AND WHAT YOU
CAN SEE IS THAT AT THE LAST TIME
POINT AT DAY 152 WE SEE THE
EMERNLG ENSEL OF MUTATIONS THAT
YOU CAN SEE HERE IN RED THAT
HAVE BEEN REPORT INDEED A
VARIANCE OF CONCERN PREVIOUSLY.
NEXT SLIDE, PLEASE.
THIS FIGURE ALSO SHOWS US
MUTATIONS THAT OCCUR IN THE
VIRUS IN A PATIENT INFECTED OVER
TIME.
THIS PATIENT HAD SARS-COV-2
INFECTION FOR OVER A YEAR.
THIS WAS A PATIENT WHO HAD
UNDERGONE HEMATOPOIETIC STEM
CELL TRANSPLANTATION 6 MONTHS
PRIOR TO INFECTION AND HE
RECEIVED RETUX MAB AT THE SAME
TIME FOR ACTIVATION SO THIS
PATIENT PROLONGED COURSE
RECEIVED CONVALESCENT PLASMA
MULTIPLE TIMES THROUGHOUT HIS
INFECTION WITH THE SECOND 1
OCCURRING HERE AROUND DAY 200
AND THEN BECAUSE HE DIDN'T
IMPROVE, HE WAS ALSO GIVEN
MONOCLONAL ANTIBODY AT THE END
OF HIS INFECTION.
AND WHAT YOU ARE SUPPOSED TO BE
SEEING ON THE SLIDE, I'M NOT
SURE IF YOU CAN SEE IT, I'M NOT
SEEING IT ON MINE BUT WHAT YOU
SLEEP APNEA AND OBESITYY IN
THE--WITH THE BLUE LINE HERE IS
THAT THE EMERGENCE OF A MUTATION
AGAIN THAT'S BEEN ASSOCIATE WIDE
VARIANTS OF CONCERN IN THE PAST
AND BY THE END OF HIS INFECTION,
A HUNDRED PERCENT OF HIS VIRAL
MUTATION SAW THIS HAPPEN.
SO AGAIN SEEING THIS HAPPEN OVER
A LONG PERIOD OF TIME IN A
PATIENT WITH INFECTION.
NEXT SLIDE, PLEASE.
SO WHAT I WOULD LIKE TO SHARE
WITH YOU NOW IS A CASE THAT I
CAN AND ALLISON RODER, A
COMPUTATION BIOLOGIST IN
ELODIE'S LAB PUBLISH INDEED THE
JOURNAL OF INFECTIOUS DISEASES
AND THIS IS THE CASE OF A NEARLY
YEAR LONG COVID-19 INFECTION IN
A PATIENT WHO WAS TREATED HERE
AT THE NIH CLINICAL CENTER.
AND IN WHOM WE ALSO FOUND
IN-HOST EVOLUTION OF SARS-COV-2.
NEXT SLIDE, PLEASE.
SO THIS IS A 48 YEAR-OLD WOMAN
WITH A HISTORY OF DIFFUSE LARGE
B-CELL EMILY POEM FOAMA AND SHE
WAS--B-CELL LYMPHOMA AND SHE WAS
TREATED WITH THE CAR-T CELL
THERAPY AND AS A RESULT SHE HAD
ONGOING DISPLACIA, CD4 T-CELL
LYMPHPENIA AND INCREASED
RESPIRATORY INFECTIONS BECAUSE
OF THAT.
THIS WAS 1 OF THE FIRST PATIENTS
THAT ADMITTED HERE AT THE
CLINICAL CENTER WITH COVID-19.
SHE WAS 1 OF OUR FIRST PATIENTS
THAT WE TOOK CARE OF AND SHE
REPRESENTED TO UTION ON
APRIL 27th, 2020 WITH AN 11
DAY HISTORY OF FEVER, HEADACHE,
CONGESTION, COUGH AND RIGHT
AWAY, SARS-KICKOFF 2 WAS
SUSPECTED.
HOWEVER, SHE TESTED NEGATIVE ON
NAIS O-PHARYNGIAL SWAB PRIOR TO
ADMISSION AND THEN TWICE AFTER
ADMISSION.
ON ADMISSION SHE REQUIRED
SUPPLEMENTAL OXYGEN AND DESPITE
TREATMENT WITH BROAD SPECTRUM
ANTIBIOTICS, HER SYMPTOMS
CONTINUED TO WORSEN AND SHE
WIRED MORE OXYGEN.
SO ON MAY FIRST A BRANCHIAL
LAVAGE WAS PERFORMED MEANING
DEEP LUNG SPECIMENS WERE
OBTAINED.
AND AGAIN THIS WAS WAY AT THE
BEGINNING OF THE PANDEMIC AND WE
DID NOT HAVE REMDESIVIR
AVAILABLE TO US TO TREAT HER.
WE ALSO DID NOT HAVE ROBUST
CLINICAL TRIAL DATA SURROUNDING
THE USE OF CORTICOSTEROIDS FOR
ACUTE COVID-19 INFECTIONS SO
NEITHER OF THOSE AGENTS WERE
ADMINISTEREDDA THE TIME.
SO SHE WAS HOSPITALIZED HERE FOR
1 MONTH ANDURE DIDDING THAT
MONTH WE OBTAINED ORAL SWAP
SWABS TO TEST FOR SARS-COV-2,
YOU CAN SEE WITH VIRAL LOADS
HERE WITH THE PURPLE CIRCLE, SHE
WAS POSITIVE THE ENTIRE TIME.
SO AFTER A MONTH, BECAUSE WE
RECOGNIZE THAT JUST LIKE WITH
OTHER INFECT YOWZ DECEASES, THAT
AS AN IMMUNE O COMPROMISED
PATIENT, SHE MAY NOT RECOVER AS
QUICKLY AS RECALLINGS.
WE SENT HER HOME WITH A PLAN FOR
HER TO CONVALESCE AT HOME AND TO
GET BETTER.
NEXT SLIDE, PLEASE.
SO FROM THE PERIOD OF TIME WHEN
SHE WENT HOME UNTIL
DECEMBER 2020, SO FOR SEVERAL
MONTHS SHE CONTINUED TO HAVE
WAXING AND WANING SYMPTOMS.
SHE HAD A PERSISTENT COUGH,
STILL SHORT OF BREATH BUT SHE
WOULD TELL US THIS WOULD GET
MUCH, MUCH, BETTER ONLY TO GET
WORSE A FEW WEEKS LATER.
SHE ALSO HAD WAXING AND--SHE HAD
INTERMITTENT LOW GRADE FEVERS AS
WELL.
SO ALL OF THOSE SYMPTOMS WERE
STILL PRESENT BUT WAXING AND
WANING AND SHE ALSO HAD A
PERSISTENT OXYGEN REQUIREMENT SO
CLEARLY SOMETHING WAS GOING ON
IN HER LUNGS.
DURING THAT PERIOD OF TIME, WE
ALSO OBTAINED NAIS O PHARYNGIAL
SWABS THAT WERE EITHER NEGATIVE
PC Rs FOR SARS-COV-2 OR HAD
VERY LOW VIRAL LOADS.
AND SO AT THAT POINT BECAUSE OF
HER OVERALL MILD SYMPTOMATOLOGY
AND LOW VIRAL LOADS, THESE
POSITIVE PC Rs WERE THOUGHT TO
BE MOST LIKELY DUE TO SHUTTING
OF NONVIABLE VIRAL PARTICLES
WHICH WAS ALREADY RECOGNIZED TO
HAPPEN IN BOTH IMMUNE O
COMPROMISED AND NONIMMUNE O
COMPROMISED INDIVIDUALS.
NEXT SLIDE, PLEASE.
SO WHAT YOU CAN SEE HERE ARE THE
PATIENT CT SCANS.
SO, ON YOUR LEFT THIS IS THE CT
SCAN FROM APRIL 2020 SO THIS IS
WHEN SHE RESENTED TO US.
SO IMAGINE THE PATIENT IS LYING
ON A TABLE WITH HER HEAD BEHIND
THIS IMAGE, SHE'S LYING ON HER
BACK WITH THE HEAD BEHIND THIS
IMAGE AND WE ARE STANDING AT HER
FEET AND THIS IS A CROSS SECTION
OF HER CHEST.
SO IN THE MIDDLE IS HER HEART
AND ON BOTH SIDES ARE HER LUNGS
AND WHAT THE BLUE ARROWS ARE
SHOWING YOU ARE THESE KIND OF
ROUND IRREGULAR KIND OF WHAT WE
WOULD CALL FLUFFY INFILTRATES
THAT REPRESENT COVID-19
PNEUMONIA.
ON THE RIGHT IS HER CT SCAN FROM
DECEMBER 2020.
AND I'M NOT SHOWING YOU THE SAME
CUT IN HER CHEST BUT YOU CAN
PROBABLY APPRECIATE THAT THE
INFILTRATE NOW THAT'S IN THE
CIRCLE LOOKING DIFFERENT THAN
THE 1 FROM 2020.
SO THESE CHANGES HERE ARE
CONSIST WENT SOMETHING CALLED
ORGANIZING PNEUMONIA, AND
ORGANIZING PNEUMONIA IS AN
INTERSTITIAL LUNG DISEASE THAT
ESSENTIALLY REPRESENTS THE LUNG
TRYING TO HEAL ITSELF, SO IT'S
AN IMMUNE DRIVEN PROCESS AND WE
SEE THIS IN DIFFERENT CLINICAL
SCENARIOS, INCLUDING AFTER
SARS-COV-2 INFECTION.
AND THIS TYPE OF--SO ORGANIZING
PNEUMONIA IS TREATED WITH
STEROIDS.
SO THIS WAS BROUGHT UP AS
PERHAPS A CAUSE OF OUR PATIENTS
ONGOING SYMPTOMS.
NOW BEFORE TREATING HER WITH
STEROIDS, WE DID WANT TO MAKE
SURE THAT SHE ESPECIALLY AS AN
IMMUNE O COMPROMISE TD HOST DID
NOT HAVE ANY OTHER INFECTIONS WE
HAD TO WORRY ABOUT BEFORE GIVING
HER STEROIDS.
NOW THE PATIENT DECLINED ANOTHER
BRANCHIAL ALVEOLAR LAVAGE BUT WE
WERE ABLE TO GET INDUCED SPUTUM
AND THAT WAS NEGATIVE FOR
BACTERIAL OR FUNGAL PATHOGENS.
NEXT SLIDE, PLEASE.
SO THE DECISION WAS MADE TO
TREAT WITH PREDNISONE, BECAUSE
WE THOUGHT WE WOULD IMPROVE HER
SYMPTOMS AND GET BETTER AND SO
ON DECEMBER DAY 242 PREDNISONE
WAS STARTED AND THAT WAS WITH A
MILD IMPROVEMENT IN SYMPTOMS,
VERY MILD IMPROVEMENT IN HER CT
SCAN.
NEXT SLIDE, PLEASE.
BUT ON DAY 284, WE WERE TIPPED
OFF THAT SOMETHING WAS NOT RIGHT
BECAUSE WE OBTAINED ANOTHER
NASO-PHARYNGIAL SWAB AND THAT 1
HAD A VIRAL LOAD THAT WAS MUCH
HIGHER THAN THE 1S SHE HAD
PREVIOUSLY AND THAT TIPPED US
OFF THAT SOMETHING WAS NOT RIGHT
ESPECIALLY IN THE SETTING OF
HAVING STARTED THE STEROIDS.
SO THEN WE STARTED ASKING
OURSELVES THE QUESTION:--AND SHE
REQUIRED A LOT MORE OXYGEN SO WE
BROUGHT HER INTO THE HOSPITAL.
WE TREATED HER WITH CONVALESCENT
PLASMA, THIS TIME WE DID GIVE
HER REMDESIVIR FOR 10 DAYS, AND
WE STARTED WEANING HER STEROIDS.
AND HER SYMPTOMS GOT BETTER, SO
HER COUGH GOT BETTER HER
SHORTNESS OF BREATH GOT BETTER
AND ABOUT 3 WEEKS LATER, ON DAY
334 SHE CLEARED THE VIRUS.
AND AND IN ADDITION, YOU KNOW WE
SAW THAT HER INFLAMMATORY
MARKERS HAD GOTTEN BETTER AND
THAT HER CT SCAN WAS IMPROVING.
SO THANKFULLY A HAPPY ENDING
HERE.
NEXT SLIDE PLEASE.
BUT AGAIN, THIS CASE REALLY
BROUGHT UP A LOT OF QUESTIONS IN
OUR MINDS ABOUT, YOU KNOW WHAT
HAD GONE ON THIS ENTIRE TIME IS
QUITE A LEARNING CASE AND YOU
KNOW THE MAIN QUESTION THAT WE
REALLY HAD WAS HAD WE
RECRUDESCED, THIS UNDER LYING
YEAR LONG SARS-COV-2 INFECTION
OR MAYBE THAL PATIENT BEEN
EXPOSED TO COVID-19, AND COULD
SHE BEEN EXPOSED ABOUT, SHE LIVE
INDEED A MULTIGENERATIONAL
HOUSE, AND WOE SOPHISTICATEDY WE
APPROACHED HER AND WE TOOK VIRAL
ISOLATES FROM THE BEGINNING OF
THE INFECTION AND THE END OF HER
INFECTION AND THEY WERE
SEQUENCED AND WITH THAT I WILL
PASS THE MIC TO ELODIE.
>> THANK YOU, VERONIQUE.
SO THAT WAS THE MAIN QUESTION
SHE HAD WHEN THIS CASE HAPPENED.
WAS IT THE SAME VIRUS OR WAS IT
A REINFECTION?
AND SO WHAT YOU SEE HERE IS A
PHILOGENETIC TREE, A CIRCULAR N
TREE AND WE SEQUENCED THE WHOLE
GENOME FROM THESE SAMPLES FROM
EARLY MAY AND THEN FROM
MARCH 2021 AND WHAT WE SAW WAS
THAT ACTUALLY ALL THE SAMPLES
CLUSTERED TOGETHER IN THE TREE
SHOWING THAT THEY'RE ALL RELATED
IN SOME WAY.
WHAT YOU SEE HERE, THIS VERY
LONG BRANCH INDICATES THAT THE
VIRUS HAS EVOLVED OVER THAT
PERIOD OF TIME, BUT IT'S STILL
ALL--THEY ALL BELONG TOGETHER.
THIS LINEAGE WAS BASICALLY AN
OLD LINEAGE WE SAW CIRCULATING
IN 2020 BUT THAT WAS NO LONGER
CIRCULATING IN 2021.
SO THAT FURTHER JUSTIFIED AGAIN
THAT THIS WAS ONCE INFECTION
THAT WAS JUST A LONG, LONG
INFECTION.
THE BUT WHAT WAS MORE
INTERESTING WHEN YOU LOOK AT THE
VIRUS AND THE VIRUS GENOME
INFORMATION IS REALLY WHERE THE
VIRUS EVOLVES AND HOW IT
EVOLVES.
SO THIS IS A REPRESENTATION
ESCHEMA OF THE DIFFERENT GENES
OF THE WHOLE GENOME OF
SARS-COV-2.
THE SPIKE IS RIGHT HERE.
AND BELOW IS JUST A BLOCK WITH
LITTLE COLORED BOXES THAT
INDICATE POSITIONS ALONG THE
GENOME WHERE YOU DO SEE A
MUTATION OCCURRING OVER TIME.
SO EACH ROW REPRESENTS A
DIFFERENT SAMPLE.
AND EACH OF THESE SAMPLES ARE
COMPARED TO THE FIRST 1 TAKEN IN
MAY FIRST 2020.
THAT WAS THE BALL SAMPLE THAT
VERONIQUE MENTIONED.
YOU CAN CAN SEE ACCUMULATIONS
OCCURRING OVER TIME.
NOW IF THIS WAS JUST A VIRUS
CIRCULATING IN THE POPULATION,
YOU WOULD EXPECT TO SEE
MUTATIONS OVER THIS 335 DAYS AND
YOU WOULD EXPECT AN EVOLUTIONARY
RATE OF ABOUT, YOU KNOW 1
MUTATION OCCURRING EVERY 2 WEEKS
WHICH IS A LITTLE WHAT WE WERE
SEEING IN THIS PATIENT BUT THESE
MUTATIONS WERE ACCUMULATING
WITHIN THE HOST BUT WE DID SEE A
LITTLE BIT MORE THAN WE WOULD
HAVE EXPECTED SIMPLY WITH THE
EVOLUTIONARY RATE.
WHAT'S MORE INTERESTING IS WHEN
YOU FOCUS SPECIFICALLY ON THE
TYPES OF MUTATIONS YOU IDENTIFY
AND SO FOR EXAMPLE, IF YOU LOOK
AT THE SPIKE IN ANOTHER REGION
OF THE GENOME, WE SAW 2
DELETIONS.
NOW 1 OF THESE DELETIONS IS WELL
REPORTED AND I'LL GO INTO THAT
IN A MINUTE AND IT'S IN THE
SPIKE PROTEIN BUT ANOTHER 1 THAT
IS QUITE INTERESTING AND THERE
HAVE BEEN OTHER STUDIES PUT IN
IMMUNE O COMPETENT MUTATIONS
WHERE YOU SEE DELETION OF
PORTIONS OF CERTAIN GENES, 67 B
AND ORF8, IN OUR CASE WE SAW
FULL DELETION OF THESE 2 GENES
AND DELETION IS PARTICULARLY
INTERESTING BEFORE AND IMMUNE O
COMPROMISED PATIENTS, THESE
KINDS OF DELETIONS AND I
WILL--DESPITE THIS IN THE REGION
AND DESPITE THE TERMINAL DOMAIN
THAT BINDS TO THE RECEPTOR,--TRY
TO CONTROL THE VIRUS, SO WE
OBSERVE THIS DELETION IN THE
GENOME.
WHAT WAS MORE INTERESTING IS
ACTUALLY THE DYNAMICS OF THIS
MUTATION SO WE ONLY OBSERVE THIS
DELETION WITHIN THE 2 LAST
SAMPLES THIS NUCLEOTIDES GENOME
RECEIVE THE DELETION AND
REPRESENTED HERE BASICALLY A
CLIFF SO WHAT I NOTED HERE IS
ACTUALLY THE READ COVERAGE, AND
IF YOU DON'T KNOW WHAT READ
COVERAGE IS, THIS IS WHAT IT
MEANS SO WHEN YOU SAMPLE
SOMEBODY, THEY DON'T JUST HAVE 1
VIRUS, THEY HAVE A POPULATION OF
VIRUSES AND EACH OF THESE
VIRUSES HAVE A GENOME.
SO WHEN WE BASICALLY BREAK UP
THESE GENOMES, SO THAT WE CAN
DECODE THEM AND SEQUENCE THEM,
WE HAVE THE SEQUENCE READS THAT
WE THEN READ BACK.
SO WHEN YOU HEAR A GENOMICS
PERSON TALKING ABOUT HIGH
COVERAGE OR LOW COVERAGE, THIS
IS WHAT WE MEAN, IT MEANS A
REGION OF THE GENOME THAT IS
VERY WELL REPRESENTED BY A LOT
OF SEQUENCE READS OR A REGION
THAT IS UNDERREPRESENTED BY
SEQUENCE READS, BUT THEN WE
GENERATE WHAT'S CALLED A CONE
CENSUS SEQUENCE, SO GOING OVER
THE WHOLE GENOME, AND EVERY
POSITION, WE TAKE WHAT SEEMS TO
BE THE MOST DOMINANT NUCLEOTIDE
AND YOU GENERATE THIS VIRUS
GENOME, SO WHEN YOU'RE HEAR
ABOUT VIRUS GENOMES THAT ARE
BEING DECODED AND RIGHT NOW IF
PUBLIC DATABASES CLOSE TO
9 MILLION SARS-COV-2 VIRUS
GENOMES, IT'S ALWAYS TALKING
ABOUT A CONSENSUS SEQUENCE BUT
THERE'S INFORMATION IN THESE
UNDERLYING READS.
SO IF WE GO BACK TO OUR REGION
OF THE VIRUS AND HOW IT MUTATED
OVER TIME, WE SEE THAT THAT ORF7
B OR 8 REGION HAS A FEW VIRUSES
STILL IN THE POPULATION OF
VIRUSES THAT HAVE THAT REGION
THAT IS INTACT AND THAT'S WHY
YOU SEE 24 X OR 24 READS THAT
WILL COVER THAT REGION, BUT VERY
QUICKLY WITHIN 1 DAY, THIS
PATIENT LOST ALL THE REGIONS SO
7 B AND ORF8 ARE COMPLETELY
DELETED IN THAT GENOME.
NOW THAT DELETION IS PRETTY
LARGE, CLOSE TO 500 NUCLEOTIDES
AND IT'S IN FACT THE LARGEST
REGION THAT HAS BEEN REPORTED TO
DATE.
NOW WHAT DOES ORF8 OR 7 B DO?
SO ORF8 EXPRESSION IS THOUGHT TO
NOT BE ESSENTIAL FOR
REPLICATIONS AND SAME THING FOR
ORF 7 B BUT THEY ARE THOUGHT TO
BE INVOLVED IN IMMUNE RESPONSE
SO IT COULD BE THAT IN PATIENT,
THERE IS NO USE FOR THIS VIRUS
TO CARRY THESE GENES BECAUSE THE
IMMUNE RESPONSE IS PRETTY LOW.
NOW THERE HAVE BEEN OTHER
STUDIES SHOWING OTHER LARGE
DELETIONS IN THAT REGION SUCH AS
THIS 382 NUCLEOTIDE DELETION AND
THEY FOUND THAT IT DID CORRELATE
WITH MILDER DISEASE IN 1 STUDY
LOWER INCIDENCE OF HYPOXIA.
SO THESE ARE DIFFERENT STUDIES
AND DIFFERENT PARTS OF THE WORLD
WHERE THEY HAVE OBSERVED
DELETIONS IN THAT REGION.
SO IT SEEMS THAT THE ORF 8
REGION IS A PRETTY MALLEABLE
REGION OF THE GENOME, SO THERE'S
A LOT OF DIVERSITY IN THAT
REGION.
SO THIS TAKES ME TO THE
DIVERSITY OF THE POPULATION THAT
EXISTS IN A PATIENT BE IT AN
IMMUNE O COMPETENT PATIENT OR
IMMUNE O COMPROMISED PATIENT SO
IF YOU GO BACK TO MY SCHEMA OF
LOOKING AT THE SEQUENCE READS,
THE OTHER INFORMATION WE CAN
CAPTURE IS YOU SEE AN ORANGE
HERE, WHAT WOULD BE MUTATIONS.
BUT THEY'RE NOT IN THE MAJORITY
OF THE SEQUENCE READS, MEANING
THAT SOME OF THE VIRUSES WITHIN
THE POPULATION, WITHIN THAT
PATIENT OR CARRYING DIFFERENT
MUTATIONS BUT THEY'VE
ACCUMULATED AT ENOUGH HIGH LEVEL
THAT WE CAN CAPTURE THEM AS
PRETTY IMPORTANT MINOR VARIANTS.
SO FROM THIS SEQUENCE DATA, YOU
CAN ACTUALLY PULL OUT THE
CONSENSUS SEQUENCE BUT ALSO SOME
INFORMATION OF MINOR VARIANTS.
SO ON THE LEFT HERE, HOW YOU CAN
SHOW THIS ALSO, SO IN THIS
PATIENT, WE HAVE THE DIFFERENT
COLLECTION DATES, WE HAVE
DIFFERENT GENES AND THESE ARE
IMMUNE O ACID ACID POSITIONS WHERE
THE--SO THERE IS CHATTER IN THE
VIRAL POPULATION THAT CAN LEAD
TO NEW VIRUS GENOMES THAT HAVE
NEW MUTATIONS INSERT REGIONS OF
THE GENOME.
NOW I'M MENTIONING THIS BECAUSE
IF YOU GO BACK TO SOME OF THESE
IMMUNO COMPROMISED PATIENTS AND
SOME OF THESE STUDIES, THERE'S 1
STUDY BY HENSLY WHERE THEY'VE
LOOKED OVER TIME AT DIFFERENT
MINOR VARIANTS AND YOU CAN SEE
HOW THERE ARE DELETIONS THAT CAN
OCCUR, THAT CAN APPEAR IN SOME
OF THESE MINOR VARIANTS AND
POSITIONS ALSO IN THE RECEPTOR
BINDING DOMAIN THAT SEEM TO
OCCUR ALSO OVER TIME AND THAT
YOU CAN CAPTURE IN THE MINOR
VARIANTS.
NOW ANYTHING THAT CIRCULATING IN
THE WORLD THAT BECOMES YOU KNOW
A VIRUS THAT'S CIRCULATING
GLOBALLY, YOU CAN SEE EVOLUTION
HAPPENING BETWEEN HOSTS SO AS WE
TRANSMIT VIRUSES, THEY CAN ADAPT
DIFFERENTLY IN DIFFERENT HOSTS
BUT EVOLUTION ALSO HAPPENS OF
COURSE WITHIN THE HOST AND
THAT'S THE INFORMATION WE'RE
TRYING TO CAPTURE ESPECIALLY IN
THE CONTEXT OF IDENTIFYING
POTENTIALLY EMERGING VARIANTS
AND VARIANTS OF CONCERN.
AND SO, WHEN YOU LOOK AT THIS
POPULATION AND EMERGENCE OF A
NEW VARIANTS.
SO THERE'S THIS 1 STUDY THAT
POST DOC IN MY LAB
[INDISCERNIBLE] IS DOING WHERE
SHE'S TRYING TO LEVERAGE VERY
LARGE DATA SETS OF NEXT
GENERATION SEQUENCING DATA TO BE
ABLE TO ANSWER SOME OF THESE
QUESTIONS ON WHAT IS THE
DIVERSITY WITHIN A HOST.
SO ACTUALLY SASHA IS GIVING A
TALK AT THE LPD SEMINARS AT
1:00 O'CLOCK WHERE SHE WILL GO
IN DETAIL SO I WON'T BE SHOWING
TO
SHOWING--TOO MUCH ABOUT HER
STUDY BUT I WANT TO MAKE A POINT
IN THE CONTEXT OF WHAT WE'RE
TALKING ABOUT WITH EVOLUTION
WITH AN IMMUNO COMPETENT AND
IMMUNO COMPROMISED PATIENTS.
SO THERE HAVE BEEN A FEW STUDIES
LOOKING AT MINOR VALID AND
RELIABLE YABT AND COUNTING MINOR
VARIANTS WITHIN INDIVIDUALS.
AND THIS IS JUST A
REPRESENTATION OF 2 OF THESE
STUDIES.
NOW MINOR VARIANTS HAPPEN, BUT
THEY'RE NOT PRESENT AT A HUGE
NUMBER SO IT'S NOT AS IF YOU
HAVE A LOT OF DIVERSITY
OCCURRING WITHIN THIS VIRUS
POPULATION BECAUSE ALTHOUGH THE
VIRUS MAKES MISTAKES, EVERY TIME
IT REPLICATES, A LOT OF THESE
MISTAKES WILL JUST BE PUDGIERED
AND YOU WILL GET REALLY JUST
VIRUSES THAT ARE COMPETENT AND
THAT CAN REPLICATE.
SO WHAT YOU'RE SEEING IN THE
MINOR VARIANTS ARE VIRUSES THAT
HAVE MUTATIONS OR THESE
DELETIONS OR MISTAKES BUT THAT
ARE ABLE TO REPLICATE.
SO IN GENERAL, IF YOU LOOK AT
THE NUMBER OF SPECIMENS SO THIS
IS A STUDY WHERE THEY HAD YOU
KNOW ABOUT A HUNDRED SPECIMENS
HERE, THEY HAD MANY MORE AND YOU
LOOK AT THE NUMBER OF MINOR
VARIANTS PER SAMPLE, THE NUMBER
SEEMS TO BE AROUND 2-3, SO IN
GENERAL THERE ARE VERY FEW MINOR
VARIANTS IN A POPULATION OF
VIRUSES BUT YOU DO HAVE
EXCEPTIONINGS WHERE THERE ARE
SOME SAMPLES THAT HAVE A LOT OF
MINOR VARIANTS SO WE'RE TRYING
TO UNDERSTAND WHAT LEADS TO
THIS.
ARE THESE PATIENTS DO THEY HAVE
SOMETHING DIFFERENT ABOUT THEIR
IMMUNE SYSTEM, IS THERE
SOMETHING THAT WE CAN CAPTURE IN
THIS DIVERSITY IN THEIR VIRUS
POPULATION.
SO WITH SASHA HAS BEEN DOING IS
SHE'S BEEN GETTING ALL THE RAW
DATA FROM A STUDY THAT IS GOING
ON IN HOUSTON METHODIST AND LED
BY JIM MUSSER WHERE THEY'VE BEEN
SEQUENCING OR SEQUENCING FOR
EVERY SINGLE PATIENT THAT TESTS
POSITIVE FOR SARS-COV-2 AS PART
OF THE HOUSTON METHOD SESSION.
SO WE OBLIGATIONS STAINED ABOUT
40 NOVA SEEK RUNS, IT'S A
SEQUENCING TRIEWMENT THAT
PROVIDES A VERY LARGE MEMBER OF
SAMPLES AND VERY HIGH DEPTH OF
COVERAGE.
AND WE'VE LOOKED AT ABOUT 21,000
WHOLE GENOMES THAT WERE
SEQUENCED BETWEEN DECEMBER 2020
AND JULY 2021 TO LOOK AT MINOR
VARIANTS AND SEE IF WE CAN
CAPTURE SOME OF THIS INFORMATION
NOW I'M CUTTING OUT A LOT OF
STEPS BUT 1 THING THAT SASHA
OBSERVED IS THAT IF YOU LOOK AT
THE NUMBER OF SAMPLES WITH--ARE
THERE MUSEUM TAIPGZ AFFAIRS TEAM
LEADER HOT SPOTS IN THE GENOME
WHERE WE WOULD SEE CERTAIN
VARIANTS EMERGING.
I'VE HIGHLIGHTED THE SPIKED
PROTEIN HERE IN RED TO SHOW YOU
THAT IT'S NOT NECESSARILY IN THE
SPIKE WHERE YOU WOULD HAVE THE
MOST MINOR VARIANTS THAT WOULD
BE OBSERVED.
WE ACTUALLY SEE THEM A LOT IN
THE NUCLEOCAP SID PROTEIN AND
ALSO IN ORF 8.
IN ORF 8 AS YOU HEARD EARLIER,
SEEMS TO BE PRETTY MALLEABLE
REGION OF THE GENOME.
SO YOU SEE DELETIONS, BUT YOU
ALSO SEE A FEW MUTATIONS.
SO, WHAT YOU SEE IN SOME OF
THESE GENES IS THAT YOU HAVE YOU
TEND TO SEE MANY SAMPLES THAT
HAVE MULTIPLE VARIANTS SO FOR
EXAMPLE, YOU SEE HERE THAT YOU
CAN COULD GO CAP SID THAT YOU
CAN HAVE DIFFERENT NUCLEOTIDES
THAT OCCUR IN THAT SAME
POSITION.
SO AGAIN IT'S THIS CHATTER.
THERE ARE SPOTS OR REGIONS IN
THE GENOME WHERE YOU HAVE A LOT
OF DIVERSITY, A LOT OF
FLEXIBILITY AND CHATTER.
AND IF I TAKE THE EXAMPLE HERE
FROM THE SPIKE, THERE'S ACTUALLY
AN IMPORTANT POSITION WHICH IS
THE FEWER AND CLEAVAGE SITE AND
WE SEE THIS IS A SITE THAT HAS A
LOT OF MUTATIONS OFTEN IN THESE
SAMPLES.
SO, LET'S GO BACK TO OUR IDEA OF
VARIANTS OF CONCERN.
SO IF YOU LOOK GLOBALLY AT
SOMETHING LIKE ALFOBBS THAT'S
THE B117 AND THE DELTA WE'RE
MORE FAMILIAR WITH, THE 681
POSITION TENDS TO TWITCH BETWEEN
THIS H AND THE R AND WE SEE
SUBSTITUTIONS IN THIS MINORITY
FRACTION OF THE GENOME.
SO THE REASON I MENTION THIS IS
THAT VARIANTS OF CONCERN DO TEND
TO MERGE WITH A LARGE NUMBER OF
NEW MUTATIONS AND CAN WE CAPTURE
THESE MUTATIONS IN THE SEQUENCE
DATA IN THE MINOR VARIANT DATA?
NOW, HAVING A LOT OF DIVERSITY
WITHIN AN INDIVIDUAL ACCOUNTED
FACILITATE EMERGES ENSEL OF
DIFFERENT VERSIONS OF THE VIRUS,
INCLUDING AND SHE'S ACTUALLY
DETERMINED THAT THERE IS AN
ASSOCIATION BETWEEN HIGH VARIANT
NUMBERS AND DISEASE ASSOCIATION
VARIABILITY.
AND 1 QUESTION WE HAVE IS
WHETHER DIVERSE IS SEEN IN
IMMUNO SUPPRESSED PATIENTS AND
SO THIS IS THE TYPE OF ANALYSIS
THAT IS ONGOING RIGHT NOW, WHERE
WE WOULD NEED TO LOOK AT LARGER
POPULATIONS OF IMMUNO SUPPRESSED
INDIVIDUALS TO ANSWER THAT
QUESTION.
BECAUSE IF WE GO TO OMICRON AND
WE KNOW THAT OMICRON HAS SEEMED
TO ACCUMULATE A LOT OF MUTATIONS
OVER OVER ITS GENOME AND HERE'S
A REPRESENTATION OF A
PHILOGENETIC TREE THAT WAS MADE
BY NEXT STRAIN AND HERE CAN YOU
SEE OMICRON HAS THIS VERY LONG
BRANCH LENGTH AND THAT INDICATES
THAT GENETICALLY IT'S QUITE
DIFFERENT FROM THE REST OF THESE
VARIANTS OF CONCERN AND IN FACT
IF THERE'S THIS NICE PAPER THAT
IS A PERSPECTIVE TYPE PAPER IN
NATURE THAT WAS PUBLISHED I
THINK IN THE LAST WEEK OR
EARLIER THIS WEEK WHERE THEY
SHOW HERE OVER TIME THE NUMBER
OF MUTATIONS IN THE SPIKE
PROTEIN FOR OMICRON, COMPARED TO
OTHER VARIANTS OF CONCERN, CAN
YOU SEE THAT OMIKRON HAS MANY
MORE BUT ALSO IT SEEMS THAT IT'S
CLOSEST KNOWN ANCESTOR PROBABLY
DATES BACK PRETTY FAR BACK.
NOW THIS PARTICULAR PIECE IS
ABOUT WHAT WOULD BE THE SOURCE
OF OMICRON, IS IT FROM AN ANIMAL
RESERVOIR WHERE THIS IVLIEWGZ
WOULD OCCUR OR IN IMMUNO
COMPROMISED PATIENT WHERE IS THE
VIRUS COULD HAVE EVOLVED OVER
TIME AND HADN'T BEEN PICKED UP
BEFORE AND THAT'S SORT OF WHAT
WE'RE TRYING TO ANSWER.
SO LET'S GO BACK TO THAT TABLE
THAT THEY SHOWED EARLIER WHERE
SHE LISTED A LOT OF THESE
STUDIES WITH IMIEWNL O
COMPROMISED PATIENTS AND I HAD
ADDED HERE OUR OWN STUDY AND
THIS IS JUST THE SCHEMA OF THE
WHOLE GENOME, SORRY OF THE SPIKE
PROTEIN ONLY WITH DIFFERENT
DOMAINS IN THE PROTEIN THAT ARE
IMPORTANT.
THIS IS--AND YOU CAN SEE IN OUR
IMMUNO COMPROMISED PATIENTS,
THESE PATIENTS HAVE ACCUMULATED
OVER TIME SO MANY OF THESE
STUDIES SHOW THE EARLIEST TIME
POINT AND THE LATEST TIME POINT
AND WHAT I'M SHOWING HERE IS
REALLY THE LATEST TIME POINT,
THE TYPES OF MUTATIONS THAT HAVE
ACCUMULATED OVER TIME.
AND YOU CAN SEE THAT THERE ARE
CERTAIN SPOTS OF THE GENOME
WHERE THE MUTATIONS TEND TO
ACCUMULATE OVER TIME AND IF YOU
COMPARE WITH THE VARIANCE OF
CONCERN, THEY'RE VERY SIMILAR
POSITIONS SO THERE ARE--SO YOU
HAVE OMICRON HERE THAT OF COURSE
HAS MANY MORE OF THESE MUTATIONS
BUT THEY DO SEEM TO OCCUR WHERE
WE HAVE SEEN THEM HAPPENING IN
OUR IMMUNO COMPROMISED PATIENTS.
NOW THAT DOESN'T MEAN THAT ALL
VARIANTS OF CONCERN COME FROM
IMMUNO COMPROMISED PATIENTS,
INDICATING THAT THERE ARE YOU
KNOW POSITIONS THAT APPEAR TO BE
FROM THE MINOR VARIANT DATA, WE
DO SEE THERE ARE POSITIONS THAT
ARE MUTATIONAL HOT SPOTS, AND
THAT THESE VIRUSES MAY BE
FAVORED IN IMMUNO COMPROMISED
HOSTS.
AND I WILL LET VERONIQUE CLOSE
THIS OFF FROM OUR TAKE AWAYS
FROM THESE DIFFERENT STUDIES.
>> THANK YOU ELODIE.
SO JUST A FEW POINTS BEFORE WE
CLOSE, CLEARLY YOU CAN SEE
MUTATED VARIANTS EMERGING ON
INDIVIDUALS AND WE DON'T REALLY
UNDERSTAND TO WHAT EXTENT AND
ALL OF OUR IMMUNO COMPROMISED
PATIENTS IS, AND THE EMERGENCE
OF SUCH VARIANTS IN THE
COMMUNITY AND BEYOND, IT'S
REALLY IMPERATIVE THAT WE
INVESTIGATE WHAT THEIR ROLE IS
IN ALL OF THIS, AND AGAIN, WELL
WE'VE BEEN PRESENTING CASE
REPORTS HERE TODAY, I THINK THIS
IS ACTUALLY HAPPENING A LOT MORE
THAN WHAT WE'RE SEEING BEING
REPORTED IN THE LITERATURE SO
I'VE HEARD AND BEEN INVOLVED IN
SEVERAL CASES IN THE COMMUNITY
OF PATIENTS AGAIN, WITH VERY
PROLONGED INFECTIONS AND AFTER
OUR CASE WAS PUBLISHED, ELODIE
AND I RECEIVED E-MAILS FROM
INTERNATIONAL PHYSICIANS WHO ARE
TRYING TO MANAGE PATIENTS WITH
REPRUITT DESSENT INFECTIONS AND
PROLONGED INFECTIONS SO AGAIN, I
THINK THIS IS A MUCH GREATER
PROBLEM THAT WE'RE JUST SEEING
WITH THESE CASE REPORTS.
I THINK WE NEED TO BE THOUGHTFUL
ABOUT THE THERAPIES WE USE TO
TREAT OUR PATIENTS.
WE, RIGHT NOW, WE DON'T HAVE
REALLY VERY EFFECTIVE ANTIVIRALS
TO USE TO TREAT OUR PATIENTS AND
SO WE FOCUSED--WE FOCUS A LOT ON
MONOCLONAL ANTIBODIES AND ON
CONVALESCENT PLASMA.
NOW WE DO HAVE 2 NEW ORAL DRUGS
THAT HAVE JUST BEEN APPROVED
UNDER AN EUA RECENTLY BUT NONE
OF THESE THERAPIES HAVE BEEN
EXTENSIVELY INVESTIGATED IN
IMMUNO COMPROMISED PERSONS SO DO
WE KNOW WE'RE GIVING THEM THE
RIGHT DOSE, THE RIGHT TITERS,
ARE WE TREATING THEM LONG
ENOUGH?
ARE WE GOING TO GET THEM BETTER
ABOUT YOU NOT FAST ENOUGH TO
PREVENT NEW VARIANTS FROM
EMERGING?
SO I THINK THERE'S A LOT LEFT TO
BE INVESTIGATED THERE AND LASTLY
I THINK THERE ARE CONTROL
CONSIDERATIONS AND TO PUT THIS
INTO CONTEXT, I THINK WE'RE VERY
LUCKY TO HAVE A FANTASTIC
LABORATORY HERE AND ELODIE AS A
RESOURCE WHEN WE ARE TRYING TO
THINK ABOUT OUR PATIENTS AND
WHAT ON DO ABOUT OUR PATIENTS
BUT MOST LABORATORIES AND
HOSPITALS IN THE UNITED STATES
LET ALONE THE WORLD ARE NOT ABLE
TO SEQUENCE VIRUSES WITHIN A
COUPLE OF DAYS OR USE MOLECULAR
MEANS TO DETERMINE WHETHER OR
NOT THE VIRUS IS PRESENT AND
THIS IS SOMETHING WE DO
FREQUENTLY HERE AT THE CLINICAL
CENTER, MOST LABS DON'T REPORT
CT VALUES SO WE DON'T EVEN HAVE
THAT TO GO ON IN MANY PLACES IN
THE COMMUNITY.
AND SO WITH THE UC RECOMMENDING
THAT FOR IMMUNO COMPROMISE
PATIENTS THAT WE SHOULD BE USING
A TESTING STRATEGY TO DETERMINE
WHETHER OR NOT THEY NEED TO BE
IN ISOLATION OR NOT, THAT CAN
GET VERY COMPLICATED WITH MANY
OF THESE PATIENTS.
NOW OUR PATIENTS AS FAR AS WE
KNOW DID NOT TRANSMIT HER
INFECTION TO ANYBODY IN HER
FAMILY.
I KNOW WE DIDN'T TEST EVERYBODY
BUT WE WERE NOT TOLD OF ANY
INFECTIONS THERE, SO WHETHER OR
NOT THATEE EVEN OF A CONCERN, WE
DON'T KNOW BUT WE ASSUME THAT IT
IS BECAUSE AGAIN WE'RE SEEING
REPLICATING VIRUS FOR A LONG
TIME IN THESE INDIVIDUALS.
SO I THINK I'M LEAVING YOU WITH
MORE QUESTIONS THAN ANSWERS BUT
I HOPE WE'VE PIQUED YOUR
INTEREST IN THIS VERY IMPORTANT
TOPIC TODAY AND THANK YOU SO
MUCH FOR YOUR ATTENTION.
NEXT SLIDE.
--OF THE WAY WITH OUR PATIENTS
WITH THE MOLECULAR TESTING AND
TRYING TO BED --UNDERSTAND WHAT
WAS GOING ON.
DR. TARA P A LMORE WHO WAS
INSTRUMENTAL IN EVERY STEP OF
THE WAY TRYING TO UNDERSTAND
THIS VERY COMPLEX CASE AND I'D
LIKE TO THANK OUR COLLEAGUES AT
NCI, DOCTOR'S BAROCHIA AND THEY
WERE INTIMATELY INVOLVED TO HELP
US UNDERSTAND AND MANAGE OUR
PATIENT'S LUNG PROBLEMS.
>> AND I WOULD LIKE TO THANK OUR
COLLABORATORS AT HOUSTON METHOD
AND --HOUSTON METHODIST AND WE
ARE WORKING WITH THEM CLOSELY
AND SPECIFIC STUDY ON OMICRON
AND ALL THEIR SEQUENCE DATA NOW
IS OMICRON AND SO WE WILL HAVE
MORE TO REPORT SOON AND I WOULD
LOAMACYIC TO THANK MY LAB WHO
HAS BEEN WORKING REALLY HARD ON
SIGNIFYQUENCING ALL THE NIH
SAMPLES OF POSITIVE CASES ON
CAMPUS AND SO, IT'S BEEN GREAT
WORKING WITH THEM ALL.
THANK YOU VERY MUCH.
>> GREAT, THANKS SO MUCH FOR A
REALLY EXCELLENT TALK.
WE HAVE A BUNCH OF QUESTIONS,
BUT FIRST I WANT TO REPEAT THE
CME CODE, WHICH IS 37963.
THAT'S 37963 AND I PRACTICE TOO
AND STEVE ALMOST MESSED ME UP
THERE SAYING IT EARLIER.
ALL RIGHT, SO WE HAVE A BUNCH OF
QUESTIONS THAT ARE RELATED TO
DIFFERENCES IN--SO HOW DO THESE
MUTATIONS CONTRIBUTE TO BOTH
INFECTION IN THE PATIENT BUT
MOSTLY INFECTIOUSNESS VERSUS
SHEDDING, VERSUS
TRANSMISSIBILITY, CAN YOU GO
INTO MORE DETAIL ABOUT WHAT SOME
OF THESE MUTATIONS SPECIFICALLY
IN THE S1 PROTEIN, HOW THOSE ARE
GOING TO AFFECT TRANSMISSIBILITY
AND INFECTIOUSNESS AND THEN TO
FOLLOW UP WITH THAT ALSO, TO
WHAT EXTENT DO YOU THINK THAT
THE PHENOMENON OF THIS VIRUS
SIMMERING AND MUTATING IN AN
IMMUNO COMPROMISED PERSON BEFORE
THEY EMERGE INTO THE HEALTHY
POPULATION, YOU KNOW HOW MUCH DO
YOU THINK THAT ACTUALLY WOULD
CONTRIBUTE TO VIRUS
TRANSMISSION?
>> ALL RIGHT, SO THE FIRST
QUESTION EMILY WAS WHAT ARE
THESE DIFFERENT MUTATIONS DOING
PHENOTYPICALLY, RIGHT?
IS THAT THE QUESTION?
>> YEAH, SO, WE'RE INTERESTED IN
YOU KNOW, OKAY, SO THESE IMMUNO
COMPROMISED PATIENTS THEY HAVE
THE VIRUS LONGER BUT WHAT DOES
THAT MEAN IN TERMS OF BOTH
WITHIN PATIENT, DURATION OF
DISEASE BUT ALSO
TRANSMISSIBILITY AND
INFECTIOUSNESS, BECAUSE IF
THEY'RE PC R POSITIVE THEY COULD
JUST BE SHEDDING VIRUS.
>> RIGHT.
SO THE REASON WE KNOW THEY'RE
NOT JUST SHEDDING SO WE KNOW
THEY'RE SHEDDING VIRUS BUT THAT
THE VIRUS IS ACTUALLY
REPLICATING SIMPLY BECAUSE THE
FACT THAT WE'RE ABLE TO SEQUENCE
THE SAMPLE THE SEQUENCE MEANS
THE VIRAL LOAD IS HIGH ENOUGH TO
SEQUENCE AND PHENOTYPICALLY WHAT
DOES THAT MEAN FOR TRANSMISSION,
YOU KNOW YOU KNOW A VIRUS CAN
HAVE MUTATIONS THAT DO DIFFERENT
THINGS, WE HAVE A MUTATION THAT
LEADS TO EITHER BETTER
TRANSMISSION AND THAT MAY BE
BECAUSE IT TENDS TO EITHER
ACCUMULATE EITHER LOAD SO THAT
TRANSMITTING IS EASIER BECAUSE
YOU HAVE MORE THAN YOU'RE
EXPELLING WHEN YOU SNEEZE FOR
EXAMPLE, BUT THERE ARE ALSO
MUTATIONS THAT EVEN IF YOU'RE
NOT TRANSMITTING BETTER BUT YOU
ACTUALLY CAN ENTER CELLS BETTER,
WHICH I GUESS IS A KIND OF
TRANSMISSION, SO THERE ARE
SPECIFIC MUTATIONS WITH
DIFFERENT PHENOTYPES LIKE THAT,
NOW THERE'S SOME THAT HAVE BEEN
WELL CHARACTERIZED AS WE
UNDERSTAND THIS VIRUS MORE AND
MORE AND THERE ARE TEAMS WORKING
ON INVITRO EXPERIMENTS AND
INVIVO EXPERIMENTS SO IN ANIMAL
MODELS WHERE THEY ARE TESTING
SOME OF THESE MUTATIONS.
SO MANY OF THE MUTATIONS WE'VE
SHOWN FROM THE VARIANTS OF
CONCERNS, SOME OF THEM ARE WELL
CHARACTERIZED LIKE THE 501 FOR
EXAMPLE, AND THERE ARE OTHERS
THAT ARE NOT SO WELL
CHARACTERIZED SO THE QUESTION TO
INFORM THE INVITRO
EXPERIMENTALIST OR INVIVO
EXPERIMENTALIST IS TO GIVE A
LIST OF SOME OF THESE MUTATIONS
THAT APPEAR TO BE RECURRING LIKE
THESE HOT SPOTS WE'VE SEEN AND
THEN TEST THEM TO SEE REALLY
WHAT IT MEANS, BUT TO TELL YOU
TODAY FOR THAT PATIENT WHAT IT
WOULD MEAN FOR THAT PATIENT,
UNLESS WE HAVE THAT EXPERIMENTAL
DATA WE DON'T REALLY KNOW WHAT
IS HAPPENING WITH THAT PATIENT.
I DON'T KNOW IF THAT ANSWERED
THE QUESTION.
>> --WE'VE SEEN REPORTS COMING
OUT RECENTLY ABOUT POTENTIAL
VARIANTS CROPPING UP IN HIV
POSITIVE PATIENTS OR SOMETHING
LIKE THAT, HOW MUCH DOES THIS
CONTRIBUTE?
YEAH SO THAT'S THE QUESTION, IT
WAS THOUGHT THAT ALPHA CAME FROM
AN IMMUNO COMPROMISED PATIENT
WITH THESE PATIENTS THAT
ACCUMULATED AND SOME POINT A
MUTATION THAT MADE THAT VIRUS
MORE TRANSMISSIBLE HAD OCCURRED
AND SO THE QUESTION, 1 OF THE
HYPOTHESIS WITH OMICRON IS
THAT'S WHAT HAPPENED ALSO,
PROBABLY AN UNCONTROLLED HIV,
YOU WOULD HAVE HAD THIS
ACCUMULATION OF MUTATIONS AND
THEN THIS VIRUS TOOK OFF.
NOW WE DON'T KNOW IF THAT IS THE
CASE, IT'S JUST A HYPOTHESIS AT
THIS POINT.
IT'S POSSIBLE, BUT WE--YOU KNOW
WE HAVE TO THINK ALSO, THERE ARE
DIFFERENT TYPES OF IMMUNO
COMPROMISED, THERE ARE PEOPLE
WHO STILL HAVE PARTS OF THEIR
IMMUNE SYSTEM THAT DOES
FUNCTION, IT'S--THERE ARE
DIFFERENT ASSPEBTS, YOU KNOW THE
DIFFERENT CASES THAT LISTED THEY
DON'T ALL HAVE THE SAME SORT OF
IMMUNO COMPROMISE.
AND WHAT YOU CAN IMAGINE IN
SOMEBODY THAT WOULD BE HEAVILY
IMMUNO SUPPRESSED, IS THAT THE
VIRUS DOES REPLICATE, BUT IF YOU
HAVE NO IMMUNE PRESSURE AT ALL,
THIS SIGNIFY HAVE YOU SEEN COULD
JUST ACCUMULATE RANDOM MUTATIONS
THAT ARE--YOU KNOW THAT CAN BE
COMPLETELY NEUTRAL AND THEY
NEVER GET PUDGIERED BECAUSE
THERE'S NO PRESSURE FOR THEM TO
BE PUDGIERED, RIGHT?
BUT IF YOU HAVE PARTIAL
IMMUNITY, YOU CAN SEE SOME
SELECTION PRESSURE THAT HAS
OCCURRED SO CAN YOU ARGUE THAT
IN AN IMMUNO COMPETENT PERSON
YOU COULD ALSO HAVE MUTATIONS
THAT HAPPEN BECAUSE THE VIRUS IS
TRYING TO EVADE A VERY STRONG
IMMUNE RESPONSE OF AN IMMUNO
COMPETENT PERSON BUT THE
SARS-COV-2 IS AN ACUTE INFECTION
SO THAT THE VIRUS DOESN'T HAVE
THAT MUCH TIME TO EVOLVE WITHIN
AN ACUTE INFECTION.
AND SO, THAT'S WHY THERE'S SORT
OF THIS BALANCE BETWEEN LONG
INFECTION, LOW IMMUNE PRESSURE,
SHORT INFECTION, STRONG IMMUNE
PRESSURE AND THERE MAY BE
SOMETHING IN BETWEEN THAT COULD
LEAD TO SOME OF THESE VARIANTS
OF CONCERN.
>> SO HERE'S A FOLLOW UP
QUESTION FROM DR. COLLINS, YOU
ANSWERED SORT OF THE FIRST PART
SO WOULDN'T THE SELECTION IN AN
IMMUNE ON O COMPROMISE PATIENT
BE DIFFERENT THAN IN AN ANIMAL
AND ALSO AS YOU MENTIONED IN AN
IMMUNO COMPROMISED PERSON?
BUT DOESN'T OMICRON FIT 1 OF
THESE BETTER THAN THE OTHER?
>> THAT'S A VERY GOOD QUESTION,
IT'S NOT CLEAR TO ME WHICH 1
FITS BETTER.
THERE'S SOME ARGUING FOR THE
ANIMAL RESERVOIR HYPOTHESIS AND
I DON'T KNOW HOW STRONG THE
EVIDENCE IS FOR THAT AT THIS
POINT, JUST LIKE I'M NOT SURE
THE EVIDENCE IS ALL THERE EITHER
FOR THE IMMUNO COMPROMISED
PATIENT HYPOTHESIS.
SO, I DON'T KNOW, I DON'T KNOW
WHAT THE ANSWER IS.
I THINK THERE HAS BEEN A LITTLE
BIT MORE--INITIALLY IT WAS
THOUGHT, I REMEMBER WHEN OMICOON
CAME OUT, THE ANIMAL RESERVOIR
PEOPLE WERE LIKE, YOU MUST BE
ANIMAL RESERVOIR AND OTHERS WERE
SAYING I HAVE NO IDEA BUT AT
THIS POINT, I THINK IT'S 50/50
MAYBE, YOU KNOW, WHERE IT CAME
FROM.
>> GOTCHA.
ALL RIGHT, LET'S GO OVER TO
QUESTIONS ABOUT THE IMMUNE
SYSTEM.
SO THE FIRST PRESENTATION
FOCUSED ON THE ROLE OF
ANTIBODIES IN INFECTION, COULD
YOU COMMENT ON THE ROLE OF VIRUS
SPECIFIC T-CELLS, IN CLEARING
AND HOW THAT MIGHT AFFECT THIS
PROCESS.
SAME QUESTION FOR ME, SO I'M NOT
AN IMMUNOLOGYST SO I WON'T BE
ABLE TO DETAIL BUT WHAT I THINK
IS CLEAR IS THAT IN IMMUNO
COMPETENT PATIENTS, THAT WHAT
CORRELATES WITH CLINICAL
IMPROVEMENT IS THE FORMATION OF
ANTIBODIES AND I THINK THAT'S
VERY CLEAR.
IT'S ALWAYS BEEN VERY CLEAR FROM
THE BEGINNING AND THAT IT'S ALSO
VERY CLEAR THAT THE PATIENTS WHO
ARE--WHO DON'T HAVE THAT
ANTIBODY PRODUCTION JUST DO NOT
DO WELL AND SO, AGAIN, I THINK
MOST OF THESE PATIENTS WHO HAVE
B-CELL DEPLETION HAVE SOME
T-CELL IMPAIRMENT AS WELL.
SO, BUT AGAIN THE SPECIFIC ROLE
OF THE T-CELLS UNFORTUNATELY I
CAN'T--I CAN'T TOUCH ON BUT
CLEARLY--SO I THINK, YOU KNOW
T-CELLS ARE CLEARLY IMPORTANT AS
WELL, BUT OF COURSE I CAN'T SAY
MORE ABOUT THAT.
>> OKAY, THE NIH PATIENT WITH
PROLONGED SARS-COV-2 INFECTION
WAS NEGATIVE IN THEIR MP SWABS
BUT POSITIVE IN THE BALL, CAN
YOU SPEAK OUT, DO YOU KNOW HOW
OFTEN THAT OCCURS AND DOES THIS
LEAD TO US MISSING OTHER
INFECTED PEOPLE?
SORE IS IT LIMITED TO THE
SEVERELY IMMUNO COMPROMISED?
AND ALSO IS THIS IMPACTED AT ALL
BY VARIANTS?
>> SO YEAH, I CAN ANSWER THE
FIRST PART.
I DON'T KNOW HOW FREQUENTLY IT
HAPPENS BUT IT HAPPENS NOT
INFETAL COMPARTMENT -
-INFREQUENTLY AND IT
HAPPENS IN IMMUNO COMPROMISED
PATIENTS AS WELL.
AND WHEN THIS HAPPENED WE
STARTED TO TALKING TO COLLEAGUES
AT OTHER INSTITUTIONS WHO SAID
OH YEAH, WE SEE THIS, WE HAVE
PATIENT WHO IS COME IN AND YOU
KNOW WE SWAB THEM, THEY'RE
NEGATIVE AND THEN YOU ACTUALLY
LOOK FOR DEEPER SAMPLES AND
THEY'RE POSITIVE AND I THINK
WHAT'S HAPPENING THERE IS JUST
THAT YOU KNOW PEOPLE WILL HAVE
MORE VIRUS IN DIFFERENT PARTS OF
THEIR AIRWAY AND THAT'S WHY WE
DO GO LOOKING FOR DEEPER AIR WAY
SAMPLES WHEN WE SUSPECT SARKINGS
KICKOFF 2 INFECTION BUT WE HAVE
NEGATIVE TESTING AND WE DO THAT
ON A REGULAR BASIS.
AND THERE ARE SOME PATIENTS WE
DON'T TRUST, DO NOT HAVE
SARS-COV-2 INFECTION UNTIL WE
GET THOSE SAMPLES AND THOSE MAKE
US FEEL BETTER WHEN THEY'RE
NEGATIVE.
SO I THINK IT'S PECULIAR THAT
AFTER THE BALL THAT SHE THEN HAD
POSITIVE ORAL AND
NASO-PHARYNGIAL SWABS.
I CAN'T EXPLAIN THAT, I'M NOT
SURE WHAT HAPPENED THERE OTHER
THAN PERHAPS WE WERE JUST
GETTING DEEPER INTO HER
INFECTION AND IT'S SUDDENLY
BECAME POSITIVE, I'M REALLY NOT
SURE.
I THINK WHAT WAS INTERESTING IN
THIS PATIENT IS THAT IF WE
LOOKING BACK ON IT, IF WE HAD
HAD BALL SAMPLES, WHEN SHE WAS
HAVING THESE MILD SYMPTOMS WHICH
WE HAD BROUGHT UP BUT AGAIN IT'S
AN INVASIVE PROCEDURE AND
DECLINED IT, MAYBE WE WOULD HAVE
BEEN TIPPED OFF EARLIER THAT HER
VIRAL LOAD MAY HAVE BEEN HIGHER,
YOU KNOW DEEP DOWN IN HER LUNGS
AND MAYBE WE WOULD HAVE THOUGHT
DIFFERENTLY ABOUT THIS CASE.
I THINK--I KNOW I WOULD HAVE
THOUGHT DIFFERENTLY ABOUT THE
CASE.
SO, TO ANSWER THE QUESTION, WE
DO SEE THIS, I RECENTLY WAS AT
ANOTHER HOSPITAL LAST WEEKEND
AND I HAD THE SAME SITUATION A
PATIENT WHO JUST KEPT TESTING
NEGATIVE AND THANKFULLY, KEPT ON
ISOLATION BECAUSE THEY ENDED UP
BEING POSITIVE ON A BALL.
ARE WE MISSING PEOPLE?
I HOPE NOT BECAUSE I THINK
EVERYBODY IS SO CAREFUL NOW AND
ESPECIALLY IN THE HOSPITAL
SETTING, PEOPLE ARE KEPT ON
ISOLATION WHEN THERE'S SUSPICION
EVEN WITH NEGATIVE TESTING.
>> SO RELATED WHAT HAPPENS TO
THIS PARTICULAR PATIENT'S
ORGANIZING PNEUMONIA ONCE THE
VIRUS WAS CLEARED?
BUT THEN ALSO WHAT WAS THE--WHY
DOES THE CDC GUIDANCE FOR
OUTPATIENT IMMUNO COMPROMISED
PATIENTS SUGGEST ISOLATION FOR A
MINIMUM OF 10-20 DAYS?
DO YOU THINK THIS IS TOO SHORT?
>> YEAH, SO FOR THE FIRST
QUESTION FOR THE ORGANIZING
PNEUMONIA, I THINK WHAT HAPPENED
IN OUR PATIENT IS THAT YOU KNOW
SHE--I THINK MAYBE SHE HAD A
COMPONENT OF ORGANIZING
PNEUMONIA WHICH IS JUST AN
IMMUNE DRIVEN PROCESS OF TRYING
TO HEAL THE LUNG BUT CAUSING
DAMAGE AT THE SAME TIME BUT I
THINK--I THINK HER SYMPTOMS WERE
ACTUALLY FROM SARS-COV-2.
BECAUSE I THINK WHEN WE CLEARED
THAT VIRUS OR INFLAMMATORY
MARKERS THAT HAD NEVER BEEN
NORMAL, NORMALIZED.
AND SHE NO LONGER NEEDED OXYGEN
AND I THINK THAT THE ENTIRE TIME
WE WERE SEEING THIS WAS COVID
THE ENTIRE TIME.
WE DID WEAN HER STEROIDS SO WHEN
YOU PUT SOMEONE ON STEROIDS YOU
CAN'T JUST STOP THEM IMMEDIATELY
AND SHE SHE WAS ON SOME STEROIDS
FOR A COUPLE OF WEEKS WHILE
WE'RE WEANING THEM DOWN AND SO
SHE DID GET SOME TREATMENT FOR
ORGANIZING PNEUMONIA BUT I THINK
AT THE END OF THE DAY, THIS WAS
REALLY MOSTLY DRICH BY THE
VIRUS.
--DRICH --DRIVEN BY THE VIRUS.
THE SECOND WAS ABOUT ISOLATION,
I THINK THE REASON IT'S LONGER
FOR PATIENTS THAT ARE IMMUNO
COMPROMISE -ED IS BECAUSE WE
KNOW PATIENTS HAVE LONGER
INFECTIONS AND THEY TEND TO HAVE
REPLICATING VIRUS FOR LONGER AND
THAT'S WHERE THAT 20 DAYS COMES
FROM.
DO I THINK IT'S TOO SHORT?
WELL THE CDC DOES SAY IN IMMUNO
COMPROMISED PATIENTS IT SHOULD
BE AT LEAST 20 DAYS BUT TALK TO
AN INFECT YOWZ DISEASE
SPECIALIST BUT THEN WE ARE LEFT
WITH TRYING TO FIGURE THIS OUT
AND THAT'S YOU KNOW THAT'S WHERE
IT GETS COMPLICATED WHERE IN A
HOSPITAL YOU CAN ASK FOR SOME OF
THESE SPECIALIZED--ELODIE, AND
DR. DASS IN NLM AND ASKING THEM
ABOUT CT VALUES AND WHAT THEIR
THOUGHTS ARE ON WHAT'S GOING ON,
SO, DO I THINK IT'S TOO SHORT?
FOR SOME IT IS AND FOR SOME IT'S
NOT?
THERE'S REALLY NO CLEAR ANSWER
THERE.
I THINK FOR SOME IT'S CLEARLY
TOO SHORT.
BUT IT DEPENDS.
>> GREAT, SO IT'S 1:00 O'CLOCK.
IT'S THERE ARE MORE QUESTIONS SO
IF YOU DON'T MIND I'M GOING TO
ASK A FEW MORE IF THAT'S OKAY.
EXCELLENT.
OKAY.
>> SO THERE WAS A REQUESTY ABOUT
ANY CONCERN THAT THE USE OF MUTE
O GENICS AS [INDISCERNIBLE]
ELEVATE CONCERNS?
WHAT DATA DO WE NEED TO INSURE
THAT THIS ISN'T HAPPENING IN
HEALTHY OR IMMUNO COMPROMISED
PATIENTS?
>> YEAH, I THINK THE DATA WILL
BE LOOKING AT THE VIRUSES AND
JUST LOOKING AT WHETHER THERE
ARE MUTATIONS FOR ANY ANTIVIRAL,
YOU'RE ALWAYS LOOKING AT
ANTIVIRAL RESISTANCE.
I DON'T KNOW IF THAT DEPENDS
WHAT WAS TARGETED OR THE
PARTICULAR 1 IS THE ACTUAL
POLYMER ACE THAT IS TARGETED SO
I THINK WE'LL JUST BE LOOKING.
>> GREAT.
CAN YOU SPEAK A LITTLE ABOUT WHY
THERE MIGHT BE MORE SELECTION
FOR ANDROGENIC CHANGE OR SOMEONE
WHO'S NOT RECEIVING THERAPEUTIC
ANTIBODIES.
>> SO I DON'T KNOW WHY THERE
WOULD BE NECESSARILY MORE, IT
SEEMS THERE ARE ANDROGENIC
CHANGES THAT OCCUR AND YOU KNOW
I DON'T KNOW.
I DON'T KNOW WHY WE WOULD EVEN
SEE SOME OF THESE LIKE OMICRON,
THESE ANTIGENIC SITES IF IT IS
AN IMMUNO COMPROMISED PERSON,
WHY YOU WOULD SEE SOME OF THESE
MUTATED SITES SO I DON'T KNOW
THE ANSWER.
>> OKAY, I THINK WE WRAP UP WITH
THE LAST 1 HERE, DO WE KNOW HOW
TD TYPES AND LOCATIONS OF
MUTATIONS FOR THE DIFFERENT
VARIANTS IMPACT THE SEVERITY OR
LOCALIZATION OF THE DISEASE FOR
IMMUNO COMPETENT INDIVIDUALS
AS--AGAIN WE SAW TAKEN--THEY
DELTA WAS NOR SEVERE THAT
OMICRON SEEMS TO BE.
>> DO YOU MEAN THE LOCATIONS AS
IN THE TISSUE TROPISM, OR IF
THERE ARE PARTS THAT THE
RESPIRATORY TRACK.
SO THERE ARE FOR EXAMPLE, IF YOU
LOOK AT OMICRON, THERE ARE
SPECIFIC POSITIONS THAT ARE
ASSOCIATED SO FOR EXAMPLE, THE
WAY THE VIRUS ENTERS THE CELLS,
THE RECEPTORS IT USES.
IT USES A SLIGHTLY DIFFERENT
ENTRY PATHWAY AND SO IT'S
THOUGHT THAT THE CELLS THAT WE
HAVE IN OUR LOWER LUNGS OR THE
LOWER RESPIRATORY TRACT DON'T
HAVE NECESSARILY THE RIGHT
PATHWAYS FOR THE VIRUS TO ENTER
SO THAT THE VIRUS TENDS TO
INFECT MOSTLY CELLS FROM THE
UPPER RESPIRATORY TRACT.
SO THERE ARE SPECIFIC MUTATIONS
LIKE THAT BUT WILL DETERMINE
DISEASE SEVERITY BECAUSE OF THE
TROAPISM OR THE LOCATION THAT'S
AFFECTED BY THE VIRUSES, SO
THERE ARE MUTATIONS THAT HAVE
BEEN ASSOCIATED WITH THAT
SPECIFICALLY, YES.
>> GREAT.
ALL RIGHT, WELL THANK YOU BOTH
VERY MUCH, THIS IS AN EXCELLENT
TALK AND CHECK BACK LATER TO SEE
WHAT THE NEXT COVID TALK WILL
BE, WE HAVE A FEW MORE LINED UP
AND WE WILL SEE YOU ALL NEXT
TIME.
>> THANK YOU.