I'M DAN ROTROSEN, DIRECTOR
DIVISION OF ALLERGY IMMUNOLOGY
TRANSPLANTATION AT NIAID.
PLEASURE TO WELCOME Y'ALL TOLL
THE OPEN SESSION OF OUR ADVISORY
COUNCIL COMMITTEE.
WE HAVE AN UNUSUAL SET OF TALKS
THIS AFTERNOON.
WE ARE GOING TO BE FOCUSING ON
INDUCTION AND MAINTENANCE
DURABILITY OF IMMUNE RESPONSES
TO COVID INFECTION ITSELF SAND
SARS COV-2 VACCINES WITH A GROUP
OF SPEAKERS WHO ARE JUST
PIONEERS AND LEADERS IN THIS
FIELD SO WE ARE VERY HAPPY TO
HAVE THE TIMELY OPPORTUNITY TO
COVER THIS.
ALISON DECKHUT AUGUSTINE WILL
GIVE A BRIEF OVERVIEW OF THE
PROGRAMS UNDER WHICH SOME OF
THESE INVESTIGATORS HAVE BEEN
WORKING.
AND ALISON, IF YOU CAN GET YOUR
SLIDES UP AND SHARE THOSE, THAT
COULD BE GREAT.
WHILE YOU ARE DOING THAT I WILL
MENTION AT THE END OF THE PANEL
DISCUSSION WE HAVE ONE CONCEPT
CLEARANCE FOR PRESENTATION AND
DISCUSSION BY COUNCIL MEMBERS WE
DON'T WANT TO SHORTCHANGE THAT
BUT WE DO HOPE THERE WILL BE
THOUGHTS BACK AND FORTH ON THE
MAJOR TOPIC OF THE AFTERNOON.
KNOWING WE ARE VERY TIGHT ON
TIME WE HAVE UNUSUALLY LARGE
NUMBER OF SPEAKERS TODAY, I'M
GOING TO LIMIT MY DIRECTOR
OVERVIEW COMMENTS TO WHAT I
COVERED.
ALISON, PLEASE GO AHEAD.
>> THANK YOU, CAN EVERYONE SEE
MY SLIDES?
>> YES.
>> GREAT.
SO MY NAME IS ALISON DECKHUT
AUGUSTINE, I'M THE CHIEF OF THE
BASIC IMMUNOLOGY BRANCH AND I
WOULD LIKE TO THANK EVERYONE FOR
JOINING THIS OPEN SESSION AND
ESPECIALLY TO OUR SPEAKERS AND
MODERATORS FOR AGREEING TO DO
THIS WORKSHOP WITH US.
SO AS DR. PACHY MENTIONED TODAY
THE COVID-19 INCIDENCE GLOBALLY
HAS REACHED OVER 358 MILLION
PEOPLE WITH 72 MILLION OF THOSE
PEOPLE INFECTED IN THE US. IT
HAS ALSO LED TO OVER 5.6 MYTH
DEATHS GLOBALLY AND ALMOST A
MILLION IN THE US. FORTUNATELY
ALSO AS DR. FAUCI MENTIONED
VACCINE DEVELOPMENT FOR SARS
COV-2 HAS BEEN UNPRECEDENT AND
WE DO HAVE A NUMBER OF VACCINES
THAT ARE BEING USED AROUND THE
GLOBE.
IN THE U.S. WE HAVE HAD OVER 210
MILLION PEOPLE WHO WERE FULLY
VACCINATED AND YOU CAN SEE THE
BREAK DOWN OF THE AGE GROUPS
HERE, WON'T GO INTO THAT.
AND THEN WE ALSO HAVE 84-POINT
-- 8 MILLION PEOPLE WHO RECEIVED
A BOOSTER DOSE.
AND THEN MY NEXT SLIDE YOU WILL
SEE WHY THAT IS IMPORTANT.
IF WE LOOK AT COVID CASES AND
DEATH BY VACCINATION STATUS YOU
CAN SEE ON THE TOP PANEL ON THE
RIGHT THAT VACCINE WAS
PROTECTING PEOPLE VERY WELL EVEN
FROM INFECTION BUT WE HAVE HAD
INCREASES IN BREAK THROUGH
INFECTIONS DUE TO OMICRON AND
PROBABLY CHANGES IN IMMUNITY
THAT HOPEFULLY YOU WILL HEAR
ABOUT TODAY BUT STILL BETTER
THAN THE UNVACCINATED.
VACCINE AND BOOSTERS ARE FOR
SURE PROTECTING PEOPLE STILL
AGAINST HOSPITALIZATION AND
DEATH.
SO THAT'S STILL GOOD NEWS FOR
THIS.
HOWEVER THERE IS STILL A LOT OF
QUESTIONS THAT REMAIN REGARDING
THE BREADTH AND DURABILITY OF
IMMUNE PROTECTION THAT IS
INDUCED BY VACCINATION AND
NATURAL INFECTION.
NIAID AND DAIT IN PARTICULAR
HAVE BEEN ABLE TO SUPPORT OOH A
NUMBER OF OUR INVESTIGATORS TO
UNDERSTAND HOW THE IMMUNE
RESPONSE IS TRIGGERED BY NATURAL
INFECTION AND/OR VACCINATION AND
HOW THAT AFFECTS FUNCTION AND
DURABILITY OF THE ADAPTIVE
IMMUNE RESPONSE SO IN ORDER TO
GIVE EVERYONE A BRIEF OVERVIEW
OF WHAT IS GOING ON IN THESE
FIELDS, WE HAVE GATHERED SOME OF
THE LEADERS IN THE FIELD WHO
WILL GIVE US THEIR RECENT
UPDATES ON THEIR RESEARCH AS
WELL AS GIVE A LITTLE BROADER
OVERVIEW WHAT IS GOING ON IN THE
FIELD.
AND THOSE WILL BE OUR PANEL
SPEAKERS.
WE HAVE EIGHT PANEL SPEAKERS
THAT WILL TALK FOR 20 MINUTES OR
SO AND I THIS MAYBE A LITTLE BIT
OF TIME FOR QUESTION AFTER THAT.
DEPENDING HOW WE ARE DOING ON
TIME.
THEN WE'LL HAVE A PANEL
DISCUSSION THAT WILL FOCUS ON
NEW APPROACH TOOLS AND
TECHNOLOGIES THAT HAVE OR THAT
ARE NEEDED TO EXPAND OUR
KNOWLEDGE TO REALLY UNDERSTAND
THE ADAPTIVE RESPONSE TO THIS
INFECTION.
OUR MODERATORS FOR THIS PANEL
DISCUSSION AND FOR THE WORKSHOP
IN GENERAL ARE DR.S DONNA FARBER
AND RAFI AHMED.
AND WITH THAT, ACTUALLY THAT'S
ALL I WAS GOING TO SAY.
AND I WOULD LIKE TO TURN IT OVER
TO RAFI IN THE INTEREST OF TIME
AND I DON'T KNOW IF DONNA HAS
BEEN ABLE TO JOIN YET.
>> I'M HERE.
>> PERFECT.
(OVERLAPPING SPEAKERS)
>> ALISON ONE CLARIFICATION.
IF THE INDIVIDUAL TIME SLOTS 15
OR 20 MINUTES?
>> 15.
WHATEVER I TOLD YOU GUYS BEFORE.
I APOLOGIZE.
YOU DIDN'T GET FIVE MINUTE
BEAKS.
>> JUST REMINDER TO ALL THE
SPEAKERS TOTAL TIME IS 15
MINUTES.
IF YOU USE UP THE 15 MINUTES
THEN THERE'S NO QUESTIONS AFTER
YOUR TALK.
BUT AGAIN NO ONE SHOULD EXCEED
15.
DONNA, YOU WANT TO INTRODUCE THE
FIRST FOUR SPEAKERS AND I DO THE
NEXT FOUR OR DO YOU WANT TO DO
THE WHOLE THING?
(OVERLAPPING SPEAKERS)
>> I CAN'T TURN MY VIDEO ON.
WON'T LET ME TURN MY VIDEO ON.
BUT I AM HERE.
GO AHEAD PLEASE.
>> GREAT.
SO IT IS A PLEASURE TO INTRODUCE
AS THE FIRST SPEAKER SHANE
CROTTI FROM THE LA HOLLA
INSTITUTE TALKING DURABILITY OF
ANTIBODY AND T-CELL RESPONSES TO
SARS COV-2 VACCINATION.
>> GREAT. THANKS.
IS THE SLIDE UP?
>> WE CAN SEE IT
>> THIS SHOULD BE A FANTASTIC
SESSION.
SO I'LL AT LJI.
OBVIOUSLY THE COVID-19 PANDEMIC
HAS CHANGED ALL OUR LIVES IN
MANY WAYS AND I THINK THIS HITS
HOME PRETTY QUICKLY.
SO WE PARTICULARLY IN
COLLABORATION WITH ALEX AT OJI
EARLY IN THE PANDEMIC TRYING TO
UNDERSTAND IMMUNE RESPONSES TO
THIS INFECTION AND WE HAD THE
FIRST STUDY LOOKING AT VIRUS
SPECIFIC CD4 T-CELLS, CD8
T-CELLS AND ANTIBODY RESPONSES
IN PEOPLE WITH ACUTE INFECTIONS.
AND THE REASON WE DID THAT IS
BECAUSE YOUR ADAPTIVE IMMUNE
SYSTEM REALLY PREDOMINANTLY
CONSISTS OF THREE MAYOR BRANCHES
YOUR ANTIBODY RESPONSES COME
FROM B CELLS AND TWO KINDS OF
T-CELLS, CD4 T-CELLS AN CD8
T-CELLS THAT HAVE DIFFERENT
JOBS.
I'M GOING TO COVER A LITTLE BIT
OF CONTEXT TO HOPEFULLY
FACILITATE THE OTHER FANTASTIC
EXPERTS IN THIS SESSION GOING
INTO DEPTH ON MORE OF THESE.
AND YOUR IMMUNE SYSTEM HAS THESE
THREE MAJOR BRANCHES FOR A
REASON.
EACH OF THESE HAVE DIFFERENT
WEAPONS THAT ARE GOOD IN
DIFFERENT SCENARIOS GOOD AGAINST
DIFFERENT DISEASES AND I
GENERALLY SAY IT IS LIKE THE
MILITARY.
YOU HAVE MULTIPLE BRANCHES OF
THE MILITARY THEY EACH HAVE
DIFFERENT KINDS OF WEAPONS THAT
TEND TO BE BETTER IN ASSORTMENT
OF SOME ENVIRONMENTS THANS
OTHERS AND COLLABORATE WELL IN
CERTAIN DISEASES TO TRYING TO
UNDERSTAND HOW MUCH THAT HAPPENS
IN THE CONTEXT OF SARS COV-2.
OTHER SPEAKERS TODAY ARE GOING
TO TALK MORE SPECIFICALLY ABOUT
INFECTION IN COVID-19 DISEASE
AND I WILL TALK IMMUNE RESPONSES
AND MEMORY IN THE CONTEXT OF
VACCINES.
A PRIMARY PAPER FROM US ON THIS
CAME OUT A FEW MONTHS AGO
RELATED TO RNA VACCINES AND HERE
IS A SUMMARY HERE.
THE RNA VACCINES HAVE DONE
INCREDIBLY WELL PROVIDING AT
LEAST SHORT TERM PROTECTIVE
IMMUNITY TO PEOPLE AND THEY
CLEARLY ELICIT REALLY STRONG
EARLY NEUTRALIZING ANTIBODY
RESPONSES AND ONE OF THE BIG
OPEN QUESTIONS WAS HOW GOOD ARE
THESE VACCINES AT GENERATING
MEMORY.
NOT ONLY PROTECTION FOR A FEW
MONTHS BUT MEMORY FOR ONE, TWO,
FIVE, TEN YEARS WOULD DEPEND ON
GENERATION OF IMMUNE MEMORY.
SO WHAT WE DID WAS TO MEASURE
PARTICULARLY T-CELL MEMORY WHICH
HADN'T BEEN PREVIOUSLY MEASURED
IN TO AN RNA VACCINE BEFORE AND
SEE HOW WELL THESE RNA VACCINES
DO THIS.
WE DID THIS PARTICULARLY IN THE
CONTEXT OF A LOW DOSE MODERNA
VACCINE ESSENTIALLY SIMILAR TO
DOSE OF PFIZER VACCINE AND WHAT
WE OBSERVED IN PEOPLE WHO
RECEIVED TWO DOSES OF THOSE
VACCINES WAS THAT SIX MONTHS
AFTER THE SECOND DOSE, TWO DOSE
REGIMENT OF THE VACCINE, THERE
WAS A TENFOLD DROP IN ANTIBODY,
THIS IS REPORTED BY OTHERS OUT
AT SIX MONTHS BUT THE T-CELLS
HAD ABOUT THE VIRUS SPECIFIC
T-CELLS HAD A TWOFOLD DECREASE
CD4 AND CD8 T-CELLS HAD TWOFOLD
DECREASE FROM PEAK LEVELS, OUT
TO SIX MONTHS AND AFTER THE
SECOND IMMUNIZATION.
WE THINK THAT IS QUITE GOOD AND
IMPRESSIVE FOR THESE VACCINES
BECAUSE WE WOULD EXPECT THAT
THIS WOULD BE THE PERIOD OF THE
LARGEST DECLINE AND IT YOUR MORE
LIKELY TO BE MORE STABLE LATER
ON SO IT WOULDN'T BE SURPRISING
IF PEOPLE HAD CD4 AND CD8
T-CELLS MULTIPLE YEARS POST
VACCINATION BASED ON THE DATA.
WE COMPARED TO IMMUNITY
GENERATED BY PREVIOUS INFECTION
AND THEN ACTUALLY THE CD4 AND
CD8 T-CELL MEMORY TO SPIKE WAS
ACTUALLY ESSENTIALLY EQUIVALENT
BETWEEN PREVIOUS INFECTION AND
VACCINATION AT SIX MONTHS LATER
WHICH AGAIN WE CONSIDER PRETTY
IMPRESSIVE FOR TWO DOSES OF LOW
DOSE RNA VACCINE.
AND LASTLY, AGE IS CERTAINLY A
BIG FACTOR FOR COVID-19, THE
BIGGEST RISK FACTOR FOR
HOSPITALIZATION AND DEATH SO HOW
ARE THESE VACCINES WORKING IN
OLDER INDIVIDUALS?
THIS CLINICAL TRIAL HAD PEOPLE
RUN PEOPLE WHO ARE 55 AND OLDER
OR 70 AND OLDER AND IN VARY VERY
ENCOURAGINGLY THE T-CELL MEMORY
GENERATED IN THE OLDER GROUPS
WAS EQUIVALENT TO THAT OF
YOUNGER ADULTS.
I WON'T TALK ABOUT THIS TODAY
BUT A KEY REASON WE RAN THIS
STUDY WAS TO LOOK FOR BIOLOGICAL
IMPACT OF CROSS REACTIVE MEMORY
T-CELLS AND WE DID SEE THAT.
IN A SEPARATE STUDY LED BY JOHN
WEARY AND COLLEAGUES I'M
SUMMARIZING DATA NOT ONLY FROM
OUR LAB BUT OTHER LAB TEAMS,
THEY SHOWED MEMORY B CELLS WERE
ALSO GENERATED QUITE WELL BY TWO
DOSES O VACCINE AND
PRE-COMPARABLE TO THAT OF
INFECTED INDIVIDUALS WHICH WE
AND RAFI AND OTHERS HAVE SHOWN
PREVIOUSLY.
SO YOU HAVE GOT MEMORY CD4
T-CELLS, MEMORY CD8 T-CELLS AND
MEMORY B CELLS GENERATE AND
ACUTE ANTIBODY RESPONSES BEING
GENERATED WAIT WELL BY TWO DOSE
RNA VACCINATION.
SO THEN WHY AREN'T THE VACCINES
PROTECTING PERFECTEDLY AGAINST
VARIANTS?
OVER TIME?
AND SO I'M GOING TO INTRODUCE
THOSE CONCEPTS HERE.
AND SOME OF THE NEWEST DATA ON
THIS, AS IT RELATES TO VACCINE
IMMUNITY AND LONGEVITY.
I LOVE THIS ARTICLE IN
SCIENTIFIC AMERICAN THAT REALLY
HIGHLIGHTS YOUR IMMUNE SYSTEM IS
EVOLVED MULTIPLE POWERFUL
MECHANISMS TO FIGHT VIRAL
VARIANTS.
I SHOW THE ARTICLE BECAUSE IT
SHOW IT IS VIRUS EXPLODING AND
THAT IS ALWAYS A GOOD SIGN.
AND THE WAY YOUR IMMUNE SYSTEM
DOES THIS IS THAT IT HAS
MULTIPLE DIFFERENT BRANCHES AND
THEY DO SO IN DIFFERENT WAYS.
AND I THINK MAYBE SOME OTHER
SPEAKERS WILL TALK ABOUT THE
DIVERSITY OF MEMORY B CELLS, I
WILL COME BACK IN A BIT BUT ALSO
T-CELLS FIGHT VARIANTS.
SO IN WORK LED BY ALEX SETTI,
FIRST QUESTION WAS REALLY HOW
DIVERSE ARE T-CELL RESPONSES TO
THIS VIRUS?
BECAUSE IF YOU JUST HAVE ONE OR
TWO PIECES OF THE VIRUS,
EPITOPES OF THE VIRUS BEING
RECOGNIZE, THEN THERE'S A
CONCERN IF THE VIRUS RECOGNIZES
ONE OF THOSE EPITOPES MAYBE 50%
T-CELL RESPONSE AND YOU WOULD BE
MANY BIG TROUBLE BUT INSTEAD
WHAT THE SETTI LAB FOUND WAS
THAT YOUR AVERAGE PERSON IS
RECOGNIZING 30 TO 40 EPITOPES.
SO IF THE VIRUS MYTASE A COUPLE
OF THOSE EPITOPES IT IS NOT A
BIG DEAL BECAUSE YOU HAVE MANY
ESSENTIALLY LAYERS OR DIVERSITY
OF T-CELL RESPONSES TO
PROTECTION YOU IN THE CONTEXT
THIS WAS INITIALLY IN THE
CONTEXT OF INFECTION SO NOW WE
HAVE GONE AND DONE THAT IN THE
CONTEXT OF VACCINATION AND IN
THE CONTEXT OF OMICRON.
THE TWO SLIDES SUMMARY OF THAT
WORK WHICH IS YOU CAN P LEARNED
LAST WEEK IN CELL WAS THAT
T-CELL RECOGNITION OF OMICRON
WAS PREDICTED TO BE PRESERVED
AND HERE ARE THE PREDICTIONS
HERE, AND IT IS EVEN BETTER THAN
THESE NUMBERS BECAUSE MOST OF
THOSE ARE EVEN STILL PRESERVED
WHICH I WON'T GO INTO BECAUSE OF
TIME BUT IN THE ACTUAL DATA THE
EXPERIMENTAL MEASUREMENTS IN
VACCINATED PEOPLE, PEOPLE WHO
RECEIVED EITHER THE PFIZER
VACCINE OR THE MODERNA VACCINE,
THEIR T-CELL RECOGNITION OF WIDE
RANGE OF VARIANTS INCLUDING
OMICRON HERE T THE END WAS
ESSENTIALLY STABLE BOTH FOR THE
CD4 T-CELLS AND THE CD8 T-CELLS
LOOKING AT SPIKE.
SO THAT'S POSITIVE NEWS IF
T-CELL CON VARIATION OF
RECOGNITION -- CONSERVATION OF
RECOGNITION OF VARIANTS.
ANTIBODIES HAD MORE TROUBLE AND
I WILL COVER MEMORY B CELLS
BRIEFLY.
SO WHY ARE THERE CHALLENGES WITH
PROTECTION?
TO CONCEPTUALIZE THIS, THIS IS
ONE WORKING MODEL OF THIS THAT
TO PROTECT YOU AGAINST
DETECTABLE INFECTION
NEUTRALIZING ANTIBODIES ARE THE
MAJOR FACT TORR THERE AND
T-CELLS ARE MINOR FACTOR, TO
PROTECT YOU AGAINST SERIOUS
DISEASE NEUTRALIZING ANTIBODIES
CONTRIBUTE BUT OTHER PARTS OF
IMMUNE SYSTEM LIKELY CONTRIBUTE
TO YOUR NEUTRALIZING ANTIBODY
RECOGNITION OF OMICRON IS VERY
POOR AFTER TWO VACCINATIONS.
BUT THESE OTHER COMPONENTS OF
IMMUNITY ARE QUITE CONSERVED.
THIS REALLY IS PROBABLY TRUE FOR
MANY ASPECTS OF IMMUNITY, THIS
IS A LAYERED DEFENSE TYPE MODEL
WHICH IS TRUE FOR MANY THINGS,
NOT JUST IMMUNE THE I, SOMETIMES
CALLED THE SWISS CHEESE MODEL,
IF YOU HAVE MULTIPLE LAYERS THAT
IMPROVE YOUR SUCCESS IN
NEUTRALIZING ANTIBODIES ARE YOUR
FIRST LAYER OF DEFENSE.
IF THE VIRUS GETS THROUGH THAT
FIRST LAYER OF DEFENSE IT IS NO
SURPRISE HELPFUL TO HAVE
MULTIPLE ADDITIONAL LAYERS OF
DEFENSE AND WE IN MANY LABS HAVE
BEEN TRYING TO UNDERSTAND THOSE
DIFFERENT LAYERS.
THIS IS CONSISTENT WITH THE
EPIDEMIOLOGICAL DATA IN THE
UNITED STATES, THIS IS ONE OF
THE MOST PROMINENT OF THESE IN
THE U.S., THAT OBSERVED PRIOR TO
OMICRONNEN WANING OF PROTECTION
AGAINST DETECTABLE INFECTION,
POSITIVE CASES, BUT OVER THE
COURSE OF SIX MONTHS BUT AFTER
THE PFIZER VACCINE BUT NOT
WANING OF PROTECTION AGAINST
HOSPITALIZATIONS OR DEATH.
WHICH WOULD BE CONSISTENT WITH
ESSENTIALLY THIS MULTIPLE LAYERS
OF DEFENSE, THE FIRST LAYER
PARTIALLY FAILING BUT ADDITIONAL
LAYERS HOLDING UP.
AND THIS CAN BE SEEN IN DATA
FROM THE NIH VACCINE RESEARCH
CENTER IN EMORY, AFTER TWO DOSES
VACCINE, THERE IS ACTUALLY A
LACK OF DURABILITY, YOU HAVE TWO
THINGS ONGOING.
THERE IS HOW LONG DOES THE
IMMUNE MEMORY LAST AND HOW WELL
DOES THE IMMUNE MEMORY RECOGNIZE
PARTICULAR VARIANT.
SO DATA EVEN OUT TO EIGHT MONTHS
OR LONGER HAVE BEEN SEEN IN THAT
THE ANTIBODY TITER ESSENTIALLY
CONTINUOUSLY DECLINE FOR AT
LEAST EIGHT MONTHS AFTER TWO
DOSES RNA VACCINE.
SO THESE VACCINES ARE DOING A
GOOD JOB GENERATING T-CELLS
MEMORY AND B CELL MEMORY BUT NOT
GREAT JOB AFTER TWO DOSES
GENERATING DURABLE ANTIBODIES SO
WHY IS THAT THE CASE?
SO HERE IS A SIMPLE MODEL
SHOWING THIS, ACTUALLY THIS IS A
-- FROM 20 YEARS AGO, I DREW
THIS WITH RAFI.
AFTER VACCINATION YOU TRY TO
GENERATE MEMORY B CELLS AND
DURABLE ANTIBODY RESPONSE
THROUGH PLASMA CELLS BUT OTHER
TYPES OF ANTIBODY SECRETING
CELLS NOT JUST LONG LASTING ONES
AN AFTER TWO DOSE VACCINATION
YOU GENERATE GREAT NEUTRALIZING
ANTIBODIES BUT MOSTLY SHORT
LIVED SO A BIG QUESTION ABOUT
DURABILITY HAS BEEN IF YOU GO
FROM THE TWO DOSE REGIMEN TO A
THREE DOSE REGIMEN, DOES
DURABILITY STAY THE SAME, STAY
SHORT LASTING, AND OR DO YOU
START GENERATING MORE LONG LIVED
PLASMA CELLS, POSSIBLY FROM
MEMORY B CELLS.
SO THE FIRST DATA ON THIS WAS
REALLY MADE PUBLIC LAST WEEK
BOTH FOR PFIZER VACCINE AND
MODERNA VACCINE SO TO BRIEFLY
SUMMARIZE WHAT IS IMPORTANT DATA
HERE, IS THAT NOT MUCH
DURABILITY AFTER TWO DOSE
VACCINE BUT AFTER THREE DOSES
WHAT IS OBSERVED IS ADDED FOUR
MONTHS LESS THAN TWOFOLD DECLINE
MANY THE NEUTRALIZING ANTIBODY
TITERS AGAINST THE ANCESTRAL
STRAIN, BETTER DURABILITY THAN
OBSERVED AFTER TWO DOSES AND
ALSO AGAINST OMICRON A SIMILAR
DECLINE OUT OF FOUR MONTHS.
SO THESE DATA I THINK HAVE TO BE
CONSIDERED VERY ENCOURAGING NEWS
ABOUT DURABILITY BUT AT THE SAME
TIME THE NIH GROUPS PUBLISHED
DATA LAST WEEK SHOWING THAT OUT
AT SIX MONTHS AFTER THIRD DOSE
COMPARED TO ONE MONTH THERE IS
ONLY A TWOFOLD DECLINE IN
NEUTRALIZING ANTIBODIES AGAINST
ANCESTRAL SO VERY GOOD SIGN
ANTIBODY DURABILITY IS MUCH
GREATER AFTER THREE DOSES THAN
TWO, BUT FOR OMICRON IT WAS A
LITTLE MORE PERPLEXING WHERE
THERE WAS A BIGGER DROP AND
MAYBE WE CAN DISCUSS THAT LATER
SO SOME POSITIVE NEWS BUT NOT
PERFECT SO IN SUMMARY, LAYER
IMMUNOLOGICAL DEFENSES ARE
VALUABLE AND THESE VACCINES ARE
GENERATING MULTIPLE LAYERS OF
IMMUNOLOGICAL DEFENSE.
MANY OF THOSE LAYERS ARE GOOD
AFTER TWO DOSES, BUT REALLY
THESE RNA VACCINES LOOK LIKE
THEIR THREE DOSE REGIMENS
GENERATE DURABLE ANTIBODIES IN
GENERAL AS WELL AS NEUTRALIZING
ANTIBODIES THAT RECOGNIZE
OMICRON AT ALL AND THAT'S COMING
FROM MEMORY B CELLS THAT MATURE
AND OTHER SPEAKERS CAN COMMENT
ON THAT AS WELL AS NOW AFTER THE
THIRD DOSE GENERATING MORE OF
THESE DURABLE ANTIBODY RESPONSES
BUT PERHAPS NOT PERFECTLY.
IN THE INTEREST OF TIME, I'M
GOING TO SHOW THIS
ACKNOWLEDGMENT SLIDE, I WORK AT
LJI, CERTAINLY PART OF HUGE TEAM
EFFORT, AND I WANT TO CALL OUT
(INDISCERNIBLE) WHO DID AMAZING
JOB LEADING THE OMICRON STUDY
WITH LOTS OF PEOPLE WORKING
THROUGH THE HOLIDAYS TO GET THE
DATA PUBLIC.
I WILL STOP THERE.
RAFI AND DONNA.
>> THANK YOU VERY MUCH.
REALLY INTERESTING DATA.
I DON'T KNOW IF YOU CAN SEE.
SO WE'LL TAKE A FEW QUESTIONS
FOR EACH TALK THEN HAVE
DISCUSSION AT THE END.
YOU HAVE THE DIFFERENT RESPONSES
AND DIFFERENT KINETICS TO
OMICRON VERSUS THE OTHER
VARIANTS?
CAN YOU EXPLAIN WHY THAT MIGHT
BE, LIKE DIFFERENT KINETICS FOR
THAT?
>> NO.
I DIDN'T ANTICIPATE THAT, SO
IT'S GOING TO BE IMPORTANT TO
SEE DATA FROM MORE GROUPS REALLY
I HAVE BEEN SAYING FOR QUITE A
WHILE THAT THE FACT THAT AFTER
TWO DOSES OF VACCINE THE
ANTIBODY TITERS DROP PRETTY
QUICKLY, THAT'S NOT TOO
SURPRISING, LOTS OF VACCINES ARE
THREE DOSE REGIMENS.
AND TO GENERATE THOSE DURABLE
ANTIBODY RESPONSES IT CAN JUST
TAKE AN ADDITIONAL DOSE TO
CONVINCE YOUR IMMUNE SYSTEM THAT
IT IS WORTH THE RESOURCES TO GET
THAT LONGEVITY.
AND THAT DOES LOOK LIKE THAT'S
TURNING OUT TO BE TRUE, AT LEAST
FOR THE QUOTE UNQUOTE BASIC
NEUTRALIZING ANTIBODY, PFIZER AN
MODERNA REPORTS THAT.
BUT WHY OMICRON WOULD BE
DIFFERENT MANY THE MODERNA DATA
IS ACTUALLY HARD FOR ME TO
EXPLAIN.
>> SHANE, HOW MUCH OF THAT
(INAUDIBLE)
>> CAN YOU GUYS HEAR ME?
>> HOW MIGHT WHAT?
>> SORRY.
SHANE CAN YOU HEAR ME?
>> I'M SORRY.
>> GOOD.
HOW MUCH OF THAT DIFFERENCE IN
DURABILITY YOU THINK IS DISTANCE
BETWEEN THE FIRST TWO SHOTS
VERSUS TWO VERSUS THREE?
I THINK THE VACCINE WORLD WE
HAVE KNOWN FOR A WHILE THE
CLOSER YOU U PUT THE PRIME OF
THE BOOST THE MORE YOU SEEM TO
AUGMENT SORT OF SHORT TERM
EFFECTOR PLASMA BLAST KIND OF
RESPONSES VERSUS LONG LIVED
PLASMA CELL SO IS THERE ANY --
NOT AWARE OF ANY DATA INTENTION
AILINGLY SPREAD OUT THOSE FIRST
TWO mRNA DOSES LONGER AND THEN
ASK THE DURABILITY QUESTION.
>> THOSE DATA ARE AVAILABLE TO
AN EXTENT FROM THE UK AND CANADA
THAT SPREAD OUT DOSES TO EITHER
8, 12 OR 16 WEEKS.
AND I HAVEN'T SEEN ANY PUBLISHED
DATA THAT HAVE INDICATED THAT
DURABILITY IS BETTER THERE.
IT WOULD BE -- I HAVEN'T SEEN
DATA PUBLISHED -- I DON'T
REMEMBER IF I SAW DATA OUT TO
SIX MONTHS BUT AT LEAST SHORTER
THAN THAT DIDN'T SEE A BIG
SHIFT.
BUT IT IS A GOOD QUESTION.
>> SO THE THIRD MAYBE MORE
DETERMINANT THAN NECESSARILY THE
DISTANCE BETWEEN SHOTS IN YOUR
TAKE.
>> YEAH.
AND I THINK THAT'S BEEN THE
HISTORY OF SOME OTHER VACCINES.
IT'S AFTER TWO DOSES IT IS A --
OF SAY HEPATITIS B, EVEN IF
EIGHT WEEKS APART THERE'S NOT
MUCH ANTIBODY MAINTENANCE UNTIL
YOU GET THAT THIRD DOSE.
BUT IT WOULD BE GREAT TO HAVE
MORE DATA ON IT.
>> THIS IS -- (OVERLAPPING
SPEAKERS)
>> ALISON YOU HAVE YOUR HAND UP.
>> NO, SHE CAN GO.
>> OKAY.
>> I DON'T KNOW IF THIS WILL BE
COVERED BUT THANK YOU FOR THE
PRESENTATION, SHANE.
MY QUESTION HAS TO DO WITH EXTRA
FOLLICULAR ANTIBODY RESPONSES
REPORTED FROM THE MA GROUP AND
ELSEWHERE TOO, HOW DOES THAT
FACTOR IN AND THEN HAVING
CONCERNS ABOUT THAT BEING
PROTECTIVE VERSUS NOT, WOULD YOU
COMMENT ON THAT?
>> SURE.
JUST BRIEFLY BECAUSE I MEAN
THESE ARE GREAT QUESTIONS, IT
WOULD BE GOOD TO KEEP ALL THEM
IN MIND AS WE GO THROUGH THAT.
SO HERE I SPECIFICALLY FOCUS ON
VACCINE RESPONSES.
AND SO ACTUALLY YOU CAN SEE MANY
THIS MODEL HERE YOU GET EXTRA
FOLLICULAR RESPONSES TO AT LEAST
SOME VACCINES AS WELL AS
INFECTIONS AND THESE SHORT LIVED
RESPONSES CAN BE EITHER PRIOR TO
OR AFTER AND YOU DEFINITELY ARE
GETTING THESE TWO THE RNA
VACCINES. THIS IS ACTUALLY A
VIRUS THAT AT LEAST ANCESTRAL
STRAIN IS STRAIGHT FORWARD TO
MAKE SOME NEUTRALIZING
ANTIBODIES.
YOU CAN HAVE A FEW UNMUTATED B
CELLS THAT MAKE NEUTRALIZING
ANTIBODIES SO EXTRA FOLLICULAR
RESPONSE CAN BEOR CAN BE
POSITIVE FOR GENERATING RAPID
ANTIBODY RESPONSES BUT DO
RECOGNIZE AND GERMINAL CENTER
RESPONSE THE FURTHER MUTATE
THOSE FOR HIGHER AFFINITY CELLS
AND FOR THIS ANTIGEN HAVING BOTH
PATHWAYS IS QUITE PRODUCTIVE AND
IN THE CASE OF VACCINES IT IS
REALLY NOT THOUGHT THAT THE
EXTRA FOLLICULAR PATHWAY
DETRACTS AT ALL FROM THE
GERMINAL CENTER IN LONG LIVED,
THE BEST DATA FROM ROB BRINK AND
COLLEAGUES IS THAT BOTH PATHWAYS
OCCUR IN PARALLEL AND DON'T
DETRACT FROM THERE.
>> WE SHOULD MOVE ON.
>> YES.
>> OKAY.
ALL RIGHT.
SO THANK YOU VERY MUCH, SHANE.
SO THE NEXT SPEAKER WILL BE
MARION PEPPER FROM UNIVERSITY OF
WASHINGTON AND SHE WILL BE
PRESENTING DIFFERENCES IN IMMUNE
MEMORY RESPONSES IN VACCINATED
PREVIOUSLY AFFECTED OR NAIVE
INDIVIDUALS.
SHARE YOUR SCREEN MARION.
>> THANKS FOR HAVING ME, THIS IS
REALLY EXCITING TO BE ABLE TALK
ABOUT ALL THESE CONCEPTS WITH
EVERYONE.
SO I'M GOING TO BE TALKING ABOUT
HOW WE HAVE LOOKED AT THE IMMUNE
RESPONSE THAT HAS FORMED IN
PEOPLE WHO ARE EITHER INFECTED
AND THEN VACCINATED OR JUST
VACCINATED ALONE.
AND HOPEFULLY THIS CAN ACTUALLY
GET TO ANSWER SOME OF ROSS'S
QUESTIONS THAT WE CAN TALK ABOUT
IN A LITTLE BIT.
SO WHAT I'M GOING TO BE TALKING
ABOUT HERE IS BASICALLY ARE
THERE CHARACTERISTICS FROM A
PRIMARY IMMUNE RESPONSE IN WHICH
IMMUNE NAIVE INDIVIDUALS RETAIN
THESE ATTRIBUTES IN THEIR MEMORY
CELL POPULATIONS THAT THEN
IMPACT THE REST OF THEIR IMMUNE
RESPONSE TO VACCINATION.
SOLD WE KNOW A LOT ABOUT IMMUNE
MEMORY AND WHY IT PREVENTS
DISEASE, YOU HAVE LONG LIVED
QUIESCENT ENHANCED THAT CHANGES
INCLUDING MEMORY B CELLS AN CD4,
CD8 B CELLS AN LONG LIVED PLASMA
CELLS RETAINED IN BONE MARROW
THAT PRODUCE ANTIBODIES THEY
INHERIT CHARACTERISTICS DURING
THE DIFFERENTIATION PROCESS MANY
THE PRIMARY IMMUNE RESPONSE THAT
BULLIES THEM TO BE ABLE TO
RESPOND FUNCTIONALLY IN
DIFFERENT WAYS THAN IN THIS
NAIVE STATE.
THAT HAS THE ABILITY TO CONTROL
INFECTION FASTER THAN NAIVE
RESPONSE.
WE ALSO KNOW THESE CELLS ARE
LOCALIZED TO DIFFERENT REGIONS
OF THE BODY BUT LARGELY FOR
HUMAN STUDIES EXCEPT DONNA'S
LOVELY IS THE DIS WE HAVE BEEN
LIMITED TO LOOKING AT BLOOD SO
MOST OF WHAT I WILL TALK ABOUT
TODAY IS PERIPHERAL BLOOD
RESPONSES.
SO WHEN THE PANDEMIC EMERGED WE
INITIATED STUDIES LOOKING IN
INDIVIDUALS WHO HAD MILD
INFECTION TO SEE WHAT TYPES OF
IMMUNE RESPONSES THEY HAD AND
LOUNGE THEY LASTED.
WHAT WE WERE REALLY INTERESTED
IN IS AT THREE MONTHS AFTER MILD
INFECTION, DID INDIVIDUALS WHO
HAD NO HOSPITALIZATION, MILD
SYMPTOMS ACTUALLY DISPLAY
CHARACTERISTICS OF IMMUNE MEMORY
THAT WE WOULD THINK WOULD BE
PROTECTIVE AND ASSOCIATED WITH
IMMUNE VIRAL RESPONSE.
WE WERE HAPPY TO SEE THIS,
PUBLISHED LAST JANUARY.
SO NOW WHAT WE HAVE DONE IS WE
HAVE GONE ON TO KEEP TRACKING
THIS RESPONSE.
WHEN THERE IS A PANDEMIC
UNFOLDING AROUND YOU, THERE ARE
ALL SORTS OF INTERESTING IMMUNE
CONDITIONS TO FOLLOW.
AND TO STUDY.
ONE OF THE THINGS THAT HAS
EMERGED THROUGH THIS PANDEMIC IS
THAT THERE ARE DIFFERENCES IN
HOW INDIVIDUALS PREVIOUSLY
INFECTS AND VACCINATED VERSUS
VACCINATED ALONE HOW THEY
RESPOND TO INFECTION.
THAT HAS BEEN BOTH OF THE
IMMUNOLOGICAL LEVEL, THIS IS
WORK FROM CATHY PATE SHOWING
DIFFERENCES IN THE POOLS OF
MEMORY CELLS THAT CAN EMERGE
BOTH HERE MEMORY CELLS AND THE
SHORT LIVED PLASMA BLASTS THAT
EMERGE FROM THOSE MEMORY CELLS.
AFTER ONE DOSE OF mRNA VACCINE
OR TWO DOSES OF mRNA VACCINE
AND HOW THOSE CELLS PERSIST OVER
TIME, YOU CAN SEE MORE MEMORY
CELLS ARE RETAINED.
AS WELL AS EPIDEMIOLOGICAL DATA
WHICH HAVE SHOWN DIFFERENCES IN
PROTECTION THOUGH THE VACCINES
HAVE DONE AN AMAZING JOB
PROTECTING PEOPLE FROM SERIOUS
DISEASE, THE INDIVIDUALS WHO
HAVE BEEN PREVIOUSLY INFECTED
WERE ABLE TO HAVE LIGHTLY BETTER
IMMUNE PROTECTION AGAINST
INFECTION AS WELL.
SO WE WERE REALLY INTERESTED IN
TRACKING THIS IN THE SAME COHORT
THAT WE INITIALLY STARTED
TRACKING IN MARCH 2020.
AND TRYING TO UNDERSTAND WHAT
HYBRID IMMUNITY MIGHT MEAN AND
WHAT ARE THE DIFFERENCES AND
GETTING AT THAT QUESTION THAT
ROSS ASKED AS TO WHETHER THIS IS
JUST A DIFFERENCE IN THE NUMBER
OF ANTIGEN DOSES WHICH OBVIOUSLY
NAIVE INDIVIDUALS HAVE TWO DOSES
OF VACCINE AND THEN PEOPLE ARE
LOOKING AT THE EMERGING IMMUNE
RESPONSE AT THAT POINT, WHILE
PEOPLE WHO ARE PREVIOUSLY
INFECTED HAVE THIS ADDITIONAL
DOSE OF ANTIGEN FOLLOWED BY THE
TWO VACCINES.
WHAT MADE THIS A REALLY EVEN
MORE INTERESTING STUDY WAS
DURING THE TIME PERIODS WE WERE
STUDYING THESE IMMUNE RESPONSES,
NOT ONLY DID THE VACCINES EMERGE
BUT ALSO THE ABILITY TO GET
BOOSTED ALSO BECAME PART OF THE
NORMAL REGIMEN FOR MOST PEOPLE
ESPECIALLY PEOPLE OVER 65 BUT
MOST PEOPLE.
SO WE CAN ACTUALLY START TO
TRACK HOW DID THESE IMMUNE
RESPONSES COMPARE THIS THESE
SARS COV-2 NAIVE INDIVIDUAL
WHOSE ARE NEVER INFECTED BUT
VACCINATED ONE, TWO, THREE TIMES
VERSUS PREVIOUSLY INFECTED
PEOPLE.
WE CAN COMPARE THEIR SECOND DOSE
WHICH WAS EQUIVALENT TO A THIRD
DOSE IN THE SARS COV-2 NAIVE
INDIVIDUALS TO GET AT WHETHER
THIS WAS JUST AN ANTIGEN DOSE
EXPERIENCE TYPE OF RESPONSE OR
WHETHER THERE WAS SOMETHING
INHERENTLY DIFFERENT ABOUT
INFECTION THAT IMPRINTED
CHARACTERISTICS OF THIS IMMUNE
RESPONSE.
SO MUCH LIKE MANY OTHERS WE LOOK
AT THE THREE BASIC TENANTS OF
IMMUNE MEMORY.
WE LOOKED AT LONG LIVED PLASMA
CELLS AND ANTIBODIES THAT WERE
BEING SECRETED BY THOSE CELLS,
AS WELL AS ANTIBODIES THAT WERE
EMERGING FROM SHORT LIVED PLASMA
BLASTS FROM MEMORY B CELLS.
HERE WE ARE LOOKING AT BLUE IS
THE INDIVIDUALS WHO HAD NEVER
BEEN INFECT WITH SARS COV-2, WE
DOUBLE CHECKED THIS BY ELISA,
YOU CAN FOLLOW ANTIBODY
RESPONSES TO THE RBD PORTION OF
THE SPIKE PROTEIN AND WHAT YOU
SEE IS THIS NICE BOOST, THAT
DOES WEIGH IN AS DESCRIBED THIS
IS SIX MONTHS POST VACCINE TWO
BUT THIS IS A NICE BOOST AGAIN
AFTER THIRD DOSE VACCINE.
AND IF WE COMPARE THIS TO PEOPLE
WHO WERE PREVIOUSLY INFECTED
THEY TOO HAD A WANING IMMUNE
RESPONSE.
THIS TIME THIS PRE-VACCINE TIME
POINT IS ABOUT A YEAR AFTER
THEIR FIRST VACCINE BUT THAT
ALSO IS BOOSTED TO HIGH LEVELS
IN THESE INDIVIDUALS.
WHEN YOU COMPARE THESE HEAD TO
HEAD WHAT YOU CAN SEE IS THE
VACCINES DO AN EXCELLENT JOB OF
BOOSTING -- GETTING THE ANTIBODY
RESPONSES UP TO ABOUT THE SAME
LEVELS OF INDIVIDUALS WHO HAD
HAD PREVIOUS INFECTION WHICH YOU
CAN SEE HERE.
BUT WHAT WAS INTERESTING TO US
IS THAT THESE VACCINE INDUCED
RESPONSES ONLY WANED MORE
QUICKLY THAN INDIVIDUALS WHO HAD
BEEN PREVIOUSLY INFECTED.
THE BOOST HOWEVER SOMEWHAT
AMELIORATED THIS TO THE POINT
THIS DIFFERENCE IS NOT
SIGNIFICANT.
THIS IS DUE TO COMBINATION OF
FACTORS, FIRST THERE IS NOT MUCH
BOOST BETWEEN THE SECOND VACCINE
SIX MONTHS TIME POINT AND THE
THIRD BOOST IN INDIVIDUALS WHO
HAVE BEEN PREVIOUSLY INFECTED
WHILE THERE IS ONE FOR THOSE WHO
WERE NAIVE AND THEIR IMMUNITY
WANED HUMAN MORE IMMUNITY WANED
SIGNIFICANTLY.
WE CAN ALSO JUST CONCLUDE HERE,
VACCINATION VIROD TO GET OPTIMAL
ANTIBODY LEVELS FOR PREVIOUSLY
INFECTED INDIVIDUALS SO IT
REALLY HELPS FOR PREVIOUSLY
INFECTED INDIVIDUALS TO GET
VACCINATED BUT THEIR TITERS ARE
BETTER MAINTAINED THAN IN NAIVE
INDIVIDUALS AND THAT BOOST WAS
NECESSARY TO GET OPTIMAL
ANTIBODY LEVELS IN NAIVE
INDIVIDUALS SUCH A THAT THEY
WERE EQUIVALENTS TO THOSE WHO
HAD BEEN PREVIOUSLY INFECTED.
WE ALSO CHOSE TO LOOK AT MEMORY
B CELLS TO SEE IF WE COULD FIND
MEMORY B CELLS OF THE SPIKE
PROTEIN AND TRACK HOW THEY
CHANGE IN QUANTITY AND QUALITY
OVER TIME.
THIS IS SHOWING HOW WE LOOK AT
THESE CELLS, WE CAN LOOK AT THE
CELLS OF INTEREST VERSUS DECOY
REAGENT THAT WAS DEVELOPED IN
MARK JENKINS LAB AND IF WE LOOK
AT THE NUMERICAL REPRESENTATION
OF THESE ANTIGEN SPECIFIC B
CELLS OVER TIME WE CAN ALSO SEE
SIMILAR TRENDS TO WHAT WE SAW
BEFORE WHEREAS THOSE INDIVIDUALS
PREVIOUSLY INFECTED HAVE HIGHER
NUMBERS OF MEMORY B CELLS THAT
RESPOND TO RBD, THAT WAS BOOSTED
BY THE VACCINE AGAIN STAYED
HIGHER NUMBER, MAINTAINED BETTER
MORE DURABLE RESPONSE THAN THOSE
INDIVIDUALS VACCINATED ALONE BUT
THE THIRD BOOR FOR THE
INDIVIDUAL WHOSE HAD NOT BEEN
PREVIOUSLY VACCINATED RAISED
THEIR NUMBERS SO IT WAS NOT
SIGNIFICANT HERE.
WE FURTHER LOOK AT PHENOTYPE OF
MEMORY CELLS, WHAT DID THEY LOOK
LIKE AND QUALITIES DID THEY
HAVE.
WE HAD QUALITIES THAT WERE
ASSOCIATED WITH INFECTION
SPECIFICALLY CLASS SWITCHED,
CLASSICAL MEMORY B CELLS WHICH
RAPIDLY FORM ANTIBODY SECRETING
PLASMA BLAST, THESE WERE HIGHER
LEVELS BEFORE VACCINATION AND
AFTER THE SECOND VACCINE ONE
WEEK AFTER THAT.
BUT AGAIN THOSE INDIVIDUALS WHO
HAD ONLY BEEN VACCINATED AND
HADN'T HAD A PREVIOUS INFECTION
QUICKLY GAIN SIMILAR NUMBERS TO
THE INDIVIDUALS WHO HAVE BEEN
PREVIOUSLY INFECTED AND AGAIN WE
DIDN'T SEE A BOOST MANY THE
MEMORY RESPONSE OF THOSE THAT
HAD BEEN PREVIOUSLY INFECTED AND
AT THIS POINT IN THOSE WHO WERE
INFECTIOUS NAIVE EITHER.
AND LASTLY, ONE OF THE REALLY
MOST IMPORTANT THINGS WE CAN
LOOK AT WAS HOW DO THESE
ANTIBODIES FROM THESE
INDIVIDUALS FROM THEIR PLASMA
FUNCTION TO RESPOND TO EITHER
THE DELTA VARIANT OR OMICRON
VARIANT CONSIDERING THESE WERE
ALL INDIVIDUALS THAT WERE
IMMUNIZED OR INFECTED WITH THE
SPIKE PROTEIN FROM THE WUHAN
STRAIN.
SO WHEN WE LOOK AT THIS, AGAIN
RED IS PEOPLE WHO HAVE BEEN
PREVIOUSLY INFECTED, BLUE ARE
THE NAIVE INDIVIDUALS AND WHAT
YOU CAN SEE IS THAT IF WE ARE
LOOKING SIX MONTHS POST VACCINE
TO IN INDIVIDUALS WHO HAD NEVER
HAD INFECTION, THEY VERY MUCH
LOST A LOT OF THEIR ABILITY TO
NEUTRALIZE SARS COV-2 AND THIS
IS IN OUR BSL 3 USING INFECTION
BLOCKING INFECTION OF VIR ROW
CELLS BUT ONCE THE INDIVIDUALS
ARE BOOSTED THEY REGAIN THAT
ABILITY TO NEUTRALIZE DELTA.
INTERESTINGLY PEOPLE WHO
PREVIOUSLY INFECTED STILL HAVE
THAT ABILITY AT SIX MONTHS POST
VACCINE TWO, AND IT IS NOT
ENHANCED SIGNIFICANTLY BY THE
BOOST.
THAT IS SHOWN NUMERICALLY HERE.
LOOKING AT OMICRON VARIANT WE
SEE A SIMILAR PATTERN, THIS WAS
REASSURING TO US INDIVIDUALS WHO
HAVE THIS HYBRID IMMUNITY
PREVIOUSLY INFECTED AND THEN
VACCINATED ARE STILL CAPABLE OF
NEUTRALIZING LARGELY
NEUTRALIZING OMICRON, THE BOOST
DOESN'T MAKE A SIGNIFICANT
DIFFERENCE IN THAT.
BUT THOSE INDIVIDUALS WHO HAD
ONLY BEEN VACCINATED HAVE A
LOWER ABILITY TO NEUTRALIZE
OMICRON THAN AGAIN AS BOOSTED BY
THE INCREASE ANTIBODY TITER THAT
WE SAW PREVIOUSLY.
SO THAT WAS REASSURING.
SO THE THIRD VAX OR BOOST NAIVE
INDIVIDUALS CAN NORMALIZE
DIFFERENCES IN THE QUANTITIES OF
THESE RBD SPECIFIC MEMORY B
CELLS SEEN EARLIER TIME POINTS
BUT IN DATA I DIDN'T SHOW TODAY
THESE PREVIOUSLY INFECTED
INDIVIDUALS DO RETAIN
CHARACTERISTICS THAT ARE NOT
SEEN IN THE VACCINATED
INDIVIDUALS, AT TIME POINTS POST
VACCINE TWO.
THEY RETAIN QUALITY THAT LOOKS
MORE ACTIVATED, THEY HAVE MORE
CLASSICAL IGG MEMORY B CELLS BUT
AGAIN THIS IS NORMALIZED BY THAT
BOOST.
SO AGAIN, GETTING TO ROSS'S
QUESTION, SOME OF THESE
DIFFERENCES CAN BE NORMALIZE BY
A THIRD DOSE OF ANTIGEN BUT
THESE PREVIOUSLY INFECTED
INDIVIDUALS ARE BETTER ABLE TO
NEUTRALIZE VARIANTS INCLUDING
OMICRON THAN NAIVE INDIVIDUALS
AT SIX MONTHS POST VACCINE TWO,
SUGGESTING HIGH QUALITY LONG
LIVED PLASMA CELLS THAT ARE
PERSISTING IN THESE INDIVIDUALS
AND THAT MAY ALSO SPEAK TO THAT
QUESTION OF WHY DO YOU LOSE SOME
OF THE ONLY I DON'T KNOW
NEUTRALIZATION CAPACITY THAT
THAT QUESTION SHANE PRESENTED
AND I CAN TALK ABOUT THAT LATER.
LASTLY WE ALSO LOOKED AT THE CD4
T-CELLS BECAUSE WE KNOW CD4
T-CELLS ARE NOT ONLY REALLY
IMPORTANT CELLS FOR REACTIVATING
MEMORY B CELLS BUT ALSO FOR
EXPRESSING DIFFERENT CYTOKINES
THAT ACTIVATE INNATE CELLS TO
KILL THE VIRUS.
WE DID THIS USING DIFFERENT AIM
ASSAYS WE FIRST LOOKED FOR A
PEPTIDE POOL THAT WAS DERIVED
FROM PROTEINS IN THE VIRAL
INFECTION.
BUT NOT IN THE VACCINATION.
THESE MN POOLS HERE.
WE ALSO LOOKED AT THE SPIKE
SPECIFIC RESPONSES IN OUR NAIVE
INFECTION INDIVIDUALS PREVIOUSLY
INFECTED INDIVIDUALS.
WHAT YOU SEE IS THE M AND N
SPECIFIC RESPONSES ARE ONLY
VISIBLE IN PEOPLE WHO HAD HAD
PREVIOUS INFECTION TO LARGE
DEGREE, THOSE ARE STATIC OVER
VACCINATION SO THERE IS NO
DETRACTION TO THE RESPONSE FROM
THIS VACCINE THAT DOESN'T
CONTAIN THE M AND N PROTEINS
THAT STAY STATIC THROUGHOUT
EVERYTHING WE LOOK AT.
BUT YOU CAN ALSO NICELY SEE
INDUCTION OF SPIKE RESPONSE IN
PREVIOUSLY NAIVE INDIVIDUALS,
AND THE EXPANSION OF THAT
RESPONSE IN THE PREVIOUSLY
INFECTED INDIVIDUALS AFTER
VACCINATION.
THAT IS MAPPED OUT HERE YOU CAN
TRACK THIS OVER TIME.
AND WHAT YOU CAN SEE IS THE
T-CELL MEMORY OF THE M AND N
POOL MEANS HIGHER IN PEOPLE IN
PREVIOUSLY INFECTED THAN THOSE
NEVER INFECTED AS ONE WAY TO
EXPECT BUT LOOK AT THE SPIKE
SPECIFIC RESPONSE, THE RESPONSE
TO SPIKES STARTS HIGHER IN
PREVIOUSLY INFECTED INDIVIDUALS
BUT IS QUICKLY CAUGHT UP BY THE
VACCINE AND THAT'S RETAINED AT
THAT POST VAX 3 TIME POINT AS
WELL.
LASTLY, THE QUALITY OF THE
T-CELL RESPONSES WAS REALLY
INTERESTING TO US, WE WANTED TO
KNOW IF T-CELL IS CD4 T-CELL HAD
SEEN INFECTION AS OPPOSED TO
SEEING A VACCINATION IN THE ARM,
THEY ADOPT DIFFERENT QUALITATIVE
ATTRIBUTES AND ONE OF THE WAYS
WE CAN LOOK AT THIS IS
DISSECTING THE CYTOKINES THESE
CELLS CAN MAKE.
THIS IS AGAIN LOOKING AT THE
VICTIMS NOT PREVIOUSLY INFECT
BUD VACCINATED.
VACCINATION INDUCES A NICE TH 1
RESPONSE AS PREVIOUSLY DESCRIBED
DESCRIBED.
THESE INDIVIDUALS PREVIOUSLY
INFECTED HOW FAR THERE IS A MUCH
BIGGER PERCENTAGE OF CD4 POOL
MAKING INTERFERON GAMMA, THAT
HELPS THROUGH FOR EVERY TIME
POINT THAT WE LOOK AT WHICH IS
JUST LOOKING AT HERE, IT IS
ALMOST EASIER TO SEE WITH LINES
HERE SO FOR EVERY TIME POINT WE
LOOK THERE WAS HIGHER PROPORTION
OF INTERFERON GAMMA POSITIVE
CELLS IF YOU HAD PRIOR INFECTION
SO EVEN ADDITIONAL ANTIGEN DOSES
COULDN'T ALTER THE DIFFERENCE,
SUGGESTING IMPRINTING FROM THE
PRIOR INFECTION.
WE SAW SIMILAR PATTERNS WHEN WE
LOOK AT IL 10 PRODUCTION WE SAW
MORE IL 10 PRODUCTION IN THE
SUPPRESSIVE CYTOKINE IN
INDIVIDUALS PREVIOUSLY INFECTED
VERSUS THOSE VACCINATED AND TOO
WAS RETAINED A AT ALL TIME
POINTSES.
SO THIS IS JUST A QUANTIFY WHAT
I JUST TOLD YOU, M AND N
RESPONSES REMAIN STATIC BUT THE
QUANTITY OF CD4 T-CELLS ARE
NORMALIZED BY THE VACCINE BY THE
NUMBER OF ANTIGEN DOSES.
BUT THERE ARE CHARACTERISTICS
HERE THAT ARE NOT TOTALLY
NORMALIZED AND JUST IN TOTAL
CONCLUSION, THE mRNA VACCINES
ARE REALLY QUITE REMARKABLE AT
INDUCING VERY SIMILAR TH 1 TYPES
OF ANTIVIRAL RESPONSES, AND WE
OBVIOUSLY KNOW THEY INDUCE GREAT
PROTECTION.
MANY OF THE DIFFERENCES THAT WE
SAW BETWEEN PREVIOUSLY INFECTED
AND VACCINE ONLY INDIVIDUALS
WERE AMELIORATED BY THIRD DOSE
VACCINE BUT THERE WERE QUALITIES
TRULY IMPRINTED BY THAT PREVIOUS
INFECTION INCLUDING CYTOKINE
PRODUCTION BY T-CELLS AND SOME
OF THE QUALITIES WE THINK IN THE
BREADTH OF THE MEMORY B CELLS
THAT I DIDN'T GET INTO TODAY.
LASTLY IT IS IMPORTANT TO POINT
OUT ONCE THE HIGH LEVELS
IMMUNITY ARE REACHED, ADDITIONAL
HOMOLOGOUS BOOST MAY HAVE
LIMITING RETURNS, WE DIDN'T SEE
MUCH BOOST IN RESPONSE IN THE
PREVIOUSLY INFECTED VACCINATED
INDIVIDUALS.
WITH THAT I'LL THANK THE PEOPLE
WHO DID THIS AND HAPPY TO TAKE
ANY QUESTIONS.
>> THANK YOU, MARION.
SO WE ARE RUNNING A LITTLE LOW
ON TIME SO IF YOU HAVE A
QUESTION PLEASE RAISE YOUR HAND.
WERE YOU ABLE TO STRATIFY THIS
BY SEVERITY OF INFECTION?
ANY PREVIOUSLY INFECTED COHORT
LIKE SEVERE GROUP HOSPITALIZED
THEN GOT BETTER?
>> EVERYONE THAT WE WERE LOOKING
AGENT FOR THESE STUDIES HAD MILD
INFECTION SO WE WEREN'T ABLE TO
DO THAT IN THESE STUDIES.
BUT I THINK IT WOULD BE REALLY
INTERESTING ESPECIALLY WITH IL
10 PRODUCTION TO SEE HOW THAT
CHANGES.
>> ANY OTHER QUESTIONS?
THEN WE'LL HAVE OPPORTUNITY AT
END AS WELL TO DISCUSS THIS
DATA.
SO WHY DON'T WE MOVE ON THEN TO
THE NEXT SPEAKER.
IS DAVID FREEMAN, DO YOU WANT TO
STOP SHARING?
MAYBE WE HAVEN'T.
THE NEXT SPEAKER IS DAVID
FREEMONT, WASHINGTON UNIVERSITY
ST. LOUIS WHO WILL SPEAK
LANDSCAPE OF ANTIBODY RESPONSES
TO SARS COV-2 INFECTION.
GET THOSE SLIDES UP.
>> YES.
ARE MY SLIDES UP?
>> WE CAN SEE THEM.
>> THERE'S BEEN A LOT OF
MOVEMENT AND DIFFERENT
DISCIPLINES OBVIOUSLY TO DEAL
WITH COVID PANDEMIC.
ONE OF THE THINGS THAT I HAVE
BEEN PARTICIPATING IN THAT I
THINK HAS BEEN QUITE SUCCESSFUL
IS STRUCTURAL GENOMICS FOCUSED
ISSUES WITH LOOKING AT THE MANY
PROTEINS ENCODED BY SARS COV-2.
I WANT TO HIGHLIGHT WORK,
CONTRACT WORK THROUGH CENTER FOR
STRUCTURAL GENOMICS AND
INFECTIOUS DISEASE BASED AT
NORTHWESTERN UNIVERSITY CHICAGO
THAT I HAVE BEEN PART OF FOR 15
YEARS NOW.
THERE IS HUNDRED STRUCTURE
DEPOSITED IN THE PROTEIN DATA
BANK OF VARIOUS FULL LENGTH OR
FRAGMENTS OF VARIOUS COVID
PROTEINS AND IT'S BEEN A VERY
SUCCESSFUL ENTERPRISE.
MY WORK IS FOCUSED ONLY SOME OF
THE ACCESSORY PROTEINS THAT 7, 8
AS WELL AS SPIKE COMPLEXES WITH
ANTIBODIES AS I'M GOING TO TALK
ABOUT TODAY.
SO MANY OF YOU KNOW THIS, THE
TRIAL RICK SPIKE HAS TWO MAJOR
AREAS ANTIBODIES HAVE FOUND TO
BE NEUTRALIZING OR PROTECTIVE.
THE RECEPTOR BINDING DOMAIN
WHERE YOU CAN HAVE ANTIBODIES
THAT BIND DIRECTLY AT THE ACE 2
SITE OR THERE ARE SOME EPITOPES
SHOWN TO BE NEUTRALIZING AND
PROTECTIVE OUTSIDE OF THE ACE 2
SITE AND RBD AN COLLECTION
ANTIBODIES FOCUSED ON THE MTD.
SO THIS POINT THOSE ARE THE TWO
MAJOR AREAS OF EPITOPES WE KNOW
PROTECTION PREVAIL.
REMINDING YOU TOO, THIS IS NOT A
STATIC PROTEIN BUT ONE THAT HAS
CONFIRMATIONAL VARIATION IN
PARTICULAR RECEPTOR BINDING
DOMAINS NEEDS TO BE
CONFIGURATION TO BIND ACE 2 AND
WHAT WE LEARNED ALMOST TWO YEARS
NOW ANTIBODY CONSIST RECOGNIZE
THIS RECEPTOR BINDING DOMAIN IN
UP OR DOWN CONFIGURATION.
SO WE STARTED OUR WORK EARLY ON
THE COLLABORATION WITH
(INDISCERNIBLE) AT WASU WHO
DEVELOPED A PANEL OF MONOCLONAL
ANTIBODIES WE HELPED TO DEVELOP
AND CHARACTERIZE.
WE FOUND TWO IN PARTICULAR WHICH
WERE PARTICULARLY POTENT BOTH IN
VIVO AND IN VITRO AT
NEUTRALIZING THE INITIAL WUHAN
STRAIN OF THE VIRUS.
WE PROCEEDED TO DO MICROSCOPY
RECONSTRUCTIONS WITH THESE TWO
MORE POTENTLY NEUTRALIZING
ANTIBODIES BOUND TO THE TRIAL
RICK SPIKE.
AND AS OTHERS OBSERVED WHAT WE
FIND IS THAT THE ANTIBODIES BIND
IN UP OR DOWN CONFIGURATION FOR
OUR POPULATION ROUGHLY, ABOUT
155050 SO WE CAN HAVE STRUCTURES
WHICH ARE ALL THE WAY DOWN, YOU
CAN HAVE STRUCTURE WHICH ARE
MIXTURES OF UP AND DOWN.
WE THINK THIS IS QUITE
FUNCTIONALLY IMPORTANT BECAUSE
AGAIN THE RBD NEEDS TO COME UP
IN OTHER WORDS TO ENGAGE ACE 2
SO ANTIBODIES THAT CAN KEEP ALL
THE RECEPTOR BINDING DOMAINS IN
DOWN CONFIGURATION WILL BLOCK
ABILITY TO ENGAGE WITH ACE 2
RECEPTOR.
SO IF WE LOOK MORE DETAIL ABOUT
THE EPITOPES ENGAGED BY TWO
NEUTRALIZING ANTIBODY, 2 BL 4
AND HL 4 DON'T COMPETE WITH ONE
ANOTHER WE FIND SOME OF THE
THINGS ON BOTH OF THEM.
ONE HOWEVER HITS RECEPTOR
BINDING MOTIF WHILE THE OTHER IS
ADJACENT TO THAT RECEPTOR
BINDING MOTIF.
SO IF WE COMPARE THE ONE THAT
DOES IN FACT BIND WHAT WE CALL
RECEPTOR BINDING MOTIF, WHICH IS
ESSENTIALLY A ELONGATED LOOP,
WHICH IS WHAT IS ENGAGING ACE 2,
THESE ARE MOUSE DERIVED
MONOCLONALS THEY HAVE VERY
SIMILAR EPITOPE TO ANTIBODIES
WHICH REASON OBJECTIFIED FROM
HUMANS.
THESE HUMAN ANTIBODIES ARE
GROUPED TO DIFFERENT CATEGORIES
ESSENTIALLY BASED ON BINDING
ORIENTATION OR ANGLE, THE WAY
THEY ENGAGE RECEPTOR BINDING
MOTIF ITSELF.
BUT THEY ALL SHARE THE CAPACITY
OF POTENTLY DISRUPTING THE
INTERACTION OF THE RECEPTOR
BINDING DOMAIN.
WITH ACE 2, IF WE COMPARE ON THE
OTHER HAND OUTSIDE THE BINDING
RECENT TORR MOTIF THERE'S FEWER
CHARACTERIZED ANTIBODIES IN THIS
FAMILY, THE ONLY ONE THAT HAS
EMERGENCY USE AUTHORIZATION IS
STR 9 WHICH IS THE BRGSK
ANTIBODY, IT HAS OVERLAPPING
EPITOPE WITH -- WHICH WAS NOT
INFACT ANTIBODY RAISED AGAINST
SARS 2 BUT A PATIENT RECOVERING
FROM SARS 1.
AND AS WE KNOW IT IS IMPORTANT
ANTIBODY BECAUSE AS I WILL COME
BACK TO, IT IS THE ONLY ANTIBODY
WITH EMERGENCY USE AUTHORIZATION
THAT CONCURRENTLY CAN BE USED TO
NEUTRALIZE OMICRON.
SO I WANT TO POINT OUT
UNIVERSITIES IS A GREAT
ENVIRONMENT WITH COLLABORATIONS
WE HAVE.
WE HAVE BEEN WORKING WITH SEAN
WHELIN'S LAB WITH ESCAPE MAPPING
MUTATION AND ANTIBODIES AND
SHOWN HERE SOME OF THE EARLY
EMPERIMENTS WE DID TO DO EPITOPE
MAPPING WITH THESE PARTICULAR
ANTIBODIES AND WE FOUND A NUMBER
OF ESCAPE MUTANTS USING THE BSB
PSEUDOTYPE VIRUS AS MECHANISM
FOR GENERATING MUTANTS.
AND JUST CALL OUT FOR EXAMPLE,
THE ESCAPE MUTATIONS THAT
DISRUPT THE 2 B L 47 EPITOPE ONE
THAT CAME UP QUICKLY IS THE EK
44 MUTATION, THAT IS WHAT WE
KNOW TO BE ONE MAJOR DISRUPTERS
OF MANY ANTIBODIES, SO POINT
BEING MANY MUTATIONS WHEN ESCAPE
MUTATIONS ARE ABSOLUTELY MIRROR
WHAT WE SEE IN THE NATURAL
VARIANTS OF CONCERNS SO JUST
AGAIN LOOKING AT ANTIBODIES
WHERE WE FOUND ESCAPE MUTATIONS,
WE ACTUALLY FIND NUMBER OF COINS
DENT MUTATIONS IN THE DATABASE.
SO I WON'T GO THROUGH THE
DETAILS BUT WE DID A NUMBER OF
EXPERIMENTS TO APPRECIATE THE
MECHANISMS OF NEUTRALIZATION.
WE KNOW PHYSICALLY THAT 2 BL 4
POTENTLY BLOCKS PHASE 2 BINDING
BUT 2 HL 4 DOES NOT.
HOWEVER WE WERE ABLE TO SHOW 2
HL 4 HAS CAPACITY OF DISRUPTION
OF ADHERENCE OF THE VIRUS
PRESUMABLY ONCE THE VIRUS NEEDS
TO ADHERE EXPOSES RECEPTOR
BINDING DOMAIN AND THEN IT CAN
ENGAGE THE ACE 2 SO OUR
PREFERRED MECHANISM OF ACTION IS
2 HL 4 ACTUAL MECHANISMS
DOMINANTLY TO STOP VIRAL
ADHERENCE WE STICK LATED BASED
ON BINDING SITE AND OTHER
PEOPLE'S ANALYSIS THAT THIS
MIGHT BE BECAUSE WE ARE
DISRUPTING GAG INTERACTION.
OR SULFATE CARBOHYDRATE
INTERACTION THOUGH WE WERE NEVER
ABLE TO PROVE AS MECHANISM FOR 2
HL 4, SO IT IS CLEAR 2 HL 4 HAS
CAPACITY OF DIMINISHING THE
INTERACTION OF THE VIRUS TO
INTERACT WITH CELLS INDEPENDENT
OF PHASE 2, WE BELIEVE THAT IS
AN IMPORTANT ELEMENT OF THIS
MECHANISM.
WE ALSO DON'T HAVE MUCH MORE
UNDERSTANDING OF THE NUMBER OF
OTHER ANTIBODIES THAT BRINING
THE RBD OUTSIDE OF THE RECEPTOR
BINDING MOTIF AND THEIR MEEK
ANYMORES SO LET ME TURN YOUR
ATTENTION TO ANOTHER PANEL
MONOCLONALS WE HAVE BEEN
CHARACTERIZING COLLABORATION
WITH MICHAEL DIAMONDs
LABORATORY AT WASU.
SO WE MADE A LARGE PANEL RBD
SPECIFIC MONOCLONAL, I WILL TELL
YOU ABOUT ONE OF THEM IN
PARTICULAR, AND THAT IS THE
ANTIBODY SARS 238 ACTIVE IN
VITRO AS WELL AS IN VIVO AND
PROPHYLACTIC STUDY AS WELL AS
THERAPEUTICALLY AND ALSO
EXHIBITS QUITE HIGH SPECIFIC
ACTIVITY.
SO MY GRADUATE STUDENT WAS ABLE
TO DETERMINE THE STRUCTURE OF
THIS MONOCLONAL AND WE FIND THAT
IT BINDS KIND OF A UNIQUE
EPITOPE AT THE EDGE AND IT DOES
OVERLAP WITH PHASE 2 BINDING
SITE BUT WE FOUND QUITE
INTERESTING IS AN ANTIBODY
ENTIRELY DRIVEN FROM LIGHT CHAIN
CONTEXT, 70% INTERFACE IS LIGHT
CHAIN CDR LOOPS WHICH IS UNUSUAL
SITUATION WHERE MOST MONOCLONALS
GO THE OTHER WAY.
7 TO 080% SPECIFIC CONTEXT BY
HEAVY CHAIN CONTEXT.
WE ALSO NOTICE THE EPITOPE
ITSELF IS -- HIGHLY CONSERVED
AMONG THE VARIANTS THAT ARE
CIRCULATING.
IN FACT, THE OVERLYING MAJORITY
OF THE GRANTS CONCERN THAT WE
TESTED FOR NEUTRALIZATION BY
SARS 38 IN FACT WERE POTENTLY
NEUTRALIZED.
EXCEPT I WILL TELL YOU THE PUNCH
LINE EXCEPT FOR OMICRON.
OMICRON IS NOT NEUTRALIZED WELL
BY THIS MONOCLONAL.
SO WE ALSO CARRIED OUT A NUMBER
OF STUDIES LOOKING AT ANTIBODIES
AGAINST THE MTD, THE EXTERNAL
DOMAIN OF THE SPIKE.
SO THE MECHANISM OF ACTION THESE
NTD ANTIBODIES IS ENIGMATIC.
WE GROUPED THEM INTO THREE
COMPETITION GROUPS AND PROCEEDED
TO DO A NUMBER OF ASSAYS
EVALUATING DISRUPTING ACE 2
BINDING CAPABLE OF DOING AND
CROSS COMPETING WITH OTHER KNOWN
ANTIBODIES TO DETERMINE EPITOPES
BUT ONE STRIKING THING, WE HAVE
THREE COMPETITION GROUPS ONLY
GROUP ONE SHOWN HERE ACTUALLY
POTENTLY STAND COVID INFECTED
CELLS.
IN FACT IT STAINS THE CELLS
BETTER THAN THE RBD ANTIBODIES
WHICH USE HERE AS CONTROLS SO
THE RBD ANTIBODIES CAN FAIRLY
WELL STAIN, IT IS QUITE WELL
APPRECIATIVE THAT THE EFFECTOR
FUNCTION IS MECHANISM RBD
ANTIBODIES CAN WORK, IT WAS
RATHER DRAMATIC HOW THE GROUP
ONE BUT NOT GROUP 2 AND 3 M
TEXAS ANTIBODIES STAIN INFECTED
CELLS, HYPOTHESIS DERIVE THIS IS
THE MECHANISMS OF THE IN VIVO
PROTECTION MIGHT BE DRIVEN BY FC
MEDIATED PROCESSES.
WHEN WE MUTATE CRITICAL GLYCAN
RESIDUE MANY THE FC REGION WE
LOSE A SIGNIFICANT ASPECT OF THE
POTENCY OF PROTECTION.
WITH THIS PARTICULAR ANTIBODY
SARS 257.
SO LUCAS ADAMS IN MY GROUP WENT
TO DETERMINE THE THE CRYOEM
STRUCTURE OF THE MONOCLONAL
ANTIBODY BOUND TO END TERMINAL
DOMAIN OF TRIAL RICK SPIKE AND
IT BINDS TO HE WILL -- TRIAL
TRIMERIC SPIKE.
AND BINDS TO OTHER ANTIBODIES
COMBINE PROPOSED OF PREAN AREA
THAT HAS BEEN TERMED THE NTD
SUPERSITE.
SO IF YOU EVALUATE THE ACTUAL
EPITOPE AND LOOK AT WHERE THE
VARIANTS OF CONCERN AS WELL AS
ESCAPE MUTANTS WE DEVELOPED IN
COLLABORATION WITH SEAN WHELIN'S
GROUP WE CAN APPRECIATE THAT IN
FACT WHAT WAS A FAIR DEGREE OF
CONSERVATION WE DO HAVE A COUPLE
DELETIONS IN THE CASE OF THE 351
AND 630 GRANTS OF CONCERN WHICH
INTRODUCE DELETIONS AT THE CRUX
OF THE EPITOPE SO WE GO LOSE
PROTECTIVE VALUE OR
NEUTRALIZATION WITH ANTIBODY
UNDER THESE CIRCULATING STRAINS.
WE HAVE A REGION IN OMICRON TO
CUT TO THE QUICK, DATA NOT SHOWN
WE ALSO LOSE ANY NEUTRALIZATION
PROTECTION AGAINST OMICRON WITH
THIS ANTIBODY.
SO WHAT ABOUT OMICRON, WHAT WE
REALLY KNOW?
OF COURSE WE KNOW RELATIVE TO
ALL PROCEEDINGS VARIANTS OF
CONCERN WILL IS A SIGNIFICANTLY
INCREASED NUMBER OF AMINO ACID
SUBSTITUTIONS THROUGHOUT THE RBD
AS WELL AS THE NTD.
WE NOTE THAT MANY OF THOSE
MUTATIONS WHICH HAVE BEEN
IDENTIFIED ALL ACTUALLY IN THE
RECEPTOR BINDING MOTIF AND MANY
OF THEM IN CRITICAL LOCATIONS
THAT ARE QUOTE DISRUPTIVE
TOWARDS IMMUNE ANTIBODIES SO WE
WANTED TO FURTHER EVALUATE THAT
IN COLLABORATION WITH MICHAEL
DIAMOND'S LABORATORY.
WE TOOK ALL OF THE EMERGENCY USE
AUTHORIZED ANTIBODIES AS WELL AS
OUR OWN MORE POTENTLY SPECIFIC
ANTIBODIES AND EVALUATED
CAPACITY TO BE NEUTRALIZED.
THIS IS A COMPLETELY IN VITRO
ASSAY USING AUTHENTIC VIRUS AND
WHAT WE FOUND JUST PUBLISHED A
WEEK OR TWO AGO IS THAT OF THE
EMERGENCY USE AUTHORIZED
ANTIBODIES ONLY THE VRGSK S 3L 9
HAS ANY CAPACITY OF
NEUTRALIZING.
IT IS NOT A VERY POTENT
NEUTRALIZING ANN BODY IN
GENERAL, BUT IT DOESN'T LOSE
MUCH POTENCY AGAINST OMICRON.
AND THEN WE ALSO FOUND THAT THE
ASTRA ZENECA PROPHYLACTIC
ANTIBODIES DEVELOPED BY JIM CROW
AT VANDERBILT ALSO MAINTAIN
COLLECTIVELY TOGETHER FAIRLY
REASONABLE NEUTRALIZATION
CAPACITY AGAINST OMICRON.
AND THAT IS WHAT WE LEARNED SO
FAR.
AND THE EXPECTATIONS WITH OF
COURSE THE DEVELOPMENT OF NEXT
GENERATION MONOCLONALS IS
HOPEFULLY FIND SOME MONOCLONALS
THAT HAVE BETTER TIME DEALING
WITH BROAD SPECTRUM OF DIFFERENT
VARIANTS OF CONCERN.
SO I WANT TO THANK MY
COLLABORATORS AND MY STUDENTS
AND POST DOCS WORKING ON THESE
PROJECTS AND THANK YOU FOR YOUR
ATTENTION.
>> THANK YOU SO MUCH.
AGAIN, PLEASE RAISE YOUR HAND IF
YOU HAVE A QUESTION.
>> I WAS WONDERING SO VIKING
NONE OF THESE ANTIBODIES BIND TO
S PROTEIN.
AND I WAS WONDERING HOW IS THE
STRUCTURE OF MERS DIFFERENT FROM
SARS COV-2?
DOES THAT SAY SOMETHING ABOUT
HOW THESE ANTIBODIES ARE GOING
TO BIND?
IS THERE A CHANGE IN THE
STRUCTURE THAT'S GOING TO
PREVENT ANY ANTIBODIES FROM
BINDING?
THE RECEPTOR BINDING REGION OF
MERS IS DRAMATICALLY ALTERED
RELATIVE TO SARS 1 AND 2.
THERE ARE ANTIBODIES IDENTIFIED
WHICH ARE CROSS REACTIVE BETWEEN
MERS AND SARS BUT SAFE TO SAY
THEY ARE NOT NEUTRALIZING
PROTECTIVE OR AT LEAST NOT
NEUTRALIZED.
SO WE HAVE IDENTIFIED FROM SOME
MOUSE PANELS SOME CROSS
REACTIVITY TO MERS BUT THEY ARE
NOT NEUTRALIZING ANTIBODIES.
CERTAINLY I THINK THAT ONE WILL
FIND THAT MOST ANTIBODIES WHICH
ARE CROSS REACTIVE IN THIS WAY
ARE AGAINST S 2 SO THEY ARE
GOING TO BE IGNORING THE RBD AND
NTD REGIONS WHICH IS WHAT I HAVE
BEEN TALKING ABOUT TODAY.
>> THANK YOU.
ANY OTHER QUESTIONS?
AGAIN WE'LL HAVE TIME AT THE
END.
THANKS SO MUCH, THE NEXT SPEAKER
IS RAFI AHMED.
WHO WILL BE TALKING ABOUT
LONGITUDINAL ANALYSIS OF
ADAPTIVE IMMUNITY FOLLOWING MILD
TO MODERATE COVID-19.
>> CAN YOU SEE MY SLIDES?
>> YES, REFA.
>> GREAT.
I'LL PRESENT TO YOU SOME OF THE
-- THIS IS A COLLABORATIVE STUDY
WITH -- COLLABORATIVE STUDY WITH
JUDY AT HUTCH.
AND WE HAVE BEEN FOLLOWING
LONGITUDINALLY RESPONSES IN
COVID-19 PATIENT.
THIS IS ACTUALLY A VERY NICE
COHORT.
WE NOW HAVE SLIGHT -- OVER 450
CONVALESCENT PATIENTS WE
FOLLOWED BUT PARTICULARLY THE
COHORT AT THE ATLANTA AND SEE
SEATTLE.
AND OVER 90% CONVALESCENT
PATIENTS (INAUDIBLE).
WHICH IS NICE BECAUSE IT
REFLECTS THE INFECTION MAJORITY
OF (INAUDIBLE).
WHAT I'M GOING TO DO IN MY TALK
TODAY IS DESCRIBE THE ANTIBODY
RESPONSE AND THEN JUDY WILL
FOLLOW, SHE WILL GIVE MORE
INFORMATION OBJECT COHORT
ITSELF.
AND THEN TALK ABOUT THE CELLULAR
(INAUDIBLE).
SO I'LL ADDRESS TWO QUESTIONS IN
MY TALK TODAY.
FIRST ONE IS HOW DOES ANTIBODY
TITERS CHANGE OVER THIS 18 MONTH
PERIOD WITH INFECTED INDIVIDUALS
AND I SHOW YOU DATA LOOKING AT
BINDING ANTIBODY NEUTRALIZINGS
ANTIBODIES USING A (INAUDIBLE).
I WILL ADDRESS THE DIGRESS FROM
THE MAIN TOPIC DURABILITY AND
ADDRESS QUESTIONS WHAT HAPPENS
TO ANTIBODY RESPONSES TO THE
ENDEMIC CORONA VIRUS, INFECTIONS
WE CHANNEL.
THAT'S THE SARS COV-2 INFECTION,
IN FACT, THOSE TITERS MORE
IMPORTANTLY THE MESSAGE I WANT
TO ADDRESS IN THIS TALK IS
DURABILITY OF ANTIBODY RESPONSES
TO THE (INAUDIBLE).
SO THIS A DISEASE SLIDE I WILL
WALK YOU THROUGH.
SO THIS IS LOOKING
LONGITUDINALLY IN OVER 200 OF
OUR COHORT LOOKING AT ANTIBODY
RESPONSES TO EITHER THE SPIKE
PROTEIN, THE RBD REGION OR THE
NTD REGION.
AND WE HAVE LOOKED AT IGG IGA
AND IG -- LET'S FOCUS ON THIS
PARTICULAR -- WHICH IS SHOWING
LONGITUDINAL ANTIBODY RESPONSES
IGG RESPONSES TO THE SARS COV-2
SPIKE PROTEIN.
IN RED ARE PRE-PANDEMIC SAMPLES,
THESE ACTUALLY SERVE NEGATIVE
CONTROL, THESE ARE SOME SAMPLES
FROM STUDIES WE HAD DONE IN 2018
AND EARLIER LOOKING AT EITHER
LONGITUDINAL ANALYSIS OF PEOPLE
WHO GOT DISEASE AND FLU VACCINE
OR THERAPY -- THESE ARE DATA
FROM 2010, ANOTHER ONE AT 2014.
AND THIS SHOWS YOU THAT LOOKING
LONGITUDINALLY THESE INDIVIDUALS
FROM THE PANDEMIC NOT GETTING
INFECTION VACCINE IS PRETTY
FLAT.
SO THAT IS A NICE NEGATIVE OF
THIS.
SO WHAT THIS SHOWS ALMOST ALL OF
THESE PATIENTS MADE A NICE IGG
RESPONSE, CAME UP VERY QUICKLY
AND THEN YOU CALCULATE THE
DURABILITY OF THE RESPONSE WE
USE A (INAUDIBLE) GROUP AND IT
MADE -- GOT TO AN INTERESTING
POINT, THAT IF YOU DO JUST
EXPONENTIAL OVER THIS PERIOD YOU
GET HALF LIFE BUT IF YOU DO USE
THIS PARALLEL METHOD WHICH
ALLOWS YOU U TO LOOK AT BIPHASIC
ASPECTS OF THE RESPONSE YOU SEE
SOMETHING VERY INTERESTING, YOU
SEE THAT THERE IS A SLIGHTLY
FASTER INITIAL DECLINE BUT THEN
IF YOU DO -- FROM AROUND LIKE
THIS TIME POINT IN LIKE 100 DAY,
IT JUST STARTS TO BECOME -- YOU
CAN SEE THIS GREEN CURVE IS NOW
MOVED UP AND WHEN YOU LOOK AT
WHICH CURVE PREDICTS RESPONSE,
SO ESSENTIALLY WHAT YOU ARE
LOOKING AT IS INITIAL BURST UP
DECLINING AND THEN SLIGHTLY FAST
AERATED AND THERE THE FIRST BUT
THEN GIVING YOU A SLOWER -- THIS
IS CONSISTENT HOW WE LOOK AT
ANTIBODY FUNCTION, THIS ISSUE
THIS INTERESTING ISSUE OF EXTRA
FOLLICULAR ANTIBODY RESPONSES TO
STUDIES THAT YOU HAVE THEN
EITHER IN MOUSE MODELS OF
INFECTION AND ALSO IN HUMAN
STUDIES.
HUMANS AFTER VACCINATION VACCINE
OR (INAUDIBLE) VACCINE RESPONSE,
ANTIBODY COMES UP VERY QUICK
WITHIN TWO TO THREE WEEKS YOU
WILL HAVE ACTUALLY
ENVIRONMENTALLY BECOMING UP
VACCINATION BUT INFECTION WITH
NAIVE INDIVIDUAL, AND MOST OF
THIS ALREADY HAS SWITCHED, YOU
HAVE A LOT ALREADY SWITCHED.
MOST IS EXTRA FOLLICULAR BUT SO
THIS IS EVEN PRE-GERM CENTER
FORMATION THAT YOU GET THIS
BURST OF ICE TYPE ANTIBODIES
WITHIN A COUPLE OF WEEKS AND
AGAIN FROM ANIMAL STUDIES WE
KNOW MOST OF THAT IS EXTRA
FOLLICULAR HAPPENING OUTSIDE, IT
IS EXTRA FOLLICULAR AN THESE
WOULD BE VERY LOW (INAUDIBLE)
MUTATION.
VERY LIKELY THE MAJORITY OF
INCIDENCE WILL BE SHORTER THAN
PLASMA BLASTS OR BLAST CELLS AND
EVEN BONE MARROW (INAUDIBLE)
THIS IS IN SOME WAY THE TIP OF
THIS AS THE EFFECTOR RESPONSE
COMING UP RAPIDSLY BUT THEN AS
(INAUDIBLE) START FORMING IN A
FEW WEEKS AND SHANE AND ALI
SHOWN EGG GANTLY YOU CAN THEN IS
WHEN YOU START GETTING THE
SOMATIC HYPERMUTATION BONE
MARROW, I THINK THIS IS
REFLECTIVE OF THE RESPONSE THAT
ONE HAS TYPICALLY SEEN IN ANIMAL
MODELS.
SO THIS WAS VERY NICE GETTING
THIS NICE BIPHASIC, THE NEXT
QUESTION IS UTILIZATION.
YOU GET A SIMILAR CURVE, SHOWING
THE BIPHASIC DECAY.
THIS SHOW IT IS CORRELATION
BETWEEN BINDING ANTIBODIES AND
NEUTRALIZING ANTIBODIES, VERY
NICE CORRELATION.
ONE THING TO NOTE HERE, IS THAT
THE NEUTRALIZATION ASSAY OR VERY
IMPORTANT BIOLOGICALICALLY FORMS
OFF THE CLIFF GET TO LOWER TITER
SO WHAT YOU WILL SEE IS THAT
THERE ARE A LOT OF NEGATIVE FOR
THE NEUTRALIZATION ASSAY BUT YOU
STILL ARE GETTING LOWER LEVEL OF
-- YOU SEE THAT.
SO FANTASTIC ASSAY BUT
SENSITIVITY OF THAT IS NOT THE
GREATEST. DO TEND THE GET
THINGS FALLING OFF THE CLIFF
MORE.
TO GET IMPRESSION THAT IT HAD
DROPPED MUCH MORE BUT IN REALITY
(INAUDIBLE) OKAY.
THE NEXT QUESTION IS NOW THAT I
SHORT TN DATA OUT TO ABOUT EIGHT
MONTHS IN THIS ONE NOW WE HAVE
THE FOLLOWING SEVERAL OF THESE
INDIVIDUAL VERSUS NOT BEEN
VACCINATED, SO NOW GOING OUT
LEVELS HERE, ARE NOW WE HAVE
SOME OF THESE INDIVIDUALS THAT
HAVE NOT BEEN VACCINATED, THEIR
INFECTION WITH ANTI-DO ANTIBODIES, VERY
STABILIZING EVEN NICE.
AND NOW THE HALF LIFE OF VALUE
IS ACTUALLY LIKE A 120 NOW WHICH
WAS ABOUT 200 DAYS IS EVEN
STRONGER STATISTICALLY BUT IF
YOU NOW LOOK AT STARTING AT THE
YEAR STARTING TO GET NUMBERS OF
THOUSAND, TO REALLY VAIR VERY
NICELY BACK IT UP, VERY
CONSISTENT WITH THE MOTION AND
CONCEPT OF GENERATING LONGER
PLASMA CELLS.
THIS NEUTRALIZATION DATA VERY
SIMILAR, SMALLER NUMBER HERE BUT
YOU CAN SEE MANY OF THEM
(INAUDIBLE) LET ME QUICK WILL I
ADDRESS THE SECOND POINT --
QUICKLY ADDRESS THE SECOND
POINT.
WHAT IS THE EFFECT OF SARS COV-2
INFECTION FOR ANTIBODY TITERS TO
(INAUDIBLE) JUST TO REMIND
EVERYONE THERE ARE TWO CORONA
VIRUSES, THERE ARE TWO ALPHA
CORONA VIRUSES AND TWO BETA
CORONA VIRUSES HKU 1 AND OC 43.
THESE INFECTIONS ARE WIDE DURING
TITER AND VAST MAJORITY OF
POPULATION IS TO (INAUDIBLE) WE
HAVE LOOK AT SEVERAL HUNDRED
INDIVIDUALS, WE HAVE FOUND NO
ONE NEGATIVE.
EVERYONE HAS AT SOME POINT BEEN
INFECTED WITH SOME COMBINATION
OF HE IS ENDEMIC.
SO I SHOW YOU THE DATA FROM OUR
PRE-PANDEMIC SAMPLE.
GOING BACK TO 2010, 2015, YOU
CAN SEE THAT TWO POINTS.
ONE IS THAT EVERYONE IS SERO
POSITIVE TO THESE CORONA VIRUSES
AND THE OTHER STRIKING THING
HERE IS STRAIGHT LINE, PRETTY
MUCH STRAIGHT LINE, NO HALF LIFE
AT THIS TIME POINT SO THIS IS
REFLECTIVE OF INFECTION THAT
HAPPENED MANY YEARS POSSIBLE
SOME BOOSTING SOME REINFECTION
HAPPENING SIMILAR LEVEL BUT WHAT
IS STRIKING HERE, I PUT TOGETHER
THESE -- WE HAVE NOT SEEN THE
SPIKES AND UPS AND DOWNS SO
REALLY VERY STABLE AT THIS
STAGE.
THIS IS WHERE ALL (INAUDIBLE)
NOW WE ASKED THE QUESTION, WHAT
ABOUT THESE PEOPLE WHO ARE
INFECTED, TWO QUESTIONS, ONE, IS
THERE ANY CHANGE IN REACTING, IN
OTHER WORDS DOES ANY SARS COV-2
ANTIBODY CROSS REACT WITH THESE,
YOU THINK OF THAT IN THIS -- SO
WITH THE ALPHA VIRUSES, REALLY
BE -- DON'T PICK UP MUCH, THE
ALPHA CORONA VIRUS BUT NOW YOU
SEE THE BLACK LINES BEFORE 51
BLACK LINES NOW YOU HAVE 270
BLACK LINES SO REMARKABLE
STABILITY OF THE ANTIBODY, AGAIN
NOT MUCH (INAUDIBLE) HAPPENING.
BUT WITH THE TWO BETA CORONA
VIRUS WE DO SEE ESPECIALLY
DEFINITELY SEEING SON ANTIBODY
USED BY THIS ASSAY TO INFECTION
CROSS REACTIVE BECAUSE NOW YOU
SEE THIS HAS GONE UP, NOW THERE
A DECLINE BECAUSE THIS IS
(INAUDIBLE) CROSS REACTING AND
DECLINING SO MANY OF THE TIMES
NOW DECLINE IN THIS BLUE LINE
INFECTED.
AND LITTLE MORE STRIKING WITH
THE REACTIVITY.
WE HAVE ALSO EXTENDED THIS NOW
TO FURTHER YOU CAN SEE THE SAME
PATTERN YOU GO OUT 40 DAYS BLACK
LINES WILL CONTINUE, NOW
BECOMING MORE FLATTER AS THIS
SARS ANTIBODIES (INAUDIBLE) SO
LET ME CONCLUDE BY MAKING TWO
POINTS.
FIRST IS THAT THE INFECTION IS
ELICITING A VERY DURABLE
ANTIBODY RESPONSE TO SPIKE
PROTEINS.
AND IS REALLY NOT FLATTENED OUT
AND GIVING US HALF LIFE AS LONG
AS (INAUDIBLE) SO ONE OF THE BIG
QUESTIONS HERE IS WHAT -- THIS
IS ALREADY BEEN ADDRESSED BY
SOME OF THE SPEAKERS WHAT IS
DURABILITY AFTER INFECTION
VERSUS VACCINATION.
I THINK THIS WOULD BE A GREAT
TOPIC FOR DISCUSSION WHEN WE
HAVE SOME DISCUSSION TIME AND
THEN THE SECOND POINT IS THAT
THE RESPONSES TO THE ENDEMIC
CORONA VIRUS, STABLE OVER TIME,
INFECTIONS ACQUIRED OVER THE
GIVEN TITER AND THE QUESTION IS,
WHAT ABOUT PROTECTIVE IMMUNITY,
IS THERE SOME REINFECTION, THAT
PAPER IS DOCUMENTED (INAUDIBLE)
BUT HOW -- POPULATION TO LOOK AT
AND IS THERE SOME CLINICAL
INFECTION THAT BOOSTING A BIT IS
SOMETHING THAT COULD BE
HAPPENING BUT IN OUR COHORT, WE
DON'T SEE UPS AN DOWNS IN THE
ANTIBODY.
SO IF THERE IS REINFECTION AT
LEAST IN THIS COHORT BOOSTING
(INAUDIBLE) SO LET ME END HERE
ACTINOLENGING THE PEOPLE WHO DID
THIS WORK -- ACKNOWLEDGING THE
PEOPLE WHO DID THIS WORK.
SUSIE IN MY LAB LEADING TH LEADING THE
STUDIES IN THE LAB.
ASSAY, IN PARTICULAR (INAUDIBLE)
WHO DID THE -- WHO HEADED THE
CLINICAL COHORT, VACCINE CENTER,
(INAUDIBLE) AND SACKAL ANALYSIS.
GRATEFUL COLLABORATION
(INAUDIBLE).
I WANT TO ACKNOWLEDGE FUNDING
FROM NIH, NIAID AND IN
PARTICULAR THE WONDERFUL CCHI
SUPPLEMENTAL FUNDING.
THANK YOU VERY MUCH.
>> THANK YOU, RAFI.
THANKS SO MUCH.
YOU HAVE A QUESTION?
>> YES.
THANK YOU VERY MUCH, RAFI, FOR
THAT PRESENTATION.
SO IN YOUR OPINION, AND THERE
HAVE BEEN A FEW PUBLICATIONS, TO
WHAT EXTENT DOES THIS
PRE-EXISTING IMMUNITY AGAINST
MAYBE CROSS REACTIVE ENDEMIC
CORONA VIRUSES PROVIDE
PROTECTION SUCH THAT WE HAVE A
LARGER POPULATION REALLY THIS
MILDER TO MORE MILD MODERATE
INFECTION THAT WE SEE IS CAN BE
ATTRIBUTED TO THAT.
>> WE HAVEN'T INVESTED IN THE
DISCUSSION TIME, I WOULD PREFER
TO' ON THAT, WE LOOKED AT THIS
ISSUE MORE DETAIL.
IN TERMS OF HOW SOME (INAUDIBLE)
BUT MY MORE BROADER -- IN TERMS
OF ANTIBODY RESPONSE, TO THE
ENDEMIC CORONA VIRUS, I DON'T
THINK THEY ARE (INAUDIBLE) THAT
WOULD BE MY POSITION.
>> THANK YOU.
ROSS KEDL.
>> RAFI, WHEN YOU LOOK AT THAT
-- WE HAVE SEEN THE SAME THING
WITH OC 43, THAT THAT PARTICULAR
SEASONAL STRAIN HAS A BETTER
CROSS REACTIVITY, (INAUDIBLE)
HAD A PAPER A WHILE AGO LOOK AT
HOSPITALIZED INDIVIDUALS AND
PEOPLE WHO HAD A PRE-EXISTING 43
RESPONSE HAD LOWER SYMPTOMS AN
LESS RISK.
>> YES.
SOMEBODY WAS RECENTLY INFECTED,
HAD A MODERATE ANTIBODY OR WAS
IN THAT HAD VERY HIGH, THAT IS
POSSIBLE.
>> AND SHE TRACKED IT DOWN AND
WE HAVE SEEN THE SAME THING THE
S 2 DOMAIN SEEMS TO BE THE PART
THAT SHARED MORE CLOSELY WITH
SARS COV-2.
HAVE YOU BROKEN DOWN TO S 1, S
2?
>> WE HAVEN'T AND WE HAVE
UTILIZATION.
WE HAVEN'T LOOKED AT THOSE CROSS
REACTIVE ANTIBODIES WHETHER THEY
ARE NEUTRALIZED OR NOT.
THOSE QUESTIONS NEED TO BE
ADDRESSED.
>> I'M WONDERING, RAFI, HOW MANY
MORE YEARS YOU THINK OF SARS
COV-2 INFECTION TO GET THOSE
FLAT LINE ANTIBODY RESPONSES?
HOW MANY MORE EXPOSURES DO YOU
THINK WE NEED?
>> I'M GETTING BOOSTED NOW SO
YOU MAY NEVER GET AN ANSWER TO
THAT QUESTION BUT IT IS
FLATTENING OUT REALLY NICELY.
YOU ARE NOW GETTING HALF LIFE OF
1,000 LOOKING AT THE COHORT
(INAUDIBLE) WE HAVE A STUDY THAT
INFLUENZA VACCINE STUDY WHERE WE
STARTED WITH ADJUVANT -- WE HAVE
BEEN FOLLOWING OUT TO SIX YEARS,
AND THIS PARTICULAR STUDY EACH
ADJUVANT AT H 5N 1 SO NO
EXPOSURE TO H 5.
THERE WE ARE SEEING A FLATTENING
OUT ABOUT -- BETWEEN -- WE HAD
ONE YEAR SAMPLE AND FIVE YEAR.
WE DIDN'T HAVE -- WE HAD BETWEEN
-- BETWEEN FIVE AND SIX YEAR
FLATTENED OUT BEAUTIFULLY.
>> GOOD.
OKAY.
ALL RIGHT.
I GUESS WE'LL GO TO THE NEXT
SPEAKER.
MY TURN TO INTRODUCE.
>> JULIE WILL TELL YOU PRESENT
ON CELLULAR RESPONSES IN THE
SAME POOL.
JUDY, ALL YOURS.
>> OKAY.
THANK YOU.
-- JULIE.
THANK YOU.
>> THANK YOU.
OKAY.
I WOULD LIKE TO THANK THE
ORGANIZERS FOR INVITING ME TO
SPEAK TODAY.
AND LET ME MAKE SURE I'M
STARTING AT THE BEGINNING HERE.
SO I WANTED TO TALK TO YOU ABOUT
A SELECTED PART OF THE LAST TWO
YEARS.
OUR TIME WITH COVID, IT IS VERY
CLEAR EARLY ON THAT IF WE WERE
TO TRY TO UNDERSTAND ANYTHING
ABOUT THIS VIRUS WE NEEDED TO DO
THIS IN NATURAL HISTORY COHORT
WITH SARS COV-2 INFECTION.
THE IDEA WOULD BE TO TRY TO LOOK
AT THE LONG TERM IMMUNE
RESPONSES ASSOCIATED WITH
CONTROL OF COVID-19.
THEN TO BE ABLE TO IMPLY THOSE
INSIGHTS INTO TESTING VACCINE
CANDIDATES TO ACCELERATE VACCINE
DEVELOPMENT.
OBVIOUSLY WE KNOW AT THIS POINT
THAT THE NATURAL HISTORY OF THIS
INFECTION IS NOW QUITE
HETEROGENOUS THING AS PEOPLE ARE
GETTING VACCINATED AND THEY GET
REINFECTED, OR GET VACCINATED
THEN GET BREAK THROUGH
INFECTION.
BUT CLEARLY I THINK THAT BETWEEN
OUR COHORTS, IN ATLANTA, WITH
RAFI AND ONES HERE IN SEATTLE,
WE STILL HAVE A GROUP THAT IS
STABLE NOT GETTING VACCINATED
AND WE HOPE THAT OVER TIME WE
CAN CONTINUE TO FOLLOW THAT MORE
CLEAN GROUP IN A SENSE.
SO REALLY IN ORDER TO BE ABLE TO
IDENTIFY CELLULAR RESPONSES, IN
A WAY THAT WE COULD COMPARE ONE
VACCINE CANDIDATE WITH ANOTHER,
WITH NATURAL INFECTION WE
DEVELOPED A VALUE DATED ASSAY
USING ULTRA GRAM REVERSE
CYTOMETRY.
WE VALIDATED THE ABILITY TO BE
ABLE TO QUANTIFY TH 1 AND TH 2
CD4 T-CELLS RESPONSES AND CD8
T-CELLS RESPONSES.
THAT WERE ANTIGEN SPECIFIC.
AND IN ORDER TO DO THAT
VALIDATION, THERE ARE FIVE
PARAMETERS WE DO AS LISTED HERE,
I WILL BRIEFLY SHOW YOU A LITTLE
BIT ABOUT JUST PICK LINEARITY
AND SHOW YOU HOW IT PERFORMS.
WE HAVE ALSO LOOKED AT THE
SPECIFICITIES BY GENE EPITOPE
MAPPING IN NOW LOOKING MORE BY
VARIANTS OF CONCERN.
AS WELL AS MEMORY AND
MULTI-FUNCTIONAL PHENOTYPES.
IN ADDITION WE DEVELOPED
STANDARDIZE ASSAYS TO PROTECT
THE FREQUENCIES OF SPIKE AND ARE
REALLY SPECIFIC B CELLS THAT IGG
IGM OR IGA THAT ARE CIRCULATING.
SO THIS IS THE PANEL FOR FLOW
CYTOMETRY THAT WE HAVE USED AND
THOSE MARKERS THAT ARE
HIGHLIGHTED ARE THE ONES THAT WE
REALLY FOCUS THE VALIDATION ON.
THEN IN ADDITION WE HAVE OTHER
FUNCTIONAL MARKERS, THAT WE ARE
ABLE TO ADD TO THAT AND
CHARACTERIZING MORE
COMPREHENSIVELY THE CELL
FUNCTIONS.
JUST POINT OUT TO YOU, THESE ARE
EXVIVO ASSAY, THEY ARE NOT LONG
TERM STIMULATION, THEY ARE SHORT
TERM AROUND SIX HOURS.
WITH OVERLAPPING PEPTIDES
SPANNING THE SEQUENCE OF THE
GENE PRODUCT WE ARE LOOKING AT.
SO JUST TO SHOW YOU HERE EXAMPLE
OF THE LINEARITY OF THE RESPONSE
AS WE ARE VALIDATING IT, YOU CAN
SEE THESE TH 1 RESPONSES TO
GAMMA INTERFERON AND/OR IL 2 FOR
S 1 AND S 2 AND THE CD8 RESPONSE
FOR THE SAME S 1 AND S 2. THESE
ARE DIFFERENT DONORS BY CD4 OR
CD8.
THEN THESE ARE RESPONSES THAT WE
ARE SEEING FOR TH 2.
THOSE RESPONSES VERY LOW IN
NATURAL INFECTION SO IT WAS
DIFFICULT TO FIND PEOPLE THAT
HAD REALLY HAD THOSE RESPONSES,
WE ARE BEGINNING TO PICK UP SOME
IN THE VACCINE GROUPS.
BUT HERE WE ARE USING IL 4 AND
CD 154, CD 40 LIGAND AS WELL AS
IL 5 IL 13 CD 40 LIGAND.
SO THESE ARE RESPONSES THAT WE
NOW FEEL WE CAN RELIABLY DETECT
FOLLOWING THE VALIDATION
PROCEDURES.
SO NOW TURNING TO THE COHORT,
REALLY VALUE OF BEING ABLE TO
COMBINE COHORTS HERE AT THE
HUTCH, THEY ARE FAIRLY SIMILAR
IN TERMS OF THE AGE GROUPS
MEDIAN AGE 45 YEARS, A LITTLE
BIT MORE FEMALE THAN MALE.
PREDOMINANTLY WHITE, 75% AND
THEN THEREAFTER SMALLER
PERCENTAGES OF OTHER RACE OR
ETHNIC GROUPS.
AS RAFI INDICATED THESE ARE
PRIMARILY MILD TO MODERATE
INFECTIONS.
THERE WERE A FEW THAT OVER TIME
WERE CATEGORIZED AS SEVERE.
AND THERE ARE A FEW THAT WE ARE
STILL CATCHING UP ON TO KNOW
EXACTLY HOW THEY ARE CLASSIFIED
OVER TIME.
I WILL NOTE THAT WE DO HAVE SOME
LONG HAULERS IN THIS GROUP THAT
WE ALSO HAVE BEEN ABLE TO FOLLOW
THIS -- IN THESE COHORT
LONGITUDINALLY.
IT IS RUNNING AT ABOUT 32% BY
STRICT DEFINITION.
SO HERE I WILL SHOW YOU
POLYFUNCTIONAL MEMORY CD4
T-CELLS, CD8 CELLS AND SPIKE
SPECIFIC A B CELLS.
JUST TO REMARK AFTER STUDYING
THESE OVER EIGHT MONTHS WE CAN
TELL YOU THEY ARE DURABLE.
AND THE HALF LIVES ARE SHOWN
HERE AROUND 200 DAYS BOTH CD4
AND CD8 T-CELLS AND FOR THE
MEMORY CELLS WE HAVEN'T SEEN
MUCH K OVER THE EIGHT MONTH
PERIOD, THEY ARE SLIGHTLY
BEGINNING -- THEY HAVE PLATEAUED
NOW AND FURTHER EVALUATION IS
ONGOING.
SO FOR THE CD4 RESPONSES USING
SIMILAR LONGITUDINAL PANELS AS
YOU SAW FROM RAFI, JUST NOTE THE
PROGRESSION OF THAT OVER TIME.
I THINK THE KEY THING TO NOTE IN
ALL THESE GRAPHSNA YOU WILL SEE
IS THAT CLEARLY ARE SOME
INDIVIDUAL WHOSE ARE NOT
RESPONSIBILITYING WELL OR THAT
THOSE RESPONSES -- RESPONDING
WELL OR THOSE RESPONSES GO AWAY.
HOWEVER THE MAJORITY ARE
RESISTANT AND THEY TEND TO PEAK
AROUND 30 DAYS.
WHAT IS IMPORTANT HERE ARE THE
TERMINATION'S OF SPECIFICITIES
OF THE RESPONSE FOR THE CD4
T-CELLS WE SAW THAT REALLY THERE
WAS PRETTY MUCH EQUAL TARGETING
ACROSS THE PROTEOME IN THESE ARE
JUST EXAMPLES THAT WE HAVE HERE
AS SHOWN FOR SPIKE ENVELOPE.
AND THE OTHER ONE SO THEY ALL
THE WAY ACROSS FAIRLY SIMILAR.
IN TERMS OF FREQUENCIES OF
RESPONSES AS WELL AS RESPONSE
RATES. WE LOOKED AT THE
POLYFUNCTIONALTY OF THESE
RESPONSES USING THE MARKERS THAT
WERE IN ADDITION TO ONES I
DESCRIBED SO HERE THE ONES THAT
WERE REALLY CONTRIBUTING TO THE
MOST POSITIVE SUB POPULATIONS
ARE SHOWN HERE GAMMA INTERFERON,
IL 2 TNF ALPHA AND WITH CD 40
LIGAND IN GRANZYME B.
WE DIDN'T REALLY SEE PERFORIN
EXPRESSION WELL IN THIS GROUP BY
THIS TYPE OF ANALYSIS, BUT YOU
CAN SEE THAT DOMINANT
POPULATIONS ARE THOSE THAT
EXPRESS GAMMA IL 2 TNF ALPHA AND
CD 40 LIGAND.
THEN WE LOOK AT THESE BY U MAP
WITH US AND I THINK JUST TO
HIGHLIGHT THAT REALLY WE AREN'T
SEEING THE TH 2 RESPONSES IN
THIS GROUP AT ALL.
AND IT IS PREDOMINANTLY THE TH 1
RESPONSES.
THERE'S SOME OTHER INTERESTING
THINGS HERE WITH MORE TIME I
WILL GET TYPE THAT.
NOW FOR THE CD8 RESPONSE AGAIN A
SIMILAR K KINETICS OF PEAK
AROUND 30 DAYS AND THEN OTHER
FREQUENCIES TEND NOT TO BE AS
HIGH AS WHAT WE SAW WITH CD4
RESPONSES AND AGAIN CLEARLY
THERE ARE SOME THAT ARE NOT
RESPONDING OR THAT DROP OFF
EARLY.
IN TERMS OF SPECIFICITIES REAL
DIFFERENT PICTURE HERE, FOR
EPITOPE SPECIFICITY, HERE WE
PREDOMINANTLY SAW NUCLEAR CAPSID
RESPONSE IN THESE EXVIVO
STIMULATED CELLS, AND THIS TO ME
IS A REMARKABLE DIFFERENCE THAN
WHAT WE ARE SEEING IN THE CD4
RESPONSES.
WE WILL COME BACK TO THIS A BIT
LATER.
POLYFUNCTIONAL RESPONSES PICKING
UP PERFORIN IN THESE GROUPS
FAIRLY RELIABLY BUT THE
PREDOMINANT CYTOKINES ARE GAMMA
INTERFERON AND TNF ALPHA.
SO THE EVOLUTION OF THIS
RESPONSE LOOKING AT
MISDEMEANORRY RESPONSE, THE CD4
RESPONSE IS VERY RELIABLY
PREDOMINANTLY SIMPLE MEMORY
CELLS, EFFECTOR MEMORIES AND
VERY LOW RESPONSE BY CONTRAST
THE CD8 T-CELLS ARE
PREDOMINANTLY EFFECTOR CELLS,
MEMORY OR TUMOR RESPONSES YOU
CAN SEE HOW THEY BEGIN TO
INTERSECT OVER TIME.
WITH THE FAIRLY STABLE BUT LOWER
CENTRAL MEMORY POPULATION.
MOVING TO THE MEMORY B CELL
RESPONSES AS I EXPLAINED
EARLIER, REALLY DID NOT SEE A
DECAY OVER THIS 200 -- OF THE
250 DAYS, AS SHOWN HERE.
AND THESE DID PEAK 30 DAYS OR
GREATER IN THIS POPULATION.
OBVIOUSLY THE PREDOMINANT
RESPONSE AFTER THE FIRST MONTHS
IS IGG SHOWN HERE DROP OFF OF
IGM AND IGA.
TO SUMMARIZE IN CARTOON WE ARE
SEEING THE DROP OFF OR IGM B
CELLS PEAKING EARLY IN INFECTION
BUT THERE IS SUSTAINED IGG B
CELL RESPONSE, THIS IS TO BOTH
DETECTION OF THE SPIKE SPECIFIC
RESPONSES AS WELL AS RBD
SPECIFIC RESPONSES.
CD4 T-CELL FREAK SHIES ARE
HIGHER THAN THE CD8 T-CELL
FREQUENCY BUT THEY BOTH PEAK
AROUND DAY 30 AND PERSIST BUT
CONTINUE TO DECAY AFTER OUT TO A
YEAR.
WE HAVE HAD AS MANY OF YOU HAVE
ALREADY DISCUSSED, INDIVIDUALS
WHO NOW ACQUIRE SARS COV-2
INFECTION WHO WERE PREVIOUSLY
VACCINATED AND SO CALL IT BREAK
THROUGH INFECTION.
SO WE HAD OPPORTUNITY TO LOOK AT
38 OF THOSE THAT RECEIVED TWO
DOSE mRNA VACCINE, MOST WERE
PFIZER VACCINES AND SOME
MODERNA.
WHAT WE WERE INTERESTED IS HOW
DO THESE T-CELL RESPONSES DIFFER
IN QUALITY AND QUANTITY.
SO LOOKING AT THE CD4 T-CELL
RESPONSES, WE ARE LABELING
UNVACCINATED COHORT WE HAVE
DESCRIBEDDED THAT IS NOT
RECEIVED ANY VACCINE JUST
EXPOSED BY NATURAL INFECTION IN
CONTRAST TO BREAK THROUGH
INFECTION THAT'S RECEIVE TWO
DOSE OF mRNA VACCINE FOLLOWED
BY BREAK THROUGH INFECTION.
SO LET'S START WITH CD4, THESE
ARE TH 1 TYPE RESPONSE AGAINST
SPIKE.
OR AGAINST NON-SPIKE ANTIGENS
AND IT IS OBVIOUS AS YOU CAN
IMAGINE IN CONSISTENT FINDING IS
THAT THE SPIKE RESPONSES COME UP
VERY FAST CERTAINLY MUCH FASTER
THAN WHAT WE SEE IN NATURAL
INFECTION.
THEY ARE PERSISTING OUT TO 61
DAY, WE HAVEN'T SEEN QUITE AS
MANY PEOPLE AFTER 61 DAYS BUT
YOU CAN SEE THEY ARE QUITE
RESISTANT --ER PERSISTENT AND
HIGHER FREQUENCY THAN WHAT WE
SEE IN NATURAL INFECTION.
BY CONTRAST, THE NON-SPIKE
ANTIGENS WHICH AS YOU KNOW,
THESE ARE NOT IN THE VACCINES
THEY ARE RECEIVING, LOOK PAIRLY
SIMILAR BETWEEN TWO GROUPS AS
YOU SEE OVER TIME.
IF ANYTHING THOSE WITH THE
NATURAL INFECTION ARE SOMEWHAT
HIGHER.
SO LOOK AT THE CD8 RESPONSES
AGAIN IN THESE SAME TWO GROUPS.
STARTING WITH A SPIKE RESPONSE,
I THINK THAT THE THINGS YOU WILL
SEE HERE ARE OBVIOUSLY THE CD8
RESPONSES RECOGNIZING THE SPIKE
ANTIGENS ARE DEFINITELY HIGHER.
IN THE BREAK THROUGHS THAN THEY
ARE IN THOSE WITH NATURAL
INFECTION WITHOUT VACCINATION.
LIKE WE SAW THE CD4 RESPONSES
THEY ARE PERSISTING BUT
SITUATION IS DIFFERENT WITH THE
NON-SPIKE ANTIGENS OBVIOUSLY WE
ARE NOT -- WE ARE SEEING A
DELAYED RISE OF RESPONSES IN
BREAK THROUGH INFECTIONS.
AND ALSO POTENTIALLY SOME
INDICATION THAT THOSE MAY BE
LESS DURABLE IN THIS GROUP IN
CONTRAST TO WHAT WE SEE WITH
THOSE THAT FIRST WERE EXPOSED TO
SARS COV-2 BY NATURAL INFECTION.
SO THE KINETICS OF THIS OVER
TIME WILL BE REALLY IMPORTANT,
THAT SOMETHING WE PLAN TO DO
WITH BOTH ATLANTA AND -- COHORT.
JUST IN SUMMARY, CLEARLY A
PERSISTENT IMMUNOVIRAL MEMORY
RESPONSE IS INDUCED IN MILD
MODERATE COVID-19.
WE SEE CONTINUED RISE AND
PLATEAU DESPITE MEMORY B CELLS,
SLOW DECAY, CD8 T-CELLS BUT
DISTINCT FEATURES AMONG THEM
BROADER SPECIFICITIES AMONG CD4
T-CELLS AND MORE DOMINANT WITH
CAPSID RESPONSE IN CD8 T-CELLS.
THERE SHALL DISTINCT MEMORY SUB
POPULATIONS OVER TIME.
THE MARKED HETEROGENEITY OF
THESE RESPONSES IS VERY
IMPORTANT AND QUITE EASY TO SEE
LOOKING AT FREQUENCY AND
MAGNITUDE OF THE RESPONSE.
NOTABLY THERE ARE SOME
PERSISTENT NON-RESPONDERS.
IN OUR GROUP.
DESPITE MEMORY IMMUNE RESPONSES
ABOUT 30% SHOWING SYMPTOMS
CONSISTENT WITH TASK AFTER 60
DAYS.
OUR PRELIMINARY FINDINGS
COMPARING THE BREAK THROUGH
INFECTION WITH THE NATURAL
INFECTION IN THE UNVACCINATED
INDICATE THAT POTENTIALLY THE
KINETICS THE MAGNITUDE AND
DURABILITY OF THESE RESPONSES BE
DIFFERENT.
SO THAT IS SOMETHING THAT WE
PLAN TO LOOK AT MORE CAREFULLY
OVER TIME.
JUST LIKE TO ACKNOWLEDGE MY
GROUP HERE AT THE HUTCH AS WELL
AS REALLY THE NICE COLLABORATION
WE ARE HAVING WITH RAFI AND HIS
GROUP AS WELL AS OUR FUNDERS AT
PARTICULARLY TO DATE WHO HAS
BEEN SUPPORTIVE OF COHORT OF THE
STUDY AS WELL AS OTHER NIAID
DIVISION OF AIDS AND DMID WHO
FUND OUR VACCINE WORK.
SO I WILL STOP THERE.
>> THANK YOU.
QUESTIONS FOR JUDY PLEASE RAISE
YOUR HAND.
>> GO AHEAD.
WILL YOU THEN TO SHANE.
>> I HAVE A QUICK ONE.
KEY HOE'S GROUP EARLY IN THE
PANDEMIC REPORTED PRETTY HIGH TH
2 USE EXTRA FOLLICULAR RESPONSE
MANY IN SUBGROUP OF INFECTED
PEOPLE.
NOW, I DON'T -- MORE SEVERE
PATIENTS IN YOUR CASE IS MORE
MILD TO MODERATE.
COULD YOU COMMENT ONNA?
YOU DON'T SEEM TO SEE THE TH 2
RESPONSE.
>> I THINK IT IS IF WE WERE
GOING TO SEE THEM WE ARE NOT
PICKING THEM UP EARLY IN
INFECTION AND THROUGH THE
DURATION OF THAT WE HAVE LOOKED
AND I THINK IF ANYTHING IT MAY
BE RELATED TO SEVERITY OF
INFECTION.
BUT WE ARE JUST NOT SEEING IT.
WE ARE BEGINNING TO PICK SOME OF
THAT UP WITH THE VACCINES.
SO WE KNOW WE CAN DETECT THEM
BUT THEY JUST WEREN'T THERE.
>> THANK YOU.
>> WE DON'T REALLY SEE ANY TH
2s EITHER.
I BELIEVE THE DATA YOU ARE
REFERRING TO WAS POLYCLONAL
STIMULATION OF T-CELL.
NOT ACTUALLY SARS COV-2 PEPTIDES
AND I THINK A NUMBER OF PEOPLE
HAVE BEEN CONFUSED ABOUT THAT
TYPE OF DATA BUT I BELIEVE -- WE
LOOKED AT THESE DATA CLOSELY AND
JULIE'S LAB, OUR LAB, MARION'S
LAB AND SEVERAL OTHERS, SEE
MINIMAL ANTIGEN SPECIFIC TH 2s
OR TH 17.
BY SEVERAL DIFFERENT TYPES OF
ICS OR SECRETION ASSAYS.
IN THE CONTEXT OF NATURAL
INFECTION.
(OVERLAPPING SPEAKERS) BUT THE
QUESTION FOR JULIE WOULD BE IT
IS ABSOLUTELY BEAUTIFUL DATA AND
I MEAN YOUR EXTENSIVE VALIDATION
OF ASSAYS IS SO IMPRESSIVE.
OBVIOUSLY T-CELL HAS COMPLICATED
BECAUSE THERE IS A NUMBER OF
WAYS TO DO IT SO I HAVE HAD A
NUMBER OF PEOPLE RAISE TO ME THE
QUESTION IF T-CELL CAN'T MAKE
CYTOKINES IN SIX HOURS BUT IS
STILL ANTIGEN SPECIFIC, YOU MISS
IT, IS IT WORTH PAYING ATTENTION
TO.
AND I HAVE HAD PEOPLE ARGUE EVEN
FOR CD8, IF THEY HAVE MEMORY
CELLS THAT DON'T MAKE CYTOKINES
GROW FAST BUT THEY WOULD OVER
NIGHT OR PROLIFERATE, THEY WOULD
STILL BE WORTH COUNTING, HOW DO
YOU GUYS THINK ABOUT THAT FACTOR
T-CELL COMPLEXITY BECAUSE
OBVIOUSLY YOU GUYS ARE GREAT AT
THIS TYPE OF STUFF.
>> I THINK WE LOOKED AT THAT IN
THE PAST.
I THINK THAT THE KEY ISSUE FOR
US IS TO -- IF WE STIMULATE FOR
LONGER PERIODS OF TIME WHICH IS
STRAIGHT FORWARD TO DO AND
HONESTLY THE PEEP MILLION THE
LAB PREFER TO DO THAT SHORTER.
-- PEOPLE IN THE LAB PREFER TO
DO THAT.
BUT WE JUST DON'T GET THE DEPTH
OF -- WE TEND TO SEE MORE FALSE
POSITIVES IN THAT CASE.
AND IN OUR HANDS THESE CYTOKINE
MARKERS HAVE WELL CORRELATED
WITH PROLIFERATION WHEN WE
LOOKED AT THAT IN THE SAME
DONORS SO I'M NOT REALLY TOO
CONCERNED ABOUT THAT.
I KNOW IT COULD BE AN ISSUE.
WE ALSO ARE SEEING PERFORIN IN
THE CD8 T-CELLS.
I THINK THAT ONE MIGHT ARGUE
THAT THOSE ARE ONES THAT MIGHT
BE CAPABLE OF DOING MORE ANTS
VIRAL ACTIVITIES.
IT IS A WAY TO QUANTITATE
RESPONSE, IT IS A WAY WHEN WE
LOOK AT TETRAMERS WE SEE GOOD
CORRELATION SO I DON'T KNOW HOW
ELSE TO --
>> QUICK QUESTION AND QUICK --
>> MAYBE THIS IS -- YOU CAN --
IF THIS IS WORTHWHILE ANSWERING
MAYBE THE GROUP CAN ANSWER IT
LATER: IT WAS A QUESTION OF IS
THERE BEEN MUCH EFFORT TO
COMPARE WHAT YOU SEE IN BLOOD IN
VACCINATION OR INFECTION WITH
WHAT YOU SEE IN THE TISSUE?
LUNG FOR EXAMPLE.
>> GREAT QUESTION.
WE ADDRESSED AT LEAST TO SOME
EXTENT BY DONNA.
AND LET'S LEAVE THAT FOR
DISCUSSION.
THE NEXT SPEAKER IS ROSS KEDL
FROM (INAUDIBLE) ROSS WILL TELL
US ABOUT ADJUVANT T-CELL
(INAUDIBLE).
ROSS.
>> CAN YOU GUYS HEAR ME?
>> YES.
>> IT IS AN INTERESTING QUESTION
FROM SHANE, THE IDEA OF
SELF-RENEWING POTENTIAL IS SUCH
A DIFFERENT -- THE CELLS THAT
MAKE THE MOST CYTOKINE TEND TO
BE THE ONES THAT ARE LESS -- AT
LEAST SELF-RENEWING.
AS PERTAINS TO THERAPEUTIC
T-CELL RESPONSES WHICH IS WHAT
I'M GOING TO TRY TO FOCUS ON
HERE.
THE ANSWERS TEND TO BE SORT OF
OPPOSITE OF THE BEST CELLS ARE
ONES OFTEN CYTOKINE RIGHT AWAY.
FIRST THANKS FOR THE OPPORTUNITY
TO PRESENT HERE.
THIS IS A GREAT GROUP OF PEOPLE
OF SPEAKERS TO BE INCLUDED IN
OUR -- AS I MENTION I'M GOING TO
EMPHASIZE THE IDEA OF ADJUVANT
ELICITED RESPONSES THAT ARE
TARGET TARGETING SPECIFICALLY
TRYING TO GENERATE AS LARGE
T-CELL RESPONSE AS POSSIBLE FOR
THE PURPOSES OF THERAPEUTIC
INTERVENTION.
WE HEARD ROBUST T-CELL RESPONSES
GENERATED BY VACCINES FOR SARS
COVID 2 AND HOW EFFICACIOUS AT
PREVENTING SIGNIFICANT DISEASE.
THE LEVEL OF THERAPEUTIC
INTERVENTION IN CHRONIC
INFECTIOUS SETTING OR CANCER
SETTING IS -- I'M GOING TO ARGUE
IS A SLIGHTLY DIFFERENT BAR.
SO THAT IS QUESTION I WILL BE
ADDRESSING HERE.
BEFORE I GET GOING, MOST OF YOU
HAVE IF YOU DON'T, MARKSATT PASS
AID WAY AFTER THANKSGIVING THIS
LAST YEAR HIS CONTRIBUTIONS TO
T-CELL BIOLOGY WILL BE KNOWN TO
EVERYBODY FROM MHC PRESENTATION
TO CO-STIMULATION, AND MODEL.
HE WAS SIGNIFICANT IN MY LIFE
BECAUSE HE WAS MY GRADUATE
SCHOOL MENTOR AND I INHERITED
THE QUITE OBSESSION HOW TO
GENERATE LARGE T-CELL RESPONSE
AS YOU CAN.
AND BESIDES THAT, I CAN ONLY TO
HAVE INHERITED SOME DEGREE OF
HIS PATIENTS OVER THE YEARS.
HE WILL BE MISSED BUT HIS
THOUGHTS ARE ABSOLUTELY DEEPLY
EMBEDDED IN EVERYTHING I HAVE
BEEN THINKING ABOUT, IN MY WORK.
ONE THING MATT ALWAYS SAID,
ALWAYS TOLD ME IS IN GIVING A
PRESENTATION YOU FIRST TELL
PEOPLE WHAT YOU ARE GOING TO
TELL THEM, THEN YOU TELL THEM
WHAT YOU TOLD THEM.
SO IN HONOR OF HIM I WILL START
THAT WAY.
HERE ARE THE QUESTIONS I HOPE TO
I DRESS AND IN BLUE ARE ANSWERS,
WE CAN SHORT CIRCUIT THE WHOLE
THING, IF WE WANT TO STOP HERE
AND SEE IF WE HAD DEBATE BUT
I'LL PROCEED WITH WALKING MY WAY
THROUGH THIS ONE.
THE FIRST QUESTION I THINK IS
REASONABLE TO ASK, WHAT IS THE
WHAT NUMBER DO WE THINK WE CAN
GENERATE BY VACCINATION.
MOST AGREE (INAUDIBLE) VACCINE
IS REASONABLE STANDARD THAT IS
NOT ADJUVANTED VACCINE IT IS A
LIVE INFECTIOUS VACCINE BUT IT
REASONABLY REPRESENTS MOST
PEOPLE'S IDEA OF ONE OF THE BEST
VACCINES OUTSIDE OF SMALLPOX.
HERE IS DATA TRAUMA RAFI'S LAB A
NUMBER OF YEARS AGO WE LOOK AT
SINGLE EPITOPE BUT WE ARE
GETTING IN FREQUENCIES AS VIRUS
RISES AND FALLS, I DON'T KNOW IF
YOU CAN SEE MY POINTER HERE.
AS VIRUS RISES AND FALLS GETTING
T-CELL FREQUENCY IN 5 TO 10%
RANGE, THAT IS INFLUENCE BY
DEGREE WHICH VIRUSES IS DIVIDING
AND MORE VIRUS MORE VIRAL LOAD
YOU HAVE HIGHER T-CELL RESPONSE
YOU GET BUT IF YOU HAVE BACK
VACCINATION HOW MUCH THERE ARE
PER LITTER AS WELL AS HOW MUCH
LITTER OF BLOOD WE HAVE IN
FREQUENCY OF CD8 T-CELL.
5 TO 10% ANTIGEN T-CELL IN THE
BLOOD TOTALS ENTER AROUND 100 TO
300 MILLION CELLS.
THAT IS A REALLY ROBUST
RESPONSE.
AND IT IS CLEARLY UNDERESTIMATE,
WE ARE ONLY LOOKING AT SINGLE
EPITOPE AND I LEARNED ANYTHING
FROM ALEX SETTI, THE EPITOPE
DOMINANCE IN HUMANS IS VERY
DIFFERENT THAN MICE. SO
MULTIPLE EPITOPES ACHIEVE THIS
BUT WE CAN PUT MAYBE AS A GOAL,
AS A REASONABLE GOAL FOR THE
SYSTEM CAN CLEARLY SUSTAIN
HUNDREDS OF MILLIONS OF CELLS
VACCINATED POST -- SO WITHIN 10
TO 14 DAYS AFTER VACCINATION.
THEN IT IS REASONABLE TO ASK HOW
MANY DO WE NEED TO MAKE.
WE CAN SPEND TIME ON THIS AND I
JUST WANT TO SHOOT THROUGH IT,
THERE IS DEBATABLE ELEMENTS BUT
SAM SILVERSTEIN HAD A PAPER
WHILE AGO WHERE HE EMPHASIZED
THE FACT THAT THE DEMANDS ON
THERAPEUTIC EFFICACY FOR T-CELL
GENERATION IS CONSIDERABLY
HIGHER THAN WHAT WE USED TO
THINK FOR PURPOSES OF PROTECTING
AGAINST ACUTE INFECTION.
I THINK HIS CALCULATIONS IN THIS
10 TO 7 T-CELLS CENTIMETERS
CUBED ARE REASONABLY BORN OUT
WITH SOME CLINICAL EVIDENCE ON
REQUISITION DOWN HERE AS WELL AS
IN CHECK POINT THERAPY, WHEN
SUCCESSFUL YOU CAN EVALUATE
TUMOR THAT'S BEEN INFILL STRAIT
TRAITED DEGREE IT IS
INFILTRATED, THE NUMBERS
REASONABLY FERRET THEMSELVES
OUT.
WHEREAS THERE IS DEBATE YOU CAN
CALCULATE WHAT THAT FREQUENCY IS
IN TERMS OF CELL TO BLOOD, CHAI
CHANGES WHEN WE LOOK AT TISSUE,
AS MIKE WAS BRINGING UP, THAT IS
A REALLY CENTRAL QUESTION THIS
WHOLE PROCESS OF TISSUE
CONCENTRATION IN CELLS THAT,
CEASE THE ACTIVE SITE WHERE
CELLS NEED TO END UP.
HOWEVER YOU CHOOSE TO LOOK IT IS
REASONABLE FOR THERAPEUTIC
EFFICACY IN THE TENS OF MILLIONS
IS WHAT WE NEED TO GET.
MAYBE OFF A FEW FOLD BUT NOT OFF
ORDER OF MAGNITUDE.
SO THAT TO ME IS INARGUABLY
HIGHER.
ONE WAY WE KNOW THIS IS WE HAD
YET TO PRODUCE THERAPEUTIC
VACCINE WE HAVE SEEN FREQUENCY
OF T-CELLS VACCINES ARE
GENERATING.
SARS COV-2 AND REASONABLE TO ASK
DO WE HAVE OTHER VACCINES
GENERATE BETTER FREQUENCIES.
SOME OF THE DATA YOU HAVE SEEN
DESCRIBED PREVIOUSLY BY SPEAKERS
IS LISTED HERE.
AND I ORIGINALLY HAD SLIDES WITH
ALL THE DATA WALK THROUGH BUT
INTERESTING THAT OBVIOUSLY
DOESN'T WORK WHAT IS INTERESTING
IS IT IS AMENABLE TO ATTAIN
BECAUSE EVERYBODY REASONABLY
COMES ONE THE SAME ANSWER.
WHEN YOU LOOK AT ADJUVANT E LEE
SITED T-CELL RESPONSES YOU GED
CD4 T-CELLS AUTO THE OTHER END
AND 1.1% OF CD8 T-CELLS.
AT LARGE.
THERE ARE OTHER PEOPLE THAT I
APOLOGIZE IF I LEFT OFF, I TRIED
TO SKEW TOWARDS SPEAKERS IN THIS
FOR OBVIOUS REASONS SPEAKERS IN
THE SESSION.
BUT EVERYBODY IS REASONABLY
GETTING THE SAME ANSWER AND SOME
FEEDBACK IF ANYBODY THINKS THAT
IS DIFFERENT.
THERE IS AN INTERESTING ELEMENT
TO MIKE'S QUESTION.
ABOUT FREQUENCY OF CELLS ONCE
YOU GETS INTO TISSUES AND AWAY
FROM PERIPHERAL BLOOD, BOUGH BOB
HAS WORK, IT IS WORTH NOTING
THIS IS HUMAN OR NON-HUMAN
PRIMATE, NONE OF THIS HERE IS
MOUSE.
IN A DIRECTION MORE APPROPRIATE.
BOB'S WORK LOOKING IN NON-HUMAN
PRY MATES HAVE SEEN IF YOU LOOK
IN THE LUNG THE LUNG IS REALLY
SENSITIVE PLACE TO FIND ANTIGEN
SPECIFIC T-CELLS SO WHEN YOU ASK
THE SUCCESS OF ADJUVANT TO
ELICIT T-CELL RESPONSES YOU MAY
STOP T-CELLS IN THE BLOOD BUT
TISSUE YOU FIND SIGNIFICANTLY ON
CAN SEN TRAITING THERE AND BEING
A USEFUL WAY OF GAUGING THE
USEFULNESS OF VACCINE.
THESE NUMBERS LOWER THAN TOTAL
IN THE BLOOD BUT THE OVER ALL
FOCUS CONCENTRATION COULD HAVE
SIGNIFICANT IMPACT AND SO
WHEREAS TISSUE EVALUATION OF
THOSE T-CELLS MAY OFFSET
DEFICIENCY IN GENERATING
ADJUVANTS T-CELLS, I WOULD SAY
WE ARE AT LEAST 100 FOLD OFF IN
HOW WELL ADJUVANTS ARE MAKING
T-CELL RESPONSES, TO THE GOAL WE
NEED THE ACHIEVE.
THIS IS PARTICULARLY CONFUSING
TO ME AND HAS BEEN FOR MANY
YEARS WHEN YOU TAKE A LOOK AT
THE DEGREE OF INNATE IMMUNITY
ADJUVANTS SEEM TO GENERATE.
T SO THIS IS SOME DATA FROM
BALI'S LAB TAKEN FROM ANY OF US
LOOKING AT APC SUB SETS AT
DIFFERENT ADJUVANT
ADMINISTRATIONS AND WHOLE HOST
OF ANTIGENS OF CO-STIMULATORY
MARKERS AND CYTOKINES AND
MIGRATION OF DCs AND INNATE
PATHWAY STIMULATED, ET CETERA.
ET CETERA.
AND GIVEN ALL THIS ROBUST INNATE
ACTIVATION VERY CLEARLY MONITOR
TERRIBLE AND MEASURABLE WITHIN
PRIMATES AND HUMANS IT IS
BAFFLING WHY GIVEN THAT
MAGNITUDE OF AGGREGATION WHY WE
HAVE REASONABLE -- I WOULD SAY
POOR T-CELL RESPONSES COMPARED
TO HOW MUCH INNATE IMMUNITY
SEEMS TO BE HAVE BEEN ACTIVE.
AND TO SOME EXTENT THAT'S
REINFORCED INFLAMMATION BEGETS
INFLAMMATION.
IT IS A RARE INFLAMMATION THAT
SUCCESSFULLY TRANSITIONS TO A
SUCCESSFUL ADAPTIVE IMMUNE
RESPONSE FOR T-CELLS PURPOSES SO
WE HAVE SPENT TIME CAMPING AT
THAT AND ASKING THE QUESTION
WHAT IS THE DIFFERENCE BETWEEN
INFLAMMATION THAT TRANSITIONS
EFFECTIVELY AND THE KIND THAT
DOESN'T AND THEY HAVE DONE SO
FROM PERSPECTIVE OF T-CELL
RESPONSE BECAUSE THOSE RULES ARE
DIFFERENT IF YOU ASK HOW WELL B
CELLS AND WELL T-CELLS, THE
ADJUVANT EVALUATION HAS BEEN
GEARED ALMOST EXCLUSIVELY I
WOULD SAY TOWARDS THE QUESTION
HOW GOOD WAS THE NEUTRALIZING
ANTIBODY RESPONSE OVERALL
ANTIBODY RESPONSE.
AS IT TURNS OUT ADJUVANTS THAT
MAKE GOOD ANTIBODY RESPONSES ARE
NOT NECESSARILY IN FORMULATION
ARE NOT NECESSARILY THE SAME
MADE GOOD T-CELL RESPONSE, WHAT
IS GOOD FOR THE GOOSE NOT GOOD
FOR GRANDER SO THE CATEGORY OF
DIFFERENCES THINKING OF BETTER
T-CELL RESPONSES FROM ADJUVANTS
THE FIRST IS STRUCTURAL.
IN CERTAIN TERMS FORMULATION
ADMINISTRATION OF VACCINE AND
THE SECOND IS MORE BIOLOGICAL
MECHANISTICALLY SPEAKING.
SO THE FIRST IS DIFFERENCE IN
FORMULATION OF ADJUVANT, IS
OBVIOUSLY ORIGIN OF ADJUVANT ARE
MORE DEEP ORIENTED OR PRETIP AT
A TIME ORIENT AND MAKE GOOD
ANTIBODY RESPONSE, SLOW LEAK
ANTIGEN FROM SITE IS IN CHAINS
DATA LOOKING AT THE MANY PUMPS
THAT LEAK ANTIGEN MONTH AND A
HALF OR SOMETHING CRAZY AND
ROBUSTNESS OF ANTIBODY RESPONSE,
IS UNBELIEVABLE THAT IS NOT A
GOOD THING FOR T-CELLS, THE GOOD
WAY TO DEMONSTRATE IS LOOKING AT
ADJUVANT HERE, OF COMBINED
ADJUVANT ADMINISTRATION, REALLY
ROBUST CD8 RESPONSE, REALLY HIGH
PERCENTAGE WITH BLOOD, BACK TO
MICE FOR MECHANISTIC STUDIES.
ALL I HAVE TO DO TO TANK THAT IS
-- MIMIC.
IF I MAKE EPIMISSION I CAN
DESTROY GENERATING POTENTIAL AND
-- DID A GOOD JOB CLARIFYING
EXACTLY WHAT IT IS ABOUT THAT
EPIMUDGES, AS WELL AS LEE RYAN
HARD IN TH 1 CELLS IN MARK
JENKINS LAB IN THAT T-CELL JOB
IS TO GOEN TO PERIPHERAL TISSUE
SEEK OUT SITES OF ANTIGEN AND
DESTROY AND IF YOU CREATE AN
ANTIGEN DEPOT USING EPIMUDGES,
THE ANTIBODIES ARE TURN, THE
T-CELLS WILL ACCESS THAT VACCINE
SITE, EVEN IF IT IS GIVEN TUMOR
YOU RATHER GO TO AND SPEND ALL
THEIR TIME ATTEMPTTOLOGY DESTROY
AND (INAUDIBLE) IF YOU STAIN
LEAD TO DO THAT, VACCINATION,
YOU CAN RECONCENTRATE CELLS AT
THAT INDIVIDUAL SITE.
SO THAT FORMULATION IS REALLY
DETERMINANT AND THESE ARE ALL
OVER SPECIFIC STUDIES SO THE
ANTIGEN IS THE BEST KNOWN TO
HUMAN KIND, I CAN DESTROY BY
MAKING THE DURABILITY OF THE
RESPONSE BY MAKING DEPOT OUT OF
IT.
SO THAT IS FORMULATION QUESTION.
BUT IN ADDITIONAL WAY OF GETTING
AT THE SAME PROBLEM, IS EVEN IF
I FORMULATE THE SAME IF I ADD
EXTRA INFLAMMATORY COMPONENTS I
CAN PUSH THAT SYSTEM A LITTLE
TOO FAR AND OUT OF REALM OF
DURABLE SELF-SUSTAIN T-CELL
RESPONSE SO IN THIS CASE TAKE
YOUR COMBINED AG VERDICT WHICH
GENERATES ROBUST MEMORY POOL,
AND PHENOTYPE CELLS, IF I ADD
CPG WHICH NUMBER OF US PLAYED IN
CPG AS WAY OF AUGMENTING
INFLAMMATORY RESPONSE FROM
(INAUDIBLE).
WHEN I DO THAT I GENERATE A
TREMENDOUS NUMBER OF EFFECTORS
WHICH SEEMS LIKE A GOOD IDEA, IT
IS DOUBLING THE CELLS BUT OVER
TIME THOSE EFFECTERS IN THAT
INFLAMMATORY RESPONSE IS SLOWLY
STEALING MY MEMORY POTENTIAL SO
THAT AT THE END LOWER FREQUENCY
OF MEMORY CELLS TO DO THE JOB
THAT I WOULD LIKE THEM TO STICK
AROUND TO DO,EN THAN IF I HAD
NOT DONE THAT.
THAT IS TRUE OF ANY ADJUVANT,
DUAL ADJUVANT SINGLE ADJUVANT
THE SAME THING, WE CAN HAVE
EXPANSION OF THIS INFLAMMATION
GENERATING MAKES A LOT OF
EFFECTORS BUT EVENTUALLY STEALS
FROM THE CAPACITY TO MAINTAIN
HIGH CAPACITY OF MEMORY T-CELLS
AT END OF THE DAY CRITICAL FOR
THERAPEUTIC POTENTIAL.
LASTLY ON THIS TOPIC BOB HAS
SOME OF THE BEST DATA LOOKING AT
IF YOU STICK WITH THE SAME
FORMULATION AND CHANGE THE SITE
OF DELIVERY, THAT CAN HAVE A
REALLY SIGNIFICANT IMPACT OF
DETERMINING IMPACT OF SUCCESS OF
THERAPEUTIC VACCINATION.
SO IN THIS CASE HE HAS A TLR 70
CONJUGATE INTO LIPID MICE CELL
AND IF YOU INJECT THAT
SUBCUTANEOUSLY YOU GET A TENFOLD
INCREASE IN FREQUENCY OF ANTIGEN
SPECIFIC CD8 RELATIVE TO IV
DELIVERY.
WHEN YOU LOOK AT THE PHENOTYPE
OF THOSE CELLS, THE IED DELIVERY
CREATES A MORE MEMORY PRECURSOR
CELLS WHEREAS SUBCUTANEOUS GIN
RATES AS SHOWN WITH CPG HIGH
NUMBER OF EFFECTORS AND THOSE --
THAT SEVERELY COMPROMISES THE
CAPACITY TO MAINTAIN
THERAPEUTICETH EFFICACY AGAINST
TUMOR.
SO ADDITIONALLY ONE OTHER THING
THAT BOB SHOWED IN COLLABORATION
WITH -- USING PRY MATES USING
THE COMBINED ADJUVANT
ADMINISTRATION THERE IS AN
ELEVATED IL 10 PRODUCTION THESE
ARE HIGH FREQUENCY OF RESIDENCE
T-CELLS, THIS ONLY HAPPENS IN
THE IV DELIVERY SETTING SO IV
DELIVERY IS OBVIOUSLY BEEN LOW
WHEN EVERYBODY TOTEM POLL WHEN
IT COMES TO VACCINE
ADMINISTRATION.
AND IT'S THOUGHT TO BE SORT OF
LIKE THAT'S THE THING YOU JUST
CAN'T GO THERE.
BUT WHAT IS -- AND ADMITTEDLY
THERE ARE CHALLENGES WITH THAT,
WHAT IS WORSE THAN IV
ADMINISTRATION OF VACCINE IS
HAVING NO THERAPEUTIC VACCINE
WHATSOEVER.
THAT IS A BIGGER PROBLEM SO SOME
OF THESE MECHANICAL AND
FORMULATION QUESTIONS HAVE TO
START GRAPPLING SPEAKING FOR
ALTERING THE PURPOSE OF
THERAPEUTIC CELL VACCINATION
OPPOSED TO PROTECTING AGAINST
ACUTE DISEASE.
SO LASTLY, I WANT TO TALK ABOUT
BIOLOGY WE THINK IS REALLY
CRITICALLY IMPORTANT WHEN WE
THINK ABOUT T-CELL GENERATING
VACCINES.
NARROWED DOWN TO JUST THE TERM
27s.
TURNS OUT IN FIT OF GOOD
SERENDIPITY, CD 27 AND IL 27 ARE
CRITICAL FOR VACCINE MANAGEMENT
T-CELL RESPONSE.
SO WE HAVE BEEN PLAYING WITH
THIS COMBINED ADJUVANT SOMETIME
AND WE KNOW THAT COMBINING
POLY-- TLR AGONIST WITH AGONIST
ANTIBODY TO CD 40 GIVES A
SYNERGISTIC EXPANSION CD4 AND 8
T-CELLS ABOVE WITH EITHER SINGLE
ADJUVANT.
AND ONE THING WE NOTICE ABOUT
THE DIFFERENCE BETWEEN SINGLE
VERSUS DUAL ADJUVANT
ADMINISTRATION IS IF YOU DIDN'T
ADMINISTER BOTH ADJUVANTS
TOGETHER, YOU WOULDN'T GET ANY
UPREGULATION OF CD 7 WHICH IS
LIGAND FOR CD 27 AND GENERALLY
TRUE OF OTHER GENE RECEPTOR
LIGANDS, THEY NEEDED MULTIPLE
HITS IN ORDER TO BE UPREGULATED.
THIS IS DIFFERENT THAN IN VITRO,
THIS IS ALL DONE IN VIVO.
WE HAVE SEEN IT IN PRIMATES AS
WELL.
IN VITRO STICK IN A DISH YOU GET
CD 7 TO DO WHATEVER YOU WANT.
SO IN VIVO REGULATION OF THIS
PARTICULAR MARKER THIS TNF
LIGAND FAMILY MEMBER IS
DEPENDENT ON MULTIPLE
INFLAMMATORY SIGNAL AND THE
T-CELL RESPONSE DOWNSTREAM CD8
T-CELLS RESPONSE IS REALLY
HAMSTRUNG SOON AS YOU BLOCK THAT
PARTICULAR INTERACTION BETWEEN
CD 7 AND CD 27.
CD4 CELLS ARE MORE DETEN DENT ON
OX 40 AND ANTI-CD 70 AS WELL AS
CD 27 BUT CD8 ARE VERY FOCUSED
ON CD 27.
VACCINE RESPONSE IS OVEREPIFA US
SHOD.
THIS IS NOT JUST US SAYING THIS
BUT HEAVY HITTERS ACROSS THE
BOARD ACKNOWLEDGING THE CENTRAL
NATURE OF CD 27, CD 7
DETERMINING THE OUTCOME OF
SUCCESSFUL T-CELL RESPONSES.
AND IL 7 IS SOMETHING WE HAVE
BEEN LOOK AT.
IL 27 AS FAR AS WE CAN TELL THE
ONLY INNATE FACTOR THAT
SUCCESSFULLY PREDICTS T-CELL
ADAPTED OUTPUT.
WE MADE A REPORTER MOUSE WHERE
WE CAN SEE THAT AFTER ADJUVANT
ADMINISTRATION CDC 1 PREDOMINANT
DC SUBTYPE THAT MAKES IL 27
AFTER ADJUVANT ADMINISTRATION.
YOU CAN STRATIFY THE AMOUNT OF
GFP MADE BASED AFTER DIFFERENT
ADJUVANTS.
AND WHEN YOU DO THAT, WHAT YOU
END UP SIGHING IS THAT THE
AMOUNT OF GFP MADE WITHIN SIX
HOURS OF ADJUVANT ADMINISTRATION
IS PREDICTIVE AND CORRELATIVE OF
THE T-CELL RESPONSE 80 DAYS
LATER.
10 AS WELL AS 80 DAYS LATER.
THIS IS NOT TRUE, IMPORTANTLY OF
CYTOKINES THAT EVERYBODY THINKS
SHOULD BE MORE PREDICTIVE OF
T-CELL RESPONSES DOWNSTREAM LIKE
IL 12.
SIX HOURS AFTER ADJUVANTS I CAN
SAY WITH GOOD ACCURACY
REMARKABLE ACCURACY, WHAT TO
EXPECT T-CELLS RESPONSE
DOWNSTREAM.
WE LOOK AT THIS FOR PREDICTIVE
PURPOSES BECAUSE WE FOUND FROM
KNOCK OUTS IF WE TRY TO IMMUNIZE
ALPHA ONE RECEPTOR KNOCK OUT WE
GET ANTIBODY RESPONSES THAT ARE
T-CELL RESPONSES CD4 AND 8 ARE
SUPER (INAUDIBLE).
THAT'S NOT TRUE OF INFECTION
WHERE IN THIS CASE IT IS
SLIGHTLY ELEVATED VACCINE BUT
OTHER INFECTIONS DRAMATICALLY
ELEVATED WHERE IL 27 JOB IS
BRING THINGS WITH THE END
OPPOSED TO RAMPING UP AT THE
BEING.
HERE IS QUANTIFICATION OF THAT,
COMPARED TO ADVANTAGE SINIA.
THIS IS -- VAX SINIA.
THIS IS NOT A DUAL VACCINE
ADJUVANT PROBLEM THIS IS ALL
ADJUVANTS SEEM TO BE HEAVILY IL
27, MORE RECENTLY DONE mRNA
VACCINE THAT ARE CLEARLY IL 27
FOR PURPOSES OF GENERATING
T-CELL RESPONSES. SO LET ME
THINK STRUCTURALLY HOW TO
DELIVER VACCINES IN FORMULATING
THEM AS WELL AS THE 27s, AS
BIOLOGICAL MECHANISM ARE REALLY
IMPORTANT SUCH THAT WE SHOULD BE
THINKING HARD AS WE ARE
SCREENING NEW ADJUVANTS WE
ADVOCATE TO THINK MORE ABOUT
WHAT INDUCES CD 78 EXPRESSION
AND WHAT INDUCES IL 27.
AS WE ARE LOOKING FOR THAT.
WHAT IS MY -- I FORGOT TO START
MY TIME, WHAT IS -- JULIE
KEEPING TRACK?
>> YOU SHOULD TRY TO WRAP UP.
>> GOT YOU.
YEP GOOD.
I'LL JUST MENTION LASTLY, I
FIGURED I WOULDN'T GET THROUGH
THIS.
BUT GO -- SKIP TO THE END, WHAT
WE THINK IL 27 IS DOING, -- WHAT
WE THINK IL 27 IS DOING CD 27
AND IL 27 PROBLEM IN VACCINE
ELICITED RESPONSE IS GETTING
MOSTLY MEMORY CELLS, FADED MOST
MEMORY INFECTIOUS SETTING IS
FADED TO BAIL OUT OF CLONAL
EXPANSION AND BIOMASS
ACQUISITION AND GO MORE
QUIESCENT, WHEREAS EFFECTER
CELLS ARE DRIVEN TOWARDS BIOMASS
CLONAL EXPANSION.
IN A VACCINE SETTING WE ARE
DRIVING MEMORY PHENOTYPE SO ITS
FATE IS DISCONNECTED FROM
BIOMASS DEMANDS.
BUT IL 27 AND CD 27 ARE
SIGNIFICANTLY CONTRIBUTING TO
MAINTAINING CMIC FUNCTION AFTER
TRANSCRIPTION DECLINES AN
FACILITATING CLONAL EXPANSION
WITHIN SPECIFICALLY MEMORY
PHENOTYPE CELL AND WE CAN GAUGE
THAT.
SO WE THINK THAT IS THE
BIOLOGICAL MECHANISM OF 27s
AND WE ARE IN THE PROCESS OF
SINGLE CELL DATA AND
TRANSCRIPTIONAL DATA BEHIND THAT
AS WELL AS FUNCTIONAL DATA.
SO THAT IS WHERE WE THINK THAT
IS GOING.
AGAIN THINKING HARD SCREENING
FOR AGONISTENINGS ADJUVANTS THAT
DRIVE THOSE PARTICULAR PATHWAYS
IS AN IMPORTANT FEATURE.
SO IN OUR MAP, THANKS TO ALL
THOSE THAT WERE IN THE LAB DOING
THE WORK, PRIMARILY DARIA SCOTT
AND JARROD AS WELL AS
COLLABORATION WITH (INAUDIBLE).
>> THANKS, ROSS.
QUESTIONS FOR ROSS?
PLEASE RAISE YOUR HAND.
>> I'LL STOP.
>> ROSS LET ME ASK YOU A
QUESTION.
SO THIS CONCEPT OF EXPANDING
MORE THAN WE LIKE LESS
DIFFERENTIATED CELL, VACCINATION
OF INTEREST BUT HAVE YOU LOOKED
AT EPIGENETICS OF THESE?
ONE OF THE THINGS THAT HAPPENS
WHEN CELLS GO TO INFECTED PHASE
AMEND DEVELOP CELLS THERE ARE
STRIKING EPIGENETIC CHANGES, CD8
PERFORIN LOCUST REMAINS
(INAUDIBLE) THE GRANZYME REMAINS
(INAUDIBLE).
THIS ALLOWS INTERFERON GAMMA --
THIS ALLOWS CELLS TO RESPOND
MUCH FASTER IN TERMS OF
EXPRESSING -- SO HAVE YOU LOOKED
AT EFFECTOR GENES TO DELIVER
NAIVE CELLS?
>> SO WE HAVEN'T SEEN -- LOOKED
AT METHYLATION STATUS BUT WE
HAVE DONE ATTACK SEQ AS WELL AS
SINGLE CELL SEQ.
THE THING CURE OUTABOUT ADJUVANT
ELICITED CELLS IS THEY GO
THROUGH A PATHWAY, A
TRANSCRIPTIONAL PATHWAY THAT IS
NOT -- DOESN'T SEEM TO BE
EXPERIENCED BY INFECTION OF
THOSE T-CELLS SO INFECTION
ELICITED CELLS SOLVED THIS
PROBLEM OF EXPANDS O AND WHO
DOESN'T AND SELF-REMULE FOR
MEMORY AND THOUSAND GET RID OF
THIS THING IN FRONT OF US BY
GAUGING THE AMOUNT OF
INFLAMMATION THAT IS AROUND AND
DRAMATICALLY EFFECTING THIS
SUSTAINED CMIC FUNCTION
TRANSCRIPTION.
WHEREAS THE MEMORY CELLS BAIL
OUT OF THAT QUESTION ENTIRELY
AND ARE THERE FOR SELF-RENEWING
PURPOSES.
ADJUVANT SETTING IT IS -- WE ARE
PUSHING ALL THE PATHWAYS AT ONCE
SO UNLIKE INFECTION WHERE IF YOU
HAVE HIGH IBIT YOU HAVE LOW TCF
1 AND IN AN ADJUVANT ELICITED
CELL YOU HAVE HIGH -- EXTREMELY
HIGH TCF 1 AND HIGH CMIC SO THIS
ODD CELL TYPE IS TRYING TO DO
ALL THAT AT THE SAME TIME AND WE
HAVE SEEN A TRAININGS
SUBSCRIPTIONAL UNIQUENESS TO
WHAT WE SEE REFERRED TO AS T
BAGS COMPARED TO THE PATH WHICH
INFECTION CREATES THESE TWO SUB
SETS AND THEN ONE KEEPS GOING
AND THE OTHER ONE DIES OFF.
SO THE METHYLATION STATUS IS
GOOD, WE HAVEN'T GOT TO IT YET
BUT WE HAVE TRANSCRIPTIONAL DATA
AND THERE'S A VERY GOOD WAY C
CELLS EVOLVE.
>>
>> THAT WAS BEAUTIFUL.
IF I REMEMBER CORRECTLY SRI
YEAH'S LAB HAD DONE WORK ON R 27
AND HE PUBLISHED ON IL 27
PROMOTING REGULATORY LIKE TR 1
TYPE CELL AND SO THIS IS IS
SOMEWHAT AT ODDS WITH
FUNCTIONING AND WE AGREE IT
PROMOTES TH 1 TYPE RESPONSES.
WOULD YOU COMMENTS OWN THAT
>> I WOULD LIKE TO FULLY A AGREE
WITH YOU IT DOES DO THAT BUT
IT'S CONTEXT APPROPRIATE SO
AFTER ADJUVANT ADMINISTRATION,
VERY RA SPIKE AND DROP OF THAT
AND T-CELLS ARE BANKING ON THAT.
FOR THE INITIALING RAMPING UP OR
T-CELL RESPONSE AND SURVIVAL
DROPS OFF SURVIVE AND BIOMASS
ACQUISITION AT CMIIC EVAPORATION.
IN A CANCER CHRONIC SETTING L 27
ABSOLUTELY THE JOB IS TO REIGN
THINGS IN SO IL 27 IS REIGNING
IN TUMOR SETTING OR CHRONIC
INFECTIOUS SETTING THE SAME WAY,
IF YOU GET RID OF IT ACUTE
SETTING OFTEN T-CELLS EXPAND SO
MUCH IT KILLS THE HOST SO MOST
THAT WAS THE SURPRISE OF ITS
CRITICAL FUNCTION AND ADJUVANT
ELICITED RESPONSE TO EVERYBODY
ELSE, NO, NO, THIS IS A
SUPPRESSIVE SETTING, ACTUALLY IN
THIS CONTEXT CRITICAL FRONT END
TO MAKE SURE EVERYONE RAMPS UP
PROPERLY.
>> THANK YOU.
LET'S MOVE TO THE NEXT SPEAKER,
DONNA FARBER, DONNA WILL TELL US
ABOUT TISSUE IMMUNITY.
>> THANK YOU.
I'M OUT OF TOWN AT AND IN PERSON
MEETING A VAIR RARE EVENT BUT
WHAT HAPPENED IS THE HOTEL
INTERNET IS PROFOUNDLY UNSTABLE
SO THAT IS WHY I HAVE TO KEEP MY
VIDEO OFF, THEY ARE SHARING THE
SCREEN FROM NIH.
SO THERE MIGHT BE A LITTLE BIT
DELAY.
>> WE CAN SEE YOUR SLIDES.
>> OKAY.
CAN YOU TAKE IT BACK TO THE
BEGINNING?
THAT IS NOT THE FIRST SLIDE.
>> I CAN DO THAT.
CAN YOU CONTROL IT?
>> I CAN CONTROL IT.
THANK YOU VERY MUCH.
SO THERE IS A LITTLE BIT OF A
LAG, SO PLEASE BEAR WITH ME,
HOPE H THIS WILL GO FORWARD.
SO I'M GOING TO BE TALKING TO
YOU ABOUT MEMORY.
CAN EVERYBODY SEE THE NEXT
SLIDE?
I'M NOT SEEING (OVERLAPPING
SPEAKERS)
>> ON YOUR FIRST SLIDE.
>> CAN YOU SET IT TO THE NEXT
SLIDE PLEASE.
THANK YOU.
>> CAN YOU MAYBE CONTROL THIS?
>> YEAH, JUST GIVE ME THE QUEUE
FOR THE NEXT SLIDE.
>> OKAY.
THANK YOU.
>> WE HEARD ABOUT MEMORY AND
WHAT I WILL BE ADDING TO THIS
WILL BE ABOUT DIFFERENT KINDS OF
MEMORY SUB SETS, IN PARTICULAR
THE ONES THAT ARE IN TISSUE.
SO THERE'S SEVERAL DIFFERENT
TYPES OF CIRCULATING MEMORY SUB
SETS, CENTRAL MEMORY THAT WILL
GO TO THE LYMPHOID TISSUE AND
EFFECTOR MEMORY THAT CAN MIGRATE
THROUGH OTHER SITES AS WELL AS
THAT CIRCULATING TUMORAL
EFFECTOR BUT THE MAJORITY OF
MEMORY CELLS AND TISSUES ARE
TISSUE RESONANT.
THEY ARE NON-CIRCULATING.
THEY HAVE UNIQUE PHENOTYPE THAT
DISTINGUISH FROM CIRCULATING,
EXPRESSING EXISTING EYE AND CD
103 AND DISTINCT PROFILE FOUND
IN MULTIPLE PERIPHERAL SITES.
NEXT SLIDE.
HAD IS IMPORTANT ABOUT TISSUE
RESIDENT MEMORY CELLS IS TO
INFECTION PARTICULARLY SITE
SPECIFIC INFECTION MEDIATE THAT
OPTIMUM IMMUNITY.
THIS IS SHOWN IN MULTIPLE
TISSUES AN MULTIPLE SITES AND
OUR CONTRIBUTION IN THE LUNG IS
WE FOUND IN FLUORESCENT STAIN OF
THE LUNG THE MOUSE LUNG A ALVEO
LIE AND TISSUE RESIDENT MEMORY
LOCALIZE AROUND AIRWAY SO THEY
ARE MAINTAINED AT SITE OF
INFECTION.
AND THE LOWER GRAPH IN THE LEFT
MOUSE MODEL WE USE TRANSFER
MODEL IN A MOUSE WITH ONLY LUNG
RESIDENT MEMORY THERE'S OOH FULL
CHALLENGE WHEREAS MICE WITH
SPLEEN DERIVED MEMORY YOU CAN GO
TO THE DIFFERENT SITES NOT
PROTECTED NOR ANY MICE THAT
DIDN'T HAVE ANY RESIDENT MEMORY
SO THAT THIS IS SHOWN TO
MULTIPLE PATHOGENS TISSUE
RESIDENT MEMORY IN FACT CAN
MEDIATE VERY EFFICIENT
PROTECTION.
WE HAVE LOOKED INTO MECHANISMS
FOR THIS AND SO ON THE RIGHT
PANEL IN THE LUNG TRM OR TISSUE
RESIDENT MEMORY CAN BOTH
PROLIFERATE IN SITU AS WELL AS
SEND SIGNALS AND RECRUIT AND
MOBILIZE A VERY EFFICIENT IMMUNE
RESPONSE FROM THAT LYMPH NODE SO
THIS COORDINATED LOCALIZED
RESPONSE AT THAT SITE BETWEEN
LUNG AND LUNG LYMPH NODE NEXT
SLIDE.
SO KNOWING THAT THE TISSUE
RESIDENT MEMORY CELLS WERE
PROTECTIVE ONES WE WANTED TO
FIND A WAY TO EXAMINE, TO
INVESTIGATE TRN IN HUMAN SO WE
SET UP AN ORGAN DONOR RESOURCE
TO GET MULTIPLE TISSUES FROM
ORGAN DONORS WE DID THIS OVER 11
YEARS AGO.
IT WAS THROUGH THE INITIAL
SUPPORT OF A CHALLENGE GRANT
FROM THE NIAID.
WE HAVE A RANGEMENT WITH THE
LOCAL ORGANIZATION FROM BRAIN
DEAD ORGAN DONORS TO CONSENT TO
USE TISSUES OR ORGANS FOR LIFE
SAVING TRANSPLANTATION AND SOME
ALSO CONSENT TO USE OF ACTIVE
TISSUES FOR RESEARCH.
ALL THE RESEARCH ORGAN VARIANTS
THAT WE HAVE TISSUE SO WE GET
ALL THE SITES, MANY AS 15 TO 20
SITES INCLUDING A REAL FOCUS ON
MUCOSAL SITES, ALL THE DRAINING
AND ASSOCIATED LYMPH NODES WITH
THESE SITES, PERIPHERAL LYMPH
NODES, SPLEEN, BONE MARROW,
TONSIL THYMUS, MULTIPLE TISSUE
SITES.
AND THE OTHER ADVANTAGE OF USING
ORGAN DONORS IS THEY ARE
PREVIOUSLY (INAUDIBLE) DISEASE
OR CANCER FREE ARE NOW PCR
TESTED AS WELL SO ONLY TAKE ONES
THAT AREN'T HAVING ACTIVE
INFECTION AND WE GET THEM FROM
ALL AGES OF LIFE, AND YOU CAN
SEE WE REPRESENT MOST OF ADULT
AGES PRACTICALLY ALL AGE OF LIFE
UP UNTIL TENTH DECADE.
THEN WE HAVE ANOTHER RESOURCE WE
CAN ALSO GET SAMPLES FROM
PEDIATRIC ORGAN DONOR, THIS IS
THROUGH THE N POND, THIS IS
ACTUALLY SET UP THROUGH THE
CHARITABLE TRUST WHERE WE GET
MULTIPLE ORGAN DONORS.
SO WE USE THE ORGAN DONORS TO
CHARACTERIZE AND MAP T-CELL
IMMUNITY AS WELL AS OTHER IMMUNE
CELLS, IN THROUGHOUT THROUGHOUT
LIFE AND DIFFERENT TISSUES.
TO TELL YOU TRM YOU CAN SEE
BLOOD AT TOP TISSUE AT THE
BOTTOM.
TRM CONSTITUTE MAJORITY OF
MEMORY CELLS AND T-CELLS, IN
BOTH INTESTINES LUNGS AND EVEN
OUR LYMPHOID TISSUE NOT IN
BLOOD, AND THAT WE HAVE SHOWN BY
MULTIPLE CHARACTERIZATION THAT
THE PHENOTYPE AT CD 69 AND/OR CD
103 REPRESENT TRANSCRIPTIONALLY
DISTINCT SUBSET OF TRM, I WON'T
GO OVER THE FEATURES BUT
MULTIPLE WE IDENTIFIED THROUGH
SINGLE CELL PROFILING.
NEXT SLIDE.
BUT WHAT I WOULD LIKE TO
DESCRIBE TO YOU TODAY ARE
INVESTIGATIONS USING THESE
TISSUES TO UNDERSTAND ANTIVIRAL
AND VACCINE IMMUNITY.
SO WE LOOKED AT T-CELL SPECIFIC
FOR DIFFERENT VIRUSES, INCLUDING
FROM A NUMBER OF COHORT ACROSS
AGE AND PROBABLY THE LARGEST WE
HAVE DONE IS FLU AN CMV.
AND FLU IS OF COURSE
UBIQUITOUS@PATHWAY, MULTIPLE DI
CLOSURES OVER YOUR LIFETIME,
CYTOMEGALY VIRUS IS CONTINUOUS
EXPOSURE OR AT LEAST CONTINUOUS
CONTROL AND COMPARING MORE
RECENTLY TO SMALLER COHORT OF
DONORS BUT THIS IS GROWK TO SARS
COV-2 INFECTION AND ALSO TO THE
VACCINATION.
SO WE LOOK AT DISTRIBUTION OF
MEMORY CELLS ACROSS TISSUE,
WHETHER THEY ARE CIRCULATING ON
RESIDENT AND FACTORS FOR WHAT
TERMS WHETHER THEY ARE
CIRCULATING OR WHERE WHERE THEY
ARE AND WE ALSO IN COLLABORATION
WITH CROTTI TO MEMORY B CELL AND
TISSUE RESIDENT.
SO IN RESPONSE TO -- WHEN WE
LOOK AT RESPONSES TO UBIQUITOUS
PATHOGENS PRE-PANDEMIC STUDIES
AND ALSO DURING THE PANDEMIC, WE
USED MULTIPLE WE KNOW HLA TYPE
AND ROLE OF DONORS AND WE CAN
ASK WHERE INFLUENZA SPECIFIC
MEMORY ON THE TOP ROW, THAT IS
ONE PERSON, AND ALL THE
DIFFERENT TISSUES AND WE ARE
SEEING THE FLU AND THE CMV
SPECIFIC MEMORY IN THE LOWER
ROW.
OBESE THE MEMORY T-CELLS ARE ALL
MEMORY CD8 OTHER INFECTION
EPITOPE, MOSTLY CONCENTRATED IN
THE LUNG AND THE (INAUDIBLE) IS
LUNG ASSOCIATED LYMPH NODE.
MLM IS GUT MESSENGER LYMPH NODE
WHEREAS CMV SPECIFIC T-CELLS ARE
DISTRIBUTED IN MULTIPLE SITES.
AND WHEN YOU LOOK AT THE LEFT IN
THE -- IN TERMS OF TRM, THAT THE
MAJORITY OF MEMORY T-CELLS IN
THE LUNG EVEN UP TO 80%,
SPECIFIC ONES ARE TRM
PHENOTYPING WE FOUND SIGNIFICANT
TRM IN LUNG ASSOCIATED IN THE
SPLEEN.
AND THERE'S DIFFERENT FACTORS
THAT GOVERN THIS AND ONE IS
ACTUALLY -- SO MALES TEND TO
HAVE MORE TRM FORGIVEN SITE THAN
FEMALES AND FEMALES MORE
CIRCULATING.
TYPE OF RESPONSES BOTH TO FLU
AND CMV WHICH IS IN THE STUDY
THAT WAS PUBLISHED A FEW MONTHS
AGO IN CELL REPORT AND THEN
CLICK -- WE ALSO LOOKED AT AGE
AND DIFFERENT FACTORS IN AGE,
AND THERE IS ACTUALLY TWO
REGULATION WITH AGE, ONE IS
WHETHER A CHILD VERSUS ADULT, SO
IF YOU LOOK AT TRM AND FLU
SPECIFIC TRM IN A CHILD ON THE
LEFT AND ADULT ON THE RIGHT, THE
CHILDREN HAVE A LOWER FREQUENCY
OF TRM SPECIFICALLY FOR ADULT.
THAT IS LUNG ASSOCIATED LYMPH
NODE, THAT MAY BE DUE TO NOT
HAVING EXPOSURE, THAT'S ONE
HYPOTHESIS.
BUT OVER ADULT LIFE IT IS PRETTY
STEADY IN THE LUNG, BUT IT DOES
DECLINE IN LUNG BARING LYMPH
NODES AND JUST LYMPH NODES DO
UNDERGO AGING.
YOU HAVE FEWER OF THEN, THEY
UNDERGO FIBROTIC CHANGES OVER
AGE SO HA IS MANIFEST DECLINE.
MENTION SLIDE.
BUT WHAT ABOUT IN RESPONSE TO A
PATHOGEN?
THIS IS A STUDY WE DID IN
COLLABORATION WITH CROTTI'S LAB
AND ALSO ALEX SETTI, WE HAD FOUR
ORGAN DONORS WE GOT MULTIPLE
TISSUES FROM WHO HAD PREVIOUS
INFECTION, AND EITHER FROM TWO
MONTHS TO SIX MONTHS POST
INFECTION YOU CAN SEE ONE CHILD
AND THREE ADULT, SO WE DID IS WE
ASKED TO FIND THESE MEMORY SARS
COV-2 SPECIFIC MEMORY CELLS AND
MULTIPLE SITES, WE DID THE AMASA
ON THE LEFT AND YOU CAN SEE WE
ALSO HAVE BLOOD THAT WE FOUND,
THESE SPIKES SPECIFIC CENTER
COLUMN, T-CELLS IN MULTIPLE
SITES INCLUDING THE LUNG
ASSOCIATED LYMPH NODE, CLICK
AGAIN.
THEN WE COMBINED IT FROM
MULTIPLE DONORS AND ACROSS YOU
CAN SEE THAT FOR CD4 ON THE TOP
ROW AND CD8 BOTTOM IS THERE WERE
SIGNIFICANT FREQUENCIES IN THE
HIGHEST IN THE LUNG AND THE LUNG
ASSOCIATED LYMPH NODES AND ALSO
PRETTY GOOD NUMBERS IN GUT
ASSOCIATED LYMPH NODES FOR CD4
AND CD8 AND INTERESTINGLY FOR
TRM PHENOTYPE WE FOUND TRM FOR
CD4 IN THE LUNG AND TRM CD8 IN
LUNG AN LUNG ASSOCIATED LYMPH
NODE AND GUT ASSOCIATE ASSOCIATED LIMB
NODE SO WE ARE GENERATING SARS
COV-2 INFECTION THOUGH
PROPORTION IS LOWER THAN YOU SEE
WITH FLU.
NEXT SLIDE. SO THEN SHANE'S LAB
AND ALEX'S WITH KAY TOE AND
SHANE COTY'S LAB HE TOOK CAM
SAMPLES AND LOOK AT MEMORY B
CELLS IN THESE DIFFERENT TISSUES
YOU CAN SEE IN THE PANEL ON THE
LEFT IS THAT YOU HAVE MULTIPLE
SITES THAT HAVE SARS COV-2
MEMORY B CELLS AND IT IS REALLY
ACROSS ESPECIALLY IN THE LUNG
ASSOCIATED LYMPH NODE YOU SEE IN
PILE NICE FREQUENCY, HIGH
FREQUENCIES IN ALL DONORS WHO
PREVIOUSLY INFECTED IN LUNG,
LUNG ASSOCIATED LYMPH NODE AND
WE LOOK AT CD 69 EXPRESSION WITH
MARKED TISSUE RESONANT MEMORY B
CELLS, WHAT YOU CAN SEE IS IF
YOU LOOK AT THE CD 69 EXPRESSION
PARTICULARLY IN THE LYMPH NODE
IS WHERE WE REALLY FOUND AND
LUNG FOUND HIGH FREQUENCY OF
SARS COV-2 SPECIFIC MEMORY B
CELLS EXPRESSING CD 69.
BUT NOT BONE MARROW SPLEEN.
YOU LOOK AT THE PILE IT PEAKS IN
THE LUNG AND ALSO IN THE LYMPH
NODE BUT NOT IN THE BONE OR
SPLEEN SO WE ARE GENERATING
RESIDENT MEMORY B CELLS, MEMORY
RESIDENT T-CELLS AT SITE OF
INFECTION IN THE LUNG AND ALSO
LYMPH NODES INCLUDING GUT
ASSOCIATED LYMPH NODE, THERE IS
SOME SUPPORT THAT SARS COV-2
VIRUS INFECTS THE LUNG.
THE GUT SO THAT COULD BE RELATED
TO THAT.
NEXT SLIDE.
SO WE ALSO LOOKED AT SOME OTHER
PROPERTIES OF THESE CELLS AND
WHAT ALICE FOUND IS THAT IN FACT
THERE WAS SARS COV-2 SPECIFIC
MEMORY B CELLS IN THREE OF THE
FOUR DONORS INCLUDING THE CHILD,
EXHIBIT PHENOTYPE OF GERMINAL
CENTER B CELL AND THAT IS
SPECIFICALLY IN THE LUNG
ASSOCIATED LYMPH NODE.
WE WILL ALSO FOUND WE ALSO FOUND
IN THE SARS COV-2 SPECIFIC
T-CELLS IN THE LUNG ASSOCIATED
LYMPH NODE AND THE GUT
ASSOCIATED LYMPH NODE WE FOUND T
FOLLICULAR HELPER CELL
PHENOTYPES AND ALSO ONE DONOR IN
THE LUNG.
SO WE ARE GENERAL -- THERE IS
EVIDENCE FOR ONGOING OR
PERSISTENT GERMINAL CENTER
REACTIONS TO SARS COV-2.
NEXT SLIDE.
SO THAT IS INFECTION.
WHAT ABOUT mRNA VACCINATION?
WE HAVE -- THIS IS VERY MUCH
WORK IN PROGRESS SHOWING YOU
SOME NEW DATA.
FOR COMPARISON.
WE HAVE EIGHT DOE NO, SIR AGE
33-75, VACCINATED WITH TWO DOSES
OF mRNA BETWEEN ONE AND SIX
MONTHS.
WE ARE ONLY GETTING DONORS SO WE
ASKED THE TRANSPLANTS
COORDINATORS TO ASK ABOUT
VACCINE HISTORY.
THESE ARE DONORS WE ARE SURE OF
VACCINE HISTORY, THEY ALL HAVE
THE VACCINATED DONORS,
VACCINATED TWICE, HAVE GOOD
ANTIBODY RESPONSES TO SPIKE.
BUT WHAT ABOUT THEIR T-CELL, SO
THE T-CELLS WITH CD4 ON THE TOP
AND CD8 BOTTOM, THE COLORS ARE
ALL VACCINATED AND PRE-PANDEMIC
CONTROLS THE LYMPH NODE, THAT IS
A LUNG ASSOCIATED ON THE LEFT,
THAT IS THE HIGHEST RESPONSE BUT
IT REALLY VARY, IT IS A WIDE
RANGE AND I PUT WHERE THE MEAN
RESPONSE IS FOR INFECTION ON
BOTH OF THESE SO IT IS A LITTLE
BIT MORE VARIABLE AND ALSO
LOWER.
SO AGAIN THE PHENOTYPE OF THESE
T-CELLS IS MEMORY TEM BUT
MEMORY, CENTRAL MEMORY, T
FOLLICULAR HELPER CELL IN LONG
DRAINING LYMPH NODE AND THEN WE
LOOK AT B CELL NEXT SLIDE WHAT
WE FIND IS THE SPIKED RBD
SPECIFIC B CELLS YOU CAN DETECT
THEM IN THE -- THIS IS LYMPH
NODE ON THE RIGHT OF THE
VACCINATED PRE-PANDEMICK YOU
DON'T SEE THEM AND WE DO FIND
THEM IN THE LUNG DRAINING LYMPH
NODE THE BONE MARROW AND SPLEEN
TO LESSER EXTENT AND OF COURSE
BLOOD.
WHAT WE ALSO FIND IS THE B CELLS
IN LUNG DRAINING LYMPH NODE
LARGE PROPORTION OF THEM ARE CD
69 TO RESIDENT MEMORY B CELLS,
THAT WAS REALLY QUITE
SIGNIFICANT IN THE LUNG DRAINING
LYMPH NODE OVER ALL THE OTHER
SITES.
FOR THE LUNG, VACCINATED, WE
DON'T FIND THAT MEASURABLE
RESPONSES BUT WE ARE REDOING
THOSE AGAIN.
AND OF COURSE WE WILL HAVE
OTHERS AND THESE B CELLS ARE NOT
GERMINAL CENTER SO THERE IS A
GERMINAL CENTER OF LUNG DRAINING
LYMPH NODE REPRESENTATIVE OF
VERY RARE TO FIND NATURALLY
OCCURRING GERMINAL CENTERS AND
ANTIGEN SPECIFIC CELLS DO NOT
HAVE GERMINAL CENTERS.
NEXT SLIDE.
TO SUMMARIZE, SO IF YOU LOOK AT
IN TERMS OF GENERATION OF TISSUE
RESIDENT VACCINATION, WHAT WE
ARE SAMPLING IS IN THE BLOOD,
BUT WE THINK IT IS IMPORTANT TO
ALSO LOOK AT WHAT SUPPORTING IT
WHAT IS BEHIND THEM WHAT LIES
WITHIN IN OUR TISSUES.
AND HOW THAT MIGHT SUPPORT AND
CONTRIBUTE TO WHAT YOU SEE IN
BLOOD SO SITE SPECIFIC VIRUSES
GENERATE SURVEYING T-CELL
IMMUNITY AND THE TUMORRER
PERSISTENCE VARIES WITH EXPOSURE
AGE SEX AND ROUTE AND WE DOING
MORE OF THESE TO VIRUSES, SO
THAT WE CAN ACTUALLY GENERATED
PREDICTIVE MODELS SO WE CAN SEE
IF YOUR A FOUR-YEAR-OLD FEMALE
INFECT WITH A CERTAIN VIRUS WE
MIGHT BE ABLE TO PREDICT BY
LOOKING AT TISSUES VERSUS BLOOD
WHAT RESPONSE YOU ARE GOING TO
GET.
SO TUMOR GENERATED TO SARS COV-2
BUT NOT VACCINES, mRNA
VACCINES SO FAR.
BUT LYMPH NODE B RESIDENT MEMORY
ARE GENERATED TO BOTH SO WE ARE
HYPOTHESIS TISSUE RESIDENT MAY
PREDICT THE DURABILITY OF MEMORY
AND ONE MORE CLICK.
THAT'S WHY WE WANT PROFILES OF
CELLULAR MEMORIES AND TISSUES TO
DURABLE VACCINE SO WE HAVE SOME
CONTEXT LIKE MEASLES MMR VACCINE
TO IDENTIFY PARTICULARS OF
PROTECTION LONGEVITY AND JUST
LAST SLIDE.
ACKNOWLEDGE THAT DID THE WORK.
INCLUDING EVERYONE IN THE LAB,
THIS IS UNDERTAKING WITH
SURGEONS AND PEOPLE IN THE LAB
AND COLLABORATORS WITH LA JOLLA
INSTITUTE AND SYSTEM BIOLOGIES
AND COLLABORATORS WITH FLORIDA
TO GET PEDIATRIC SAMPLES.
THANKS VERY MUCH.
>> VERY NICE.
QUESTIONS FOR DONNA?
FROM
>> TURN ON MY VIDEO?
THEY NOT LETTING ME TURN ON.
OKAY.
>> GO I A HEAD.
QUITE INTERESTING VACCINATION.
INDICATION OF O RESIDENT MEMORY
LUNG LYMPH NODE B CELLS AFTER
SHOT IN THE ARM.
BUT NOT THE T-CELLS?
ANY MORE THOUGHTS ON THAT?
>> IT IS CURIOUS.
I'M NEW TO B CELLS SO I DIDN'T
REALLY KNOW WHAT TO EXPECT.
WE ARE GOING TO LOOK AT OTHER
LYMPH NODES, SOME PERIPHERAL AND
WE JUST ASKED PERMISSION TO GET
DELTOID LYMPH NODE WHICH ARE NOT
SHOULDER.
WE CAN'T GET THE AXILLARY LYMPH
NODE UNDER YOUR ARM, WE WANT TO
SEE IF WE ARE GETTING IT LIKE
CLOSER TO THE SITE OF THE
INJECTION ARE WE GETTING MORE
RESIDENT MEMORY.
AND WHAT DO WE FIND RESIDENT
MEMORY T-CELLS IF WE ARE LITTLE
BIT CLOSER THE ANTIGEN MIGHT BE
HIGHER CONCENTRATION IN THAT
NODE.
>> DID YOU SAY -- AXILLARY?
>> NO WE CAN'T.
WE ARE NOT -- IT IS JUST VERY
HARD SURGICALLY TO DO, WE ARE
NOT ALLOWED TO DO EXTRA
INCISIONS FOR RESEARCH TISSUES.
IT IS HARD TO GET THROUGH BUT
PROBABLY ABLE TO DO IT NEAR THE
SHOULDER.
I WONDER IF A LOT OF MEMORY IN B
CELLS INFLUENCE IS GOING TO BE
RESIDENT MEMORY.
I THINK MOST RESIDENT MEMORY IN
LYMPH NODE'S E MOST B CELL LYMPH
NODE MEMORY IS GOT TO BE
(INAUDIBLE).
>> MARION.
>> INC. THAT.
I WAS CURIOUS DONNA, IT WAS
BEAUTIFUL, THE DIFFERENCE IN THE
RESIDENCY AFTER VACCINATION.
DID YOU ALSO SEE DIFFERENCES IN
FUNCTION LIKE IL 10 PRODUCTION,
WONDERING IF THAT IS CORRELATED
TO WHAT WE SEE IN PERIPHERAL
BLOOD LYMPHOCYTES.
>> SO WE ARE DOING THOSE
STUDIES.
NOW WE DIDN'T -- I MEAN JUST IN
SORT OF THE CYTOKINE STAINING WE
DIDN'T SEE CYTOKINE SIGNALING
WITH THESE.
SOME ARE VERY LOW.
AND WE ARE ALSO SWITCHING NOW SO
THAT INITIAL COHORT WAS ALL WE
BUILT UP A COHORT WITH FROZEN
STORED CELLS SO WE ARE ALSO
GOING TO DO FRESHER CELLS LIKE
FROM FRESH DONORS SO THAT WE CAN
MAINTAIN SOME OF THE FUNCTION AS
WELL.
>> I HAD A QUESTION YOU ALLUDED
TO POSSIBLY DIFFERENCE WITH
MEASLES.
(LOST AUDIO) ON MEASLES TRMs
OR IS THAT SOMETHING YOU ARE
LOOKING AT NOW?
>> WE ARE LOOKING NOW, WE
ACTUALLY JUST THROUGH ALEX S
SEFF'S PEPTIDES, WE JUST GOT A
BUNCH OF PEPTIDE, WE ALSO ARE
THEM FOR MUMPS.
WE HAVE DONE TITERS AND DONORS
FOR MEASLES AND IT IS STEADY SO
OLDER PEOPLE HAVE REALLY GREAT
TITERS FOR MEASLES.
WE HAVE ALSO DONE FOR MUMPS,
MUMPS DECLINE AS BIT SO WE ARE
GOING TO DO THIS WITH KNOWN
VACCINE SO WE CAN PUT THINGS IN
CONTEXT.
BUT IT IS ONGOING.
>> LAST QUESTION FROM ROSS.
>> NO ARE YOU DELINEATING
RESIDENT MEMORY AND TERTIARY
LYMPH NODE STRUCTURES IN THE
VARIOUS TISSUES YOU ARE LOOKING
AGENT, IS THERE A WAY YOU ARE
CLARIFYING THAT?
>> YEAH.
SO MOST OF THE VACCINE IT IS ALL
IN THE LYMPHOID TISSUES ALREADY
BUT IN THE LUNG SO IN THE LUNG
ADULT HUMAN ADULT LUNGS DON'T
REALLY HAVE A LOT OF -- THE ONLY
DONORS WE FOUND (INAUDIBLE) IN
-- SO BABIES AND YOUNG KIDS UP
TO SIX HAVE FOLLICLES AND THEY
CAN EVEN GENERATE GERMINAL
CENTER, ANOTHER STORY WE ARE
WORKING ON WITH PEDIATRIC DONORS
BUT IN ADULTS YOU JUST DON'T SEE
IT.
YOU DON'T SEE IT IN THE LUNG.
>> HAS THAT BEEN DONE BEFORE?
>> THERE IS A REALLY -- SO WE
STARTED LOOKING AT THIS, THERE
IS A OLD PAPER LIKE SOME ANATOMY
JOURNAL WHERE THEY DOCUMENT THAT
THERE IS BOTH IN YOUNG LUNGS AND
IN MICE MOUSE LUNGS WHEN YOU
GIVE THEM LPS, YOU CAN GENERATE
IT.
THEY INDUCE NICELY.
>> AGE ASSOCIATED, THE FACT OLD
LUNGS DONE AND YOUNG -- I HAVE
NEVER HEARD THAT.
>> IN SOME PATHOLOGY YOU WILL
FIND NOT MUCH IN ADULT AND IN
ADULT MOUSE LUNG TOO.
>> THANKS.
LET'S GO TO OUR LAST SPEAKER,
BALI PULENDRAN, TALK ADJUVANT
AND PREDICTIONS.
>> THANK YOU SO MUCH, RAFI.
THANKS, EVERYONE.
FOR INVITING ME TO THIS VERY
INTERESTING WORK SYMPOSIUM.
AND SO LET ME SEE.
SO I WOULD LIKE TO TELL YOU
ABOUT RECENT WORK WITH
ADJUVANTS, THESE ARE MY INDUSTRY
INTERACTION DISCLOSURES.
AS YOU HEARD FROM SHANE AND
MARION AND OTHERS, IT IS NOW
CLEAR THAT THE mRNA VACCINES
DEVELOPED BY PFIZER THOUGH
INDUCING EXCELLENT ANTIBODY
RESPONSES IN TMB CELL RESPONSES,
THE DURABILITY OF THE ANTIBODY
RESPONSES IS REALLY NOT VERY
HIGH.
WE HAVE ALSO GOT SIMILAR DATA
THIS IS A STUDY WE DID AT
STANFORD WHERE WE CAN SEE THE
BINDING OF THE NEUTRALIZING
ANTIBODY TITERS THE HALF LIFE IS
ABOUT 56 DAYS OR SO.
THERE ARE EXAMPLES OF LIGHT
VIRAL VACCINE SUCH AS SMALLPOX
YELLOW FEVER, MEASLES SO ON THAT
INDUCE DURABLE ANTIBODY
RESPONSES.
SO SEVERAL YEARS AGO WE WERE
INTERESTED IN WHY, WHAT ARE THE
MECHANISMS LIKE YELLOW FEVER
VACCINE INDUCE DO YOU RECALLABLE
RESPONSE.
AND IN SOME EXPERIMENTS IN MICE
WHAT WE SAW IS IMMUNIZATION OF
MITI 88 KNOCKOUT MICE WITH THE D
VACCINE RESULTED IN DRAMATICALLY
DIMINISHED ANTIBODY RESPONSES,
AND ALSO THE DURABILITY WAS NOT
VERY HIGH.
FURTHER WE SHOWED THIS WAS
THROUGH ACTING THROUGH SEVERAL
DIFFERENT TLRs SHOWN HERE, TLR
2, 7, 9 SO THIS LED TO THE IDEA
THAT A LIVE VIRAL VACCINE SUCH
AS YELLOW FEVER VACCINE WAS
INDUCING ITS IMMUNE RESPONSES
LARGELY BY ACTIVATING MULTIPLE
DIFFERENT TLRs.
SO TO ADDRESS THIS ISSUE WE
ASKED THE QUESTION IS IT
POSSIBLE TO MAKE A SYNTHETIC
VIRUS LIKE PARTICLE THAT WOULD
CONTAIN THE APPROPRIATE TLR OR
COMBINATION OF APPROPRIATE
TLRs, THAT WOULD ALLOW TO
INDUCE DURABLE RESPONSES.
SO IN COLLABORATION WITH
(INAUDIBLE) COLLEAGUES AT
GEORGIA TECH WE DEVELOPED THIS
POLYLACTIC GLYCOLLIC ACID
NANOPARTICLES THAT WERE ABOUT
300 NANOMETERS IN DIAMETER AND
THAT WE TESTED COMBINATIONS OF
TLR LIGANDS TO BE ENCAPSULATED
WITHIN PARTICLES TOGETHER WITH
ANTIGEN.
THESE GLEE COTTIC ACID PARTICLES
RELEASED THEIR CARGO WITH --
THEY TAKE A FEW DAY DAYS SO WE CALL
THIS A SLOW RELEASE DELIVERY
SYSTEM.
AND SO (INAUDIBLE) WHO WAS IN MY
LAB NOW INDEPENDENT AT EMORY
DATE EMPERIMENTS WITH MICE IN
THESE PARTICLES AND SHOWED IN
FACT IF YOU GIVE THE RIGHT
COMBINATION OF TLR GUY LANDS YOU
INDUCE A DURABLE GERMINAL CENTER
RESPONSE AND DURABLE PLASMA CELL
RESPONSES.
AND YOU CAN SEE HERE POLYLACTIC
GLYCOLLIC AID SID CONTAINS
ALBUMIN, ANOTHER CONTAINS MPL RA
37, A TLR 7 LIGAND, DURABLE
RESPONSE SO THIS GAVE US A CLUE
TO THE RIGHT YOU NEED BUTTONS,
PLAY SIGNIFICANT ROLE IN THE
DURABILITY OF ANTIBODY
RESPONSES.
BUT THIS WAS IN MICE AND IT IS
EASY TO DEVELOP LONG LIVE
RESPONSES IN MICE SO THE
QUESTION DOES THIS APPLY IN HIGH
ANIMAL MODEL SUCH AS MONKEYS SO
TOGETHER WITH FUNDING FROM THE
GATES FOUNDATION IS ASK WHETHER
TLR LIGANDS INDUCE LONG LIVE
ANTIBODY RESPONSES IN RHESUS
MACAQUES AND THE ANTIGEN IS HIV
ENVELOPE ANTIGEN YOU CAN SEE
HERE THE TL 1 NEUTRALIZING
ANTIBODY RESPONSES, ON THE RIGHT
PANEL AND WHAT YOU CAN SEE AND
WE TESTED A NUMBER OF DIFFERENT
ADJUVANTS SHOWN IN THE DIFFERENT
COLORS YOU CAN SEE ALLEN IN
BLACK GLA IN BLUE, NOT STRONG
RESPONSES, HOWEVER, TLR 78
LIGANDS INDIVIDUALLY BY
THEMSELVES OR IN COMBINATION
WITH THE TLR SUCH AS GLA, OR MPL
REALLY INDUCE VERY HIGH
MAGNITUDE AND DURABLE RESPONSES.
TOGETHER WITH RAFI'S LAB, WHAT
WE DID WAS TO LOOK AT THE BONE
MARROW IN THESE MONKEYS AND ASK
WHAT IS THE FREQUENCY OF LONG
LIVED BONE MARROW PLASMA CELLS
AND OBESE ON THE X AXIS
FOLLOWING THESE MONKEYS FOR MORE
THAN A YEAR AFTER VACCINATION
CLEARLY YOU CAN SEE THAT THE
ADJUVANT SIGNAL PLAY AS MAJOR
ROLE IN THE FREQUENCY AND THE
MAINTENANCE OF THESE LONG LIVED
BONE MARROW PLASMA CELLS, IN
PARTICULAR THIS 3M 052 SYNTHETIC
TLR 78 LIGAND OR COMBINATION OF
GLA PLUS -- TLR -- HIGH
MAGNITUDE OF BONE MARROW PLASMA
CELLS.
THESE ARE ANTIGEN SPECIFIC BONE
MARROW PLASMA CELLS.
WHAT HAPPENED IN THE LAST TWO
YEARS IS WE APPLIED THIS
KNOWLEDGE TO ASKING CAN WE
ADJUVANT COVID VACCINE TO
ENDEUCE DURABLE RESPONSE AND
THAT IS A WHAT I WOULD LIKE TO
SHOW YOU.
SOME OF THIS IS PUBLISHED AND
OTHER IS WRITING THIS UP.
SO IN A STUDY THAT WE DID IN
COLLABORATION WITH NEIL KING AND
DAVID AT UNIVERSITY OF
WASHINGTON AND THIS WAS LED BY
(INAUDIBLE) IN MY LAB WE
PUBLISHED FEW MONTHS AGO, LAST
YEAR IN NATURE, WHAT WE DID WAS
TO USE THIS SUB UNIT VACCINE
THAT HAD BEEN DEVELOPED BY NEIL
WHICH IS A RECEPTOR BINDING
DOMAIN SARS COV-2 EXPRESS ON
NANOPARTICLE, WE ADJUVANTED THIS
WITH A VARIETY OF ADJUVANT, CPG
DNA ASO 3 BASED ADJUVANT FROM
GLAXOSMITHKLINE SWE ANOTHER
BASED ADJUVANT, AS 37 A TLR 7
LIGAND AND ALSO MADE BY
GLAXOSMITHKLINE AND ALLEN, AND
THIS DATA WAS PUBLISHED AS YOU
MIGHT EXPECT WE SAW TERRIFIC
NEUTRALIZING ANTIBODY RESPONSES,
WE CHALLENGE THESE MONKEYS AFTER
UNMOUNTS AFTER SECOND
IMMUNIZATION AND PROTECTION WAS
JUST FANTASTIC AND MANY, MANY
OTHERS REPORTS HAVE COME OUT
WITH OTHER KINDS OF VACCINE
SHOWING THAT IT IS FAIRLY EASY
TO GET GOOD NEUTRALIZING
ANTIBODY RESPONSES AGAINST
HOMOLOGOUS STRAIN.
WHAT I WANT TO SHOW YOU IS TO
FOLLOW-UP WITH THESE MONKEYS
SOME OF THESE WERE NOT
CHALLENGED.
SO WE WERE ABLE TO LOOK AT THE
DURABILITY OF THE RESPONSES AND
USED BY ADJUVANTS SO LET ME SHOW
YOU HERE, THESE ARE FIVE MONKEYS
IMMUNIZED DAY O DAY 21, WE
FOLLOW NEUTRALIZING ANTIBODY
RESPONSE UP TO SIX MONTHS NOW
MORE THAN A YEAR, I WILL SHOW
YOU THAT DATABASEICALLY YOU CAN
SEE AT THE PEAK VERY NICE TITER
NEUTRALIZING ANTIBODY RESPONSE,
ABOUT SEVEN FOLD DROP OVER SIX
MONTH PERIOD.
MORE OR LESS SIMILAR TO WHAT
PEOPLE HAVE SEEN WITH OTHER
VACCINE PLATFORMS.
WHAT'S HAPPENED NOW IS THESE
MONKEYS THAT WE HAVE BEEN
FOLLOWING IS MORE THAN A YEAR
SINCE THEY WERE PREVIOUSLY
IMMUNIZED AND SO LET'S -- THIS
IS A BIT COMPLEX SO LET ME TALK
YOU THROUGH IT, IN BLUE YOU SEE
RBD WUHAN DAY ZERO, RBD WUHAN
DAY 21, IMMUNIZED SEVERAL MONTHS
AGO AND WHAT HAPPENED WAS THAT
THE BETA CORONA VIRUS STRUCK
THIS WAS AT A TIME WHEN THE B 13
FIVE LINEAGE WAS EMERGING AND WE
THOUGHT WE HAVE WE HAVE HAD
MONKEYS FOR SO LONG, WHY NOT
BOOST WITH THE RBD NANOPARTICLE
WITH ASO 3 CONTAINING THE RBD
BETA FROM THE BETA CORONA VIRUS
WHICH IS WHAT WE DID HERE.
SO THIS IS AFTER A PROLONGED
INTERVAL OF SIX OR SEVEN MONTHS
THESE WERE BOOSTED WITH THE RBD
BETA WITH ASO 3.
WE ALSO HAD ANOTHER GROUP OF
MONKEYS THAT HAS BEEN IMMUNIZED
WITH HEKOPRO THE WHOLE SOLUBLE
ON NANOPARTICLE PREVIOUSLY DAY
ZERO DAY 21, SIX MONTH GAP THEN
BOOSTED THEM WITH THE RBD
NANOPARTICLE.
THEN WE HAD A CONTROL GROUP OF
MONKEYS IN WHICH WE IMMUNIZE
WITH RBD WUHAN NANOPARTICLE RBD
WUHAN NANOPARTICLE DAY 21, SIX
MONTH REST THEN RBD WUHAN BOOST
AS CONTROL FOR THESE TWO GROUPS.
WE FOLLOWED THE MONKEYS ANOTHER
SIX OR SERVE MONTHS AFTER FINAL
THIRD IMMUNIZATION.
WE ASKED THE QUESTION, WHAT IS
THE DURABILITY LIKE, HOW ARE
TITERS AGAINST OMICRON AND WHAT
IS PROTECTION AFTER OMICRON
AFTER A LONG WAIT OF SIX OR
SEVEN MONTHS.
NOW LET ME SHOW YOU THE DATA.
FIRST LET'S ASK THE QUESTION
WHAT HAPPENS IF YOU IMMUNIZE
MONKEYS AT DAY ZERO WITH RBD
WUHAN ASO 3, BOOST DAY 21 WITH
RBD 1 ASO 3 WHAT IS THE
NEUTRALIZING ANTIBODY TITERS
AGAINST WUHAN STREAM?
SO THERE YOU GO YOU HAVE SEEN IN
IN MANY, MANY PUBLICATIONS
PREVIOUSLY.
WE HAVE A VERY GOOD RESPONSE AND
THEN GRADUAL DECAY, ABOUT SEVEN
FOLD DROP.
WHAT ABOUT OMICRON TITERS?
IT IS HARDLY ANYTHING AS YOU
HAVE SEEN WITH THE PFIZER AND
MODERNA VACCINE THERE IS REALLY
A DRAMATIC HIT WHEN IT COMES TO
OMICRON.
NOW LET'S ASK THE QUESTION, WHAT
ABOUT IN THESE OTHER GROUPS THE
BLUE GROUP AND RED GROUP,
MONKEYS THAT HAD BEEN PREVIOUSRY
IMMUNIZED LONG TIME AGO TWICE
NOW AFTER SIX MONTHS BOOST,
BOOST WITH RBD BETA AND WE
WAITED ANOTHER SIX MONTHS.
HERE IS THE DATA.
SO IF YOU LOOK AT THE
NEUTRALIZING ANTIBODIES AGAINST
THE WUHAN STRAIN CLEARLY WITH
THE RBD BETA BOOST YOU SEE THIS
TREMENDOUS BOOST, IT GOES FROM
ABOUT YOU TO ABOUT 60 TO 70,000,
THAT IS A PRETTY DRAY DRAMATIC
BOOST.
IF YOU WAIT ANOTHER 130 TO 160
DAYS THERE IS A GRADUAL DECLINE,
THE TITLERS ARE STILL REALLY
QUITE HIGH.
IF YOU LOOK WHAT ABOUT THE
OMICRON?
YOU SEE THESE MONKEYS HAVE THE
CORRESPONDING TIME POINTS HAVE
REALLY QUITE A HIGH OMICRON
TITER HERE AND EVEN AT 130 TO
160 DAYS THE TITLERS SEEM TO BE
FAIRLY HIGH.
THIS IS WHAT YOU SEE AGAINST
BETA STREAM SO REALLY BY HIGH
TITERS.
I DO WANT TO EMPHASIZE THIS
POINT, I WANT TO SHOW YOU THE
PSEUDOVIRUS NEUTRALIZING
ANTIBODY AFTER THE THIRD 21 DAYS
AFTER THIRD IMMUNIZATION IN GRAY
IS TITERS THAT YOU SEE AGAINST
THE ANCESTRAL STRAIN.
MANY P RED AGAINST OMICRON
STRAIN SO THERE IS FOUR THE FIVE
FOLD HIT AFTER THIRD
IMMUNIZATION.
WHAT ABOUT 130 TO 160 DAYS AFTER
THE THIRD IMMUNIZATION?
AGAIN THE TITLERS AS YOU SAW IN
THE PREVIOUS SLIDE ARE HIGH IN
THE MONKEYS THAT WERE BLUESST
BOOST WITH THE RBD BETA BUT
THERE IS A HIT, ABOUT SIX FOLD
WHEN YOU LOOK AT OMICRON.
HOW DOES THIS COMPARE WITH WHAT
IS REPORTED IN LITERATURE IN
HUMANS WITH PFIZER?
THIS IS A STUDY WITH (INAUDIBLE)
PUBLISHED LAST WEEK IN SCIENCE
TRANSLATIONAL MEDICINE AND YOU
CAN SEE USING THE SAME ASSAY,
THESE WERE DONE IN (INAUDIBLE)
LAB THOUGH HUGE CAVEAT IS THAT
OUR STUDY IS IN MONKEYS THE
STUDY PUBLISHED ON IS IN HUMAN
SO YOU HAVE THE TAKE THIS WITH A
PINCH OF SALT BUT WHATEVER IT IS
WORTH YOU CAN SEE IF YOU BOOST
WITH PFIZER VACCINE, THIS IS A
THIRD IMMUNIZATION AT PEAK OF
THAT RESPONSE YOU SEE THE
ANCESTRAL TITERS ABOUT THE
MEDIAN ABOUT 13,000 BUT YOU TAKE
A DRAMATIC HIT WITH OMICRON.
SO YOU CAN COMPARE THESE ONE IS
IN HUMAN, THE OTHER IN MONKEYS
BUT FOR WHAT IT IS WORTH, THE
ADJUVANT PROGRAM SEEMS TO BE
HAVING LESS OF IMPACT ON THE HIT
THAT YOU HAVE WITH OMICRON.
THE LAST COUPLE OF SLIDES, WHAT
ABOUT THIS ISSUE OF DURABILITY
AFTER THE SECOND VERSUS THIRD
IMMUNIZATION.
SHANE REFERRED TO THIS BUT I CAN
SPEAK FROM OUR DATA.
SO LET ME ALLOW YOU TO FOCUS ON
THE PANEL ON THE RIGHT.
WHAT ARE WE LOOKING AT THE PANEL
ON THE RIGHT?
THE FULL REDUCTION IN THE
NEUTRALIZING ANTIBODY TITERS, AT
FIVE TO SIX MONTHS POST TERTIARY
POST SECONDARY IMMUNIZATION OR
POST TERTIARY IMMUNIZATION.
AND RELATIVE TO THE LEVELS AT
THE PEAK.
SO YOU SEE WITH THE FIRST STUDY
WE PUBLISHED WE SAW ABILITY A
FIVE FOLD DROP OVER FIVE MONTHS
PERIOD IN THE SECOND STUDY WHICH
WE ARE NOW DOING WE SEE AGAIN
ABOUT A FIVE FOLD DROP.
AFTER THE THIRD IMMUNIZATION IN
THIS CASE WITH BETA CORONA
VIRUS, WITH THE BETA STREAM, YOU
SEE ABOUT A FIVE FOLD DROP SO AT
LEAST WITH THESE ADJUVANT
VACCINE WE DON'T SEE IMPROVEMENT
IN THE DECLINE IN TERMS OF THIRD
VACCINATION.
LAST IS CHALLENGE.
WHAT DO THESE MONKEYS LOOK IF
YOU CHALLENGE ANYTHING FROM DAY
130 TO DAY 160 AFTER
IMMUNIZATION.
THESE ARE THE RESULTS, THIS IS
STILL ONGOING IN THE
UNVACCINATED MONKEYS, FIRST OF
ALL OMICRON IS A WHIMPY VIRUS BY
THAT I MEAN HARDLY HAS INFECTION
IN THE LUNG, YOU DO DETECT VIRUS
IN THE NASAL TRACKS AND YOU CAN
SEE IN THE UNVACCINATED MONKEYS
YOU CAN DETECT VIRUS BUT IN ALL
VACCINATED MONKEYS WE HAVE SEEN
SO FAR THESE ARE CHALLENGED 170
DAYS AFTER THE FINAL
IMMUNIZATION SO THAT IS ABOUT
SIX MONTHS WE SEE NOTHING.
SO THIS VARIES ONGOING IN THE
NEXT TWO WEEKS HAVE THE COMPLETE
DATA SET SO I WANT TO SUMMARIZE
WHAT WE ARE LEARNING.
I STARTED OFF BY SAYING THAT
THE mRNA VACCINE DIDN'T REALLY
INDUCE DURABLE NEUTRALIZING
ANTIBODY RESPONSE, THEN I
MENTIONED THE VIRAL VACCINES
SUCH AS YELLOW FEVER DOES INDUCE
DURABLE NEUTRALIZING ANTIBODY
RESPONSE AND WE BELIEVE THIS IS
PARTLY MEDIATED THROUGH THE
RIGHT INNATE SIGNALS INCLUDED
TOLL LIKE RECEPTOR 2, 3, 7, 9, I
DIDN'T SHOW YOU THE DATA BUT
TRIGGERS MDFI WE PUBLISHED THAT
SEVERAL YEARS AGO.
NOW, WITH THE mRNA VACCINE WE
LOOKED AT THIS IN MICE, THE
PFIZER mRNA VACCINE WE LOOK AT
DIFFERENT KNOCK OUTS AND WE SEE
THAT THE IMMUNE RESPONSE WHETHER
B CELL OR T-CELL RESPONSES, TLR
INDEPENDENT INFLAMMASOME
INDEPENDENT BUT MDA 5 DEPENDENT.
AND SO THAT IS NOT IDUCING
DURABLE RESPONSE.
WHAT IS THE SIGNAL, ADDITIONAL
SIGNATURE MALL TO MAKE THIS
VACCINE LIKE THIS VACCINE.
FINALLY I GAVE EXAMPLES OF
PROTEIN ADJUVANTED VACCINE, A
TLR 78 LIGAND ASO 3 THEY SEEM TO
BE INDUCING FAIRLY DURABLE
RESPONSES BUT I PUT A QUESTION
MARK BECAUSE THE QUESTION IS, IS
THE HALF LIFE OF THE ANTIBODY
RESPONSE REALLY AS HIGH AS THE
LIVE VIRAL VACCINE?
IF NOT WHAT IS MISSING PICTURE
HERE?
SO THAT IS ALL I HAD TO SAY,
THESE ARE ALL THE GREAT PEOPLE
WHO DID THE WORK, THE MONKEY
WORK IS BEING LED BY ABSOLUTELY
FANTASTIC POST DOC NOW SENIOR
SCIENTIST IN COLLABORATION WITH
(INDISCERNIBLE) THIS WAS A
STRONG COLLABORATION WITH NEIL
KING AND DAVID AND
GLAXOSMITHKLINE AND FUNDING FROM
THE BILL AND MELINDA GATES
FOUNDATION.
THANK YOU.
>> QUESTIONS FOR BALI.
LET ME ASK A QUESTION.
SO IN THIS BIT OF A BROADER
QUESTION FOR DAVID, I WAS GOING
TO ASK HIM THIS MANY THE
DISCUSSION.
SO WHAT -- A LOT OF PEOPLE ARE
USING RBD FOR POTENTIAL VACCINE.
AND JUST WANT TO THROW THE
QUESTION OUT TO DAVID AND TO
YOU.
WHAT ARE THE PROS AND CONS OF
USING RBD AS A VACCINE OPPOSED
TO (INAUDIBLE)?
>> DAVID IS CLEARLY THE BEST
PERSON TO ANSWER THIS BUT I ARE
GIVE MY TWO CENTS WORTH.
OF COURSE WE ARE NOT STRUCTURAL
PEOPLE SO WE ARE COMPLETELY
AGNOSTIC.
IF YOU LIST REASONS WHY PROTEOME
YOU MIGHT IMAGINE A PROTEIN HAS
MANY DIFFERENT EPITOPES
INCLUDING T HELPER EPITOPES SO
OBVIOUSLY ONE MIGHT THINK THAT
IT IS ADVANTAGEOUS TO USE A
WHOLE PROTEIN IN TERMS OF
GETTING PROPER T HELPER CELL
RESPONSE BUT ALSO MAYBE MORE
BREADTH THAN OTHER END TERMINAL
DOMAIN AND RBD.
IN OUR CASE WE HAVE COMPARED THE
RBD AND THE HEXAPRO SIDE BY SIDE
AND IN TERMS OF DURABILITY OR
MAGNITUDE WE DON'T SEE A
DIFFERENCE.
WE ARE LOOKING AT ISSUES OF
BREADTH BUT NOT TOO MUCH DATA ON
THAT.
BUT DAVID SHOULD ANSWER THIS
QUESTION.
>> AND SPECIFICALLY SPECIFICALLY
IN CONTEXT OF OMICRON.
THAT -- SO MAYBE FROM DAVID THEN
TO ROSS AND MARK.
>> SIMPLE ANSWER IS THAT THE RBD
CAN GIVE YOU VERY, VERY POTENT
NEUTRALIZING ANTIBODIES.
BUT WHAT WE ARE MISSING IS ALL
THESE ASSAYS ARE ONLY LOOK AT
NEUTRALIZATION, NOT PROTECTION.
SO WHAT WE DON'T KNOW IS TO WHAT
EXTENT WE ARE LOSING PROTECTIVE
ANTIBODIES WHICH ARE AGAINST
EPITOPES WHICH MIGHT BE MORE
CONSERVATIVE.
BUT THAT BEING SAID THERE'S LOTS
OF GREAT DATA TO SUGGEST THAT
PROTEIN DELIVERY OF RBD, BECAUSE
CLEARLY THE MONOMERIC RBD IS
WORTHLESS ANTIGEN BEEN SHOWN
BECAUSE IT IS NOT LARGE ENOUGH
TO BE TRACK PROPERLY IN GERMINAL
CENTERS NOT ENOUGH GLYCOSYLATION
TO BE USEFUL BUT CLEARLY AS
THESE NANOPARTICLES CAN BE VERY
SUCCESSFUL BUT WHAT WE ARE
MISSING IS IN VITRO ASSAYS THAT
WE DO TO MEASURE DURABILITY IS
ONLY EVALUATING NEUTRALIZATION.
>> THANKS, DAVID.
ROSS AND THEN MARK.
>> THIS IS KIND OF FOR EVERYBODY
AS WELL BUT FOR YOUR DATA, BALI,
WE HAVE SEEN IN ANALYZING BOTH
POST SECOND IMMUNIZATION VERSUS
POST BOOST, THAT AFTER THE
SECOND IMMUNIZATION FOR mRNA
VACCINE IT IS EXPONENTIAL DECAY,
A GEOMETRIC DECAY, WHEREAS AFTER
BOOST IT IS LINEAR SO THAT IS
MATHEMATICALLY THOSE FIT
INCREDIBLY WELL.
WE DON'T KNOW IF THAT IS TRUE,
WE HAVE GOT 30 TO 40 RESPONSES
TO LOOK AT BUT OTHER PEOPLE GOT
HUNDREDS AND WONDERING BROADLY
SPEAKING IS THAT TRUE?
GREAT QUESTION.
WE HAVEN'T YET CALCULATED THE EK
RATES ON MONKEY EXPERIMENTS.
WE PLAN TO DO THIS WITH VERONICA
WHOEVER WORKS WITH ROSS AT
EMORY, SHE A PERSON WHO WORKED
WITH US ON THE PFIZER VACCINE SO
WE ARE SENDING SAMPLES AND
HOPEFULLY THE NEXT MONTH OR SO
WE WILL HAVE A PROPER DECAY RATE
CALCULATION FOR MONKEY ADJUVANT.
WE DON'T HAVE THAT DATA YET.
>> THERE WAS THESE OLD ASSAYS
WHERE YOU COULD ADD TROPIC
AGENTS, AS A WAY TO GET SOME
SENSE OF LIKE THE AVERAGE
AFFINITY OF A POPULATION OF
ANTIBODIES, IS ANYONE TRIED THAT
WITH THESE KINDS OF -- WITH
ANTIBODIES IN THE SERUM OF THESE
PATIENTS OR PEOPLE WHO ARE GET
VACCINATED TO SEE HOW THE
AFFINITY OF THE ANTIBODIES ARE
CHANGING?
>> GREAT QUESTION.
WE HAVEN'T BUT I DON'T KNOW.
>> ARE THERE BETTER WAYS TO DO
THAT NOW?
I'M THINKING OF THIS IS STUFF
FROM PROBABLY THE '80s, BUT I
GUESS WE COULD JUST HAVE
MICHELLE SEQUENCE EVERY ANTIBODY
AND MEASURE AFFINITY BUT I STILL
THINK THERE COULD BE SOME
ADVANTAGE TO DOING THIS WITH
POLYCLONAL SIERRA, BEFORE COVID
HIT THERE WAS A HUGE DEAL IN THE
B CELL FIELD WAS HOW GOOD
SECONDARY GERMINAL CENTERS DID
THEY HAPPEN, AND WHERE ARE THE
BOOSTED ANTIBODIES COMING FROM
AND HOW GOOD ARE THEY?
>>PROFESSOR: YEAH.
>> I WOULD SAY THE STRONGEST
EVIDENCE COMES FROM SEQUENCE
MONOCLONALS, WHICH IS THAT
SHORTLY AFTER INFECTION THEY
IMPROVE FOR SIX PLUS MONTHS AND
AFTER VACCINATION CLEARLY PRETTY
GOOD, OBSERVATION OF
NEUTRALIZING ANTI-BOY IT IS
AFTER OMICRON GETTING HIT BE --
ANTIBODIES OF OMICRON WITH THREE
ANCESTRAL -- THE MEMORY B CELLS
AFTER SECOND LINE DID CONTAIN
MEMORY B CELLS THAT RECOGNIZED
OMICRON, THOSE THEN COME OUT AT
THE POLYCLONAL LEVEL NO, PEOPLE
THAT USE UREA BASED ASSAYS BUT
PEOPLE DO SOMETIMES GO INSTEAD
WITH ANALYZES WITH AREA UNDER
CURVE ANALYSIS INTEGRATING THE
END POINT TITER AND THE OVERALL
SHAPE WHICH DOES GIVE YOU A
COMBO OF AFFINITY AND TOTAL
QUANTITY AND SHIFT OVER TIME BUT
IT IS TOUGH TO -- YOU STILL
CAN'T EXTRACT HOW MUCH IS
AFFINITY IMPROVING OVER TIME
VERSUS THE ACTUAL AMOUNT.
>> ALISON AND DAN.
WE A OVER TIME.
>> SO SHOULD WE TAG EVERYONE AND
CONCLUDE OR DO YOU WANT TO
CONTINUE?
>> RAFI, WE HAVE GOTTEN A
DISPENSATION, YOU CAN GO OVER
TIME AND WE'LL EXTEND THE
BROADCAST, THAT'S PROVIDED THE
COUNCIL MEMBERS CAN STAY PAST 4
O'CLOCK TO HEAR THE CONCEPT
CLEARANCE.
>> MAYBE WE CAN GO -- TEN --
ANOTHER TEN MINUTES THEN OPEN UP
TO THE AUDIENCE FOR QUESTIONS.
>> YEAH.
GOOD.
COUNCIL MEMBERS, QUESTIONS FOR
ANYONE, ANY OF THE SPEAKERS OR
ANY OF THE TOPICS THAT ARE OF
INTEREST OR ANY BROAD QUESTION.
>> YES, I HAVE A QUESTION FOR
MARION, I WANTED TO ASK THEN,
THIS VERY INTERESTING FIRST OF
ALL REALLY ENJOYED YOUR
PRESENTATION VERY NICE DATA.
THE VERY INTERESTING EFFECTOR,
BY THAT I MEAN THE CYTOKINE
PRODUCING POTENTIAL OF THE
T-CELLS, IN THE PRE-INFECTED
VERSUS VACCINATED AND YOU SHOWED
INTERFERON GAMMA AND IL 10,
GRANTED THESE ARE PERIPHERAL
T-CELLS, BUT WHAT IS THE
PHENOTYPE, ARE THESE ALL RO
POSITIVE OR SIMULTANEOUS?
>> THANKS, IT IS A COMBINATION,
THEY ARE -- I DIDN'T HAVE TIME
TO GO INTO THAT DATA.
MOST OF THE CELLS LOOK LIKE
EFFECTOR MEMORY CELLS.
SO NOTHING SUPER EXCITING ABOUT
THEM AND WE LOOK AT ALL THE
CHEMOKINE RECEPTORS AND TO
IDENTIFY IF THERE WAS SOMETHING
UNIQUE ABOUT THEM BUT THEY LOOK
PRETTY MUCH GENERIC EFFECTOR
MEMORY CELLS.
>> EVEN IN THE CD8 SUBSET YOU
SEE MOSTLY THE EFFECT --
>> NOT IN THE CD8 SUBSET.
WE DIDN'T DO A LOT WITH THE CD8
SUBSET.
OUR PEPTIDE POOLS WERE 15 MERS
AND WE THINK PROBABLY BETTER AT
ACTIVATING CD4 CELLS THAN CD8
CELLS SO WE REALLY DIDN'T FOCUS
TOO MUCH ON THE CD8 CELLS IN
THESE ASSAYS.
BUT FOR THE CD4s THEY WERE
PRIMARILY EFFECTOR MEMORY CELLS.
>> IF I COULD HAVE ONE QUESTION
ADDRESSED TO BOTH YOU AND DONNA
WHICH IS SOMETHING INTRIGUING
FOR US, VERY DIFFERENT CONTEXT
STUDY (INAUDIBLE) (INAUDIBLE)
ARE NOT THAT WELL STUDIED YET
YOU SEE THEM IN SOME PATIENTS IN
GOOD NUMBERS.
NOW, DO THEY TRAFFIC TO IF LUNG?
WHAT ARE YOUR THOUGHTS ON WHEN
THERE IS A KEY, WHEN THERE IS A
LOCAL INFECTION, THE RRMs ARE
THERE AND WE CAN BRING UP WHOLE
DISCUSSION ABOUT THEM
CIRCULATING BUT HOW ARE THE THEM
RAS?
ARE THEY COLD?
>> SO THE TEMORAS GET TO THE
LUNG.
YOU FIND THEM IN THE LUNG.
BUT -- AND YOU CAN FIND VIRUS
SPECIFIC IN THE LUNG LIKE TO CMV
AND WE HAVE DONE ALSO TCR
SEQUENCING IN DIFFERENT SITES
AND THEY TEND TO BE HIGHLY
CLONAL EXPANDED AND THEY ARE
TRUE CIRCULATING SO THEY HAVE
THE SAME CLONE.
EXHIBITS ALMOST COMPLETE OVERLAP
IN ALL THE SITES FOUND IN.
SO ABLE TO GET PLACES.
>> SO THEY CAN BE LODGED THERE
BUT ALSO PROBABLY CIRCULATE.
>> YES.
>> MIC.
>> THANKS.
THIS WAS REALLY FUB FOR ME
BECAUSE WORKING IN AUTOIMMUNE --
FUN FOR ME BECAUSE I DON'T
UNDERSTAND AS MUCH ABOUT
INFECTIOUS DISEASE SO I LEARNED
A LOT BUT ONE THING I WAS
WONDERING, THERE HAVE BEEN A
NUMBER OF REPORTS OF SINGLE CELL
RAB SEQUENCING ANALYSES IN
LUNGS, LOOKING AT MILD MODERATE
SEVERE COVID, I KNOW YOU LOSE
THE ANTIGEN DEVELOPING TO SEE
WHICH OF THOSE CELLS ARE ANTIGEN
SPECIFIC SO IT IS REALLY A VERY
DIFFERENT CONTEXT BUT I WAS JUST
ROUNDING WITH CAN YOU LEARN
ANYTHING LOOKING AT MILD SEVERE
COVID WHAT IS THE COMPOSITION OF
THE T-CELL COMPARTMENT IN THE
LUNG, AND THEN DOES THAT INFORM
IN ANY WAY, WHAT YOU MIGHT SEE
IN BLOOD WITH VACCINES, IS
ANYONE DONE T-CELL SINGLE CELL
RNA SEQUENCING IN BLOOD OF
VACCINATED VERSUS INFECTED
PATIENTS, SO ON?
IS THAT A HELPFUL CONCEPT OR
BECAUSE YOU CAN'T DO
SPECIFICITY, IS IT A MESS
ANYWAY, CURIOUS WHAT YOU THINK
ABOUT THAT.
>>
>> I CAN ADDRESS THE LUNG
QUESTION.
THERE'S BEEN SINGLE CELL
SEQUENCING OF LUNG FROM AUTOPSY
SHOWING T-CELLS ABOUT WE HAVE
DONE IT FROM AIRWAY SAMPLES SO
WE COLLECTED AIRWAY SAMPLES IN
SEVERE COVID WHEN PEOPLE ARE
INTUBATED.
WHEN THE TUBE IS WASHED OUT --
(LOST AUDIO) AND WE SHOWED THAT
BY SINGLE CELL AS WELL AS FLOW.
SO THEY ARE THERE.
AND ARE RESPONDING.
NOW, SINGLE CELL IN THE LUNG
MILD RECOVERED, I DON'T KNOW IF
THAT'S BEEN DONE.
>> BUT THE BLOOD WHETHER SINGLE
CELL OF THE BLOOD.
T-CELLS.
>> WHAT WAS THAT, DONNA?
I DIDN'T HEAR YOU.
>> YOU ALSO ASKED ABOUT SINGLE
CELL OF THE BLOOD AND WHETHER
THAT'S INFORMATIVE?
WITH DIFFERENT SEVERITY?
>> OR I MEAN, WHEN WE LOOK IN
THE LUNG IN COVID Z AND LIKE IN
AUTOIMMUNE DISEASE AND OTHER
TISSUES, THERE ARE BETWEEN 15
AND 25 CLUSTERS DEPENDING ON
PARAMETERS.
IT IS QUITE DIFFERENT FROM
THINKING ABOUT FROM THE WAY THAT
YOU HAVE DESCRIBED MANY TERMS OF
RESIDENT MEMORY AND CLASSICALLY
DEFINED T-CELL POPULATIONS.
HERE YOU GET POPULATIONS, YOU
ARE NOT EXPECTING WE DON'T KNOW
EXACTLY WHAT THEY ARE, WE DON'T
KNOW WHAT MANY OF THEM ARE
DOING.
JUST CURIOUS, T-CELLS THROUGH
SINGLE CELL RNA SEQUENCING AND
HAVE SOME WAY TO CAM PAIR THE
TISSUE AND I'M -- COMPARE THE
TISSUES.
SOUND LIKE NO ONE HAS DONE THAT.
THERE ARE PUBLISHED PAPERS ON
COVID PNEUMONIA SHOWING BRON
KEOGH LAR LAVAGE FOR MILD AND
SEVERE SO YOU CAN GET
COMPARISONS AT THE CELLS THERE.
BUT DON'T MEAN TO BELABOR.
>> NO, THEY GOOD QUESTIONS,
DEFINITELY STUDIES DONE STRAIGHT
ON BLOOD OF ANTIGEN SPECIFIC
CELLS FROM SIMILAR LAYER AT
THIS.
(INAUDIBLE) HAS DONE SOME OF
THOSE AND THE -- FROM MY
PERSPECTIVE STUDIES CHALLENGING
TO INTERPRET FOR COUPLE OF
REASONS, ONE, TO LACK OF
KNOWLEDGE ABOUT ANTIGEN
SPECIFICITY YOU ARE SEEING SHOW
UP AT INFLAMMATORY SITE AND ARE
THEY SHOWING UP BECAUSE THEY ARE
NOT ANTIGEN SPECIFIC CELLS?
INFLAMMATION KEEPS GOING.
ARE THEY TON OF ANTIGEN SPECIFIC
CELLS AND THE OTHER IS YOU
CHICKEN AND EGG PROBLEM.
THEY FREQUENTLY THESE PEOPLE ARE
SAMPLES ALREADY EXTREMELY ILL SO
WHAT ARE YOU OBSERVING IS CAUSE
AND EFFECT THAT IS A BIG
CHALLENGE WITH HUMAN IMMUNOLOGY
IF YOU CAN'T DO, THAT'S WHERE
LONGITUDINAL STUDIES COME IN.
WITH GREAT STRENGTH THERE.
IT WAS A LITTLE BIT OF THAT FROM
CHICAGO GROUP BUT NOT MUCH
BECAUSE IT WAS EXTREMELY HARD TO
DO.
>> I WAS REALLY STRUCK BY
JULIE'S POPULATION HAVING 32%
LONG HAULERS.
I WAS WONDERING IF WE CAN CIRCLE
BACK AND TALK -- IS THERE A
CONSENSUS THEN GROWING CONSENSUS
ON WHAT IS GOING ON, DEPOT OF
ANTIGEN, HOW DOES THE FIELD
GOING TO PURSUE UNDERSTANDING
THIS PROBLEM?
>> THIS IS JULIE.
I WILL START BUT OTHERS HAVE
OPINIONS.
>> I THINK THAT IT IS TAKEN
NUMBER -- A YEAR TO FIGURE OUT
WHAT CAN BE DEFINITION.
OF THIS BECAUSE THE WAY THEY
MANIFEST ARE MULTIPLE SYSTEMS.
WHO MARRY CARD YES VAS QUEUE
LAWYER NEUROLOGIC, THERE ARE A
LOT OF THEM.
THEY VARY BY SEVERITY OF THOSE
SYMPTOMS.
SOME ARE NOT NECESSARILY -- SOME
ARE PERSISTENT FROM ORIGINAL
INFECTION AND SOME START ALL
OVER.
ONCE PERSON HAS SEEMINGLY
RECOVERED.
SO I THINK THOSE -- THE ANSWER
TO YOUR QUESTION MY VIEW WILL
COME BUT IT IS STILL TAKING SOME
TIME TO UNDERSTAND WHAT IS THIS
DISEASE OR THIS DISEASE GROUP.
AND HOW BEST CAN WE STUDY
BECAUSE OTHERWISE I THINK IT'S
GOING TO GETS A VARIETY OF
THINGS THAT MAY NOT PAN OUT.
THERE ARE OBVIOUSLY GOOD PAPERS
COMING OUT THAT ARE LOOKING AT
THAT EVEN JUST OVER THE LAST
WEEK TO TRY TO TEASE THAT APART
MORE.
BUT I THINK IT IS GOING TO TAKE
MORE TIME.
THAT IS MY VIEW.
SO IN OUR GROUP IT WAS ABOUT 30%
AND THERE'S SOME THAT WERE
REALLY SICK AND THERE'S SOME
THAT ARE REALLY KIND OF MILDLY
SICK AND EVENTUALLY GOING TO GET
BETTER.
>> TO FOLLOW JUDY, ONE OF THE
QUESTIONS WILL BE ADDRESSING
FUTURE WORK IN THIS COHORT OF
460 PATIENTS AND 30% REPORTING
(INAUDIBLE).
IS THERE ANY CORRELATION WITH
ADAPTIVE IMMUNE RESPONSE,
BECAUSE WE HAVE DOING A DEEP
DIVE ON ALL ASPECTS OF THE
PROCESS.
WE (INAUDIBLE) DETAIL DATA ON
ADAPTIVE IMMUNITY AND LONG COVID
SYMPTOMS.
>> HOW ABOUT ALL ANTIBODY
RESPONSES.
>> THAT WOULD BE GOOD.
THANK YOU FOR REMIND MEG.
WOULD BE CHECKING TO SEE IF
THERE IS ANY OF THESE ANY
CHANGES IN POTENTIAL
AUTOREACTION.
>> DO YOU SUSPECT FROM ALL OF
YOUR I'M ASKING EVERYONE THAT
THERE IS AN ELEMENT OF DEBATED
HERE GOING ON LIKE MOLECULAR
MIMICRY OR REACH OF PERIPHERAL
TOLERANCE>>
IS THERE ANY SENSE?
>> I WOULD AGAINST BREATH OF
AUTOANTIBODIES OF COVID, THERE
IS MOLECULAR MEMICRIES ANYWAYS.
WE CAN SEARCH THE GENOME AND
LOOK FOR SIMILARITIES THAT ARE
FIVE AMAY KNOW ACIDS LON.
THERE'S NO WAY, THAT'S GOT TO BE
LOSS OF TOLERANCE.
I DON'T KNOW THERE'S ANY WAY TO
EXPLAIN.
>> YOU WOULD WITHOUT INVOKING
ANTIGEN RECOGNITION ACROSS
ACTIVITY YOU CAN GET
INFLAMMATION, INFLAMMATORY
EFFECTS MODIFY (INAUDIBLE) THAT
PRE-EXISTING AUTOREACTANTS.
POTENTIAL TO HAVE MIMICRY.
IT IS MUCH WORSE ONE CAN
IMAGINE.
>> ALL DEPENDS WHAT HAPPENS WHEN
THAT REAL INFORMATION --
>> I THINK WHAT (INAUDIBLE) IS
SO IMPORTANT IS KEY FOR THIS, WE
LOOKED ACROSS MULTIPLE
INDIVIDUALS AND WILL IS A LOT OF
HETEROGENEITY IN THE RESPONSE WE
ARE SEEING AND WE HAVEN'T SEEN
ANY ONE PARTICULAR SIGNATURE
JUMP OUT AT US.
HA IS GOING TO BE KEY GETTING
BACK TO WHAT'S GOING ON.
>> FINDING THESE INFLAMMATORY
MONOCYTES THAT PERSIST FOR
SEVERAL MONTHS.
>> SO EXACTLY.
I WOULD RATHER YOUR QUESTIONS IS
AN IMPORTANT ONE BUT CLEARLY THE
WHOLE INNATE ADAPTIVE IMMUNE
SYSTEM IS COMPLETELY
DISREGULATED WITH SOMETHING LIKE
COVID INFECTION.
SO THE OUTPUT OF THAT COULD BE
GENERATION OF AUTOANTIBODIES OF
SOME KIND BECAUSE TNT IL 6
INFLAMMATORY CYTOKINES THAT
AFFECT HOW LYMPHOCYTES
DIFFERENTIATE.
AND HOW LONG THEY DIFFERENTIATE
FOR.
HOW LONG ANTIBODIES MAINTAIN,
WHETHER YOU FIND BONE MARROW
PLASMA CELLS THAT SECRETE
AUTOANTIBODIES FOR A LONG TIME
OR IS IT JUST EPISODIC, IT GOES
AWAY?
SO IT IS VERY MURKY IN TERMS OF
WHAT PATHWAY.
>> RAFI MENTIONED THE INNATE
CELLS WE CANNOT FORGET BECAUSE
WE ALSO STUDY THEM IN SEPSIS, MY
OWN GROUP WHEN MY HUSBAND IS
ANOTHER -- AND OTHER COLLEAGUES.
AND THEY CAN BE ESPECIALLY THE
INTERMEDIATE MONOCYTES ARE
PRETTY INTERESTING IN TERMS OF
WHAT THEY UNLEASH.
>> IT DOES SEEM LIKE SOME OF THE
LONG HAULERS DON'T NECESSARILY
RESULT FROM SEVERE INFECTION.
SO DO WE THINK REALLY A MASSIVE
BURST OF CYTOKINES MIGHT BE THE
CASE.
>> I THINK THAT IS A GOOD
QUESTION.
WHEN I THINK THE PERSISTENCE OF
VIRAL RNA INSIDE A BODY IS
POORLY UNDERSTAND THE
PERSISTENCE AND IMPACT OF VIRAL
RNA HOW LONG IT LASTS WHEN DOES
ITALIAN AND THE THE IMPACT, WHAT
INNATE PATHWAYS DOES IT ACTIVATE
AND THE WHAT IS THE CONCEPT OF
PERSISTENT INNATE ACTIVATION.
THAT IS I THINK NEEDS TO BE
STUDIED AND I THINK IT COULD
EXPLAIN SOME OF THE LONG HAULER
PHENOTYPES.
>> ROSS, QUESTION.
>> ONE FOR JULIE AND ONE FOR
EVERYBODY.
THE LOUNGE HAULER QUESTION I WAS
STRUCK ON THE DATA THAT THE
DOMINANT ANTIGEN FOR CD8
RESPONSES U IS DIRECTED, IF I
REMEMBER THIS CORRECTLY, ONCE
IMMUNIZED THAT SUBSEQUENT
INFECTION, IT WAS DOMINATED BY
SPIKE BUT WHICH HAS OBVIOUS
REASONS FOR IT.
IS THERE ANY -- THERE'S
ANECDOTAL THOUGHT THAT LONG
COVID PEOPLE GOT VACCINES WERE
NOW -- WE ARE SEEING SOME
BENEFIT FROM THAT IN TERMS OF
LONG COVID SYMPTOMS.
ANY THOUGHT -- DO YOU HAVE
THOUGHTS ABOUT THAT SWITCH IN
DOMINANT CD8 RESPONSE BETWEEN
JUST INFECTED VERSUS INFECTIONED
WITH VACCINE AND WHETHER THAT
HAS A ROLE?
IT?
>> IT'S A GOOD QUESTION.
AND IN OUR EXPERIENCE WE HAVE
HAD MEEK DOTELY PEOPLE SAY THEY
CAN SMELL WHEN GETTING
ADVANTAGENATED WHEN BEFORE THEY
COULDN'T FROM THEIR INFECTION.
AND WE HAVE EVEN HAD PEOPLE WHO
HAVE GOTTEN THE VACCINE THOUGH
WHO SAID THEY ARE HAVING
PROBLEMS WITH THEIR SMELL SO I
-- IT IS REALLY -- TO ME IT IS
STILL UP IN THE AIR ABOUT THAT.
BUT ONE THING I WILL ADD THAT I
THINK IS ALSO MORE FOOD FOR
THOUGHT IS WE ARE BEGINNING TO
LOOK AT THE BREAK THROUGH
INFECTIONS, WE ARE ALSO SEEING
JUST BEGINNING TO SEE PERSISTENT
SYMPTOMS AFTER 60 DAYS.
THESE ARE ONES THAT WERE NOT
NECESSARILY INFECTED WITH
OMICRON BUT FROM THE PAST, WHO
WERE VACCINATED AND THEN ARE NOW
DISPLAYING THIS LOUNGE HAUL
PHENOTYPE.
SO I'M NOT SURE THE VACCINATION
IS GOING TO PREVENT IT BUT MAYBE
IT WILL DECREASE THE OCCURRENCE
OF IT.
IT IS STILL WITH US AND I THINK
THOSE QUESTIONS THAT ARE BEING
ADDRESSED HERE AND MENTIONED
HERE ARE GOING TO BE REALLY
IMPORTANT.
TO TRY TO --
>> MAYBE I COULD ASK A QUICK
QUESTION TO THE GROUP, SOMETHING
SIMILAR TO THE LONG HAULER
PHENOTYPES WE SEE WITH COVID,
HAS THAT BEEN SEEN WITH ANY
OTHER INFECTIOUS DISEASE?
THIS IS AN ACUTE VIRAL
INFECTION.
WE BELIEVE THE VIRUS IS CLEARED
QUITE QUICKLY THOUGH RNA MIGHT
PERSIST.
>> CHICKEN GUNIA COMES TO MIND.
>> RIGHT.
>> BUT ALSO EBV.
>> EBV.
>> MONONUCLEOSIS TYPE.
>> (INAUDIBLE) QUITE SEVERE,
MASSIVE (INAUDIBLE) (OVERLAPPING
SPEAKERS)
>> DURING THE ACUTE PHASE.
>> ESPECIALLY FOR THE ELDERLY,
FLU IS (OVERLAPPING SPEAKERS)
>> EVEN FOR THE YOUNG.
-- REASONABLE PROBABILITY THAT
YOU GET MASSIVE INFECTION AND
HUGE EXPANSION OF ANTIGEN
SPECIFIC (INAUDIBLE).
T-CELL RESPONSE DURING IM, 50%
OF CD8 T-CELLS.
>> IT WILL BE INTERESTING TO
CLASSIFY THE VIRUS AS BASED ON
WHICH ONES TYPICALLY SHOWN TO
HAVE SOME SORT OF LONG HAULER
AND WHAT ARE THE PROPERTIES OF
THESE VIRUSES AND WHY -- I THINK
--
>> ON CHICKEN GUNIA YOU HAVE
PERSISTENCE OF RNA LIKE TALKING
ABOUT BALI BUT YOU DON'T HAVE
ANY CULTURABLE VIRUS BUT YOU DO
HAVE PERSISTENCE OF MESSENGER
RNA, RNA IN THE TISSUE AND
RHEUMATOID ARTHRITIS TYPE
SYMPTOMS WHICH CAN GO ON QUITE
SOME TIME.
>> SHANE DID YOU HAVE A
QUESTION?
YOU HAND YOUR HAND UP.
>> I WAS GOING TO SAY TO ME FROM
THE COVID-19 PERSPECTIVE THE
MOST STRIKING DATA I HAVE SEEN
ON IT IS DEATH BIOPSY DATA, 90
DAYS OUT FROM NON-(INAUDIBLE)
CASES AND MAJORITY OF PEOPLE
STILL HAD BOTH VIRAL RNA AND
VIRAL PROTEIN, THESE ARE IN
SMALL GUT BIOPSIES OF VERY TINY
SECTION OF GUT WHICH SUGGESTED
THREE MONTHS OUT THE VIRUS IS
STILL EASILY DETECTABLE IN
MAJORITY OF PEOPLE AND
INDEPENDENT OF LONG COVID
SUGGESTING JUST LOOK AT ONE
TISSUE IT IS DIFFICULT TO
COMPLETELY ELIMINATE ALL VIRAL
MATERIAL WHICH I FINE PERPLEXING
AND I WOULDN'T FEEL LIKE YOU
WOULD HAVE TO INVOKE MUCH ELSE
TO SAY YEAH, YOU COULD HAVE
SEQUELAE FOR A LONG TIME IF
THERE IS STILL MATERIAL THERE.
SO I WOULD LOVE TO SEE A STUDY
TRACKING STOOL SAMPLES FROM A
LOT OF PEOPLE LONG TERM, WE KNOW
IT IS A SENSITIVE WAY TO DETECT
THE VIRUS AND YET I HAVEN'T SEEN
STUDIES THAT HAVE TRACKED THOSE
WITH ALONG WITH IMMUNE RESPONSES
TO SEE GOING BACK TO THIS --
CHICKEN GUNIA CULTURABLE VERSUS
NON-CULTURABLE.
IT IS A SIMPLE WAY TO DETECT IT.
I HAVEN'T SEEN IT FOLLOWED UP
MUCH.
>> PAPERS THAT CAME OUT FROM
WUHAN, THEY REPORTING POSITIVE
--
>> YES SO I JUST MEANT MORE
RECENTLY LIKE LONG TERM.
>> LONG TERM.
>> AND COMPARED TO IMMUNE
RESPONSES.
>> IN GENERAL TO BRING UP THIS
ISSUE FINDING VIRUS IN THE GUT.
SO WHEN THE CDC KID (INAUDIBLE)
STUDY SHARE -- DID (INAUDIBLE)
SHARED -- THE EXPERT LOOKING FOR
VIRUS IN TISSUES.
HE FOUND INFECTION WAS
PREDOMINANTLY (INAUDIBLE).
DID NOT FIND VIRUS IN OTHER
TISSUES.
BUT THE MASSIVE INFECTION AND
(INAUDIBLE) PUZZLE BY WHY IT IS
NOT THE SITE OF THE PRIMARY
INFECTION.
WHY WOULD IT PERSIST IN A SITE
WHERE -- JUST DOESN'T ADD UP.
>> IS IT POSSIBLE CIRCULATING
CELLS LIKE MONOCYTES IN THE LUNG
--
>> THAT IS POSSIBLE.
THAT IS POSSIBLE.
THE OTHER POSSIBILITY IS THAT
ALSO VIREMIA IN SARS COV-2
PATIENTS WAS PARTICULARLY LOW
BUT IN FEW CASES IT WAS SEEN AND
IT WAS USUALLY SEEN IN THE MOST
(INAUDIBLE) CASES.
ONE OF THE HYPOTHESIS AT THAT
TIME WAS THAT USUALLY FROM
SOMETHING GROWING IN THE LUNG
DOESN'T NECESSARILY COME OUT IN
THE BLOOD.
DAMAGE TO THE LUNG THAT VIRUS
WOULD COME OUT.
MORE (INAUDIBLE) COME OUT
CIRCULATION.
IN THAT CASE, THAT COULD HAVE
RESULTED IN SOME SEEDING IN
DIFFERENT CASES.
BUT AGAIN IT WOULD BE SOMETHING
THAT WOULDN'T NECESSARILY BE
PICKED UP IN IF AUTOPSY BECAUSE
THE RANGE OF TISSUE THAT WOULD
BE THE LUNG SPIKE.
>> IT'S TRUE BUT SUCCESS IN
TRACKING THE VIRUS IN WASTE
WATER AND VARIOUS PLACES MEANS
THERE IS A HECK OF A LOT GETTING
THROUGH THE GUT PRETTY QUICKLY
AND --
>> AGAIN THERE COULD BE SOME
SITE (INAUDIBLE) GET CORONA
VIRUSES IN ANIMAL MODELS, AND
RECUR DAY TWO INFECT.
>> HAVE TO LOOK WHERE ACE 2 IS
RECEPTOR.
>> (OVERLAPPING SPEAKERS)
>> SOME RESERVOIR (INAUDIBLE).
I THINK WE ARE QUITE A BIT OVER.
SO DONNA, SHOULD WE END THE
SESSION AND THANK THE -- OUR
WONDERFUL SPEAKERS?
>> I THINK ARE THERE ANY LAST
QUESTIONS?
I THINK WE HAVE A LOT TO SOLVE.
I THINK REALLY ALSO JUST
DEFINING WHAT IS PROTECTION FROM
ILLNESS TOO BECAUSE I DON'T
THINK WE ARE THERE.
WE KNOW IT IS PROTECTION FROM
DEATH BUT THE VACCINE BUT
PROTECTION FROM ILLNESS I THINK
THAT'S LIKE THE FINER LEVEL WE
NEED TO GET TO.
ANY LAST COMMENTS ON --
>> THANKS TO ALL THE SPEAKERS
AND I THINK GREAT DISCUSSION AND
GREAT SESSION.
>> THANK YOU.
THANKS EVERYONE.
>>
>> THANK YOU, ALISON.
IN YOUR HANDS NOW.
>> THANK YOU, ALL THE SPEAKERS
AND DONNA AND RAFI FOR SHARING
THIS -- CHAIRING THIS SESSION,
IT'S BEEN A TERRIFIC SESSION.
WE BEEN WELL WORTH GOING OVER
THE TIME BUT WE DO NEED NOW TO
HAVE COUNCIL MEMBERS STAY ON AND
ANYBODY ELSE IS WELCOME TO, TO
HEAR THE CONCEPT CLEARANCE
PROPOSAL THAT KENTNER IS GOING
TO PRESENT WHILE HE'S GETTING
HIS SLIDES UP REMIND YOU THAT
OCCASIONALLY COUNCIL WE HAVE
CONCEPT CLEARANCE FOR SMALL
BUSINESS APPLICATIONS THAT WE
DON'T DISCUSS BUT WE JUST NEED
TO BRING TO THE PUBLIC'S
ATTENTION AND WE WILL HAVE THREE
OF THOSE I WILL MENTION NOW, ONE
IS ON ADJUVANT DISCOVERY FOR
VACCINES AND INFECTIOUS IMMUNE
MEDIATED DISEASES.
A SECOND IS SIMILAR ADJUVANT
DEVELOPMENT FOR SAME TOPICS.
AND A THIRD IS DEVELOPMENT OF
REAGENTS FOR IMMUNOLOGIC
ANALYSIS OF NON-MAMMALIAN AND
UNDER-REPRESENTED MAMMALIAN
MODELS.
SO THOSE ARE OUT IN THE PUBLIC
DOMAIN NOW AND THEY WILL BE
FUTURE SOLICITATIONS FOR THAT.
LET'S GO ON NOW TO KENTNER'S
PRESENTATION THEN WE'LL ASK FOR
COUNCIL DISCUSSION AND HOPEFULLY
APPROVAL OF THIS TO GO FORWARD.
U
>> I'M PRESENTING CONCEPT FOR FY
23 KNISH INEFFECTIVE.
WOULD LIKE THE MOVE FORWARD WITH
THIS INITIATIVE WHICH IS
SUPPORTING THE NIAID ADJUVANT
DEVELOPMENT PROGRAM.
SO ABOUT 20 YEARS AGO NIAID
CREATED A PROGRAM TO SUPPORT
RESEARCH ON VACCINE ADJUVANTS.
THE REASON FOR THIS, WHILE
GROUPS ENGAGE IN VACCINE
DEVELOPMENT RESEARCH EFFORTS
WERE FOCUSED ON ANTIGEN
COMPONENT SO THERE IS A REAL
NEED TO SUPPORT WORK
SPECIFICALLY ON THE VACCINE
ADJUVANT SPACE.
SO IN RESPONSE WE CREATED THE
ADJUVANT PROGRAM, WHERE THERE IS
FOUR OBJECTIVES WHICH I LISTED
HERE.
THE FIRST IS DISCOVERY, WE NEED
PA PIPELINE TO EXPAND AND
BROADEN THE ADJUVANTS FOR NEW
ADJUVANTS AN EXPLORATION OF
COMBINATION ADJUVANTS.
BASIC RESEARCH, THE GOAL HERE IS
TO BUILD A FOUNDATION SO THAT
VACCINE DEVELOPERS SELECT BEST
ADJUVANT FOR THE VACCINE.
BASED ON THE TARGET.
GOALS AND PATIENT POPULATION.
THE THIRD IS PRE-CLINICAL
DEVELOPMENT, IT TAKES LOT OF
PRE-CLINICAL DEVELOPMENT WORK TO
BRING SAFE EFFECTIVE VACCINES
AND ADJUVANTS TO THE CLINIC.
INCLUDES FORMULATION STUDIES
TOXICOLOGY, MANUFACTURING, AND
THEN PRE-CLINICAL EFFICACY
STUDIES.
THERE IS ALSO A NEED TO SUPPORT
HEAD TO HEAD COMPARISON OF
VACCINE ADJUVANTS AND
PRE-CLINICAL MODELS.
BOTH FOR THE PURPOSE OF DOWN
SELECTION BUT ALSO TO GOALS
OUTLINED WITH PAY SICK RESEARCH.
-- BASIC RESEARCH.
FINALLY, TO EXPAND ACCESS.
WE AIM TO ACTIVELY LEVERAGE
ADJUVANT PROGRAM TO ADVANCE
NIAID MISSION TOWARD A PROVEN
GLOBAL HEALTH.
THIS IS DONE INTERNALLY, BY
INTERACTING WITH OTHER NIAID NIH
SUPPORTED PROGRAM BUT EXTERNALLY
THROUGH INTERACTIONS WITH
NON-PROFIT ORGANIZATIONS WITHIN
THE RESEARCH COMMUNITY.
SO HERE IS HOW WE ARE
ACCOMPLISHING THESE GOALS.
UNDER EACH HEADING IS A LIST OF
NIAID PROGRAMS THAT ADVANCE
GOALS, ALONG WITH WHEN
SOLICITATIONS ARE ISSUED OR
ACTIVITIES CONDUCTED.
SO IN ADDITION TO THIS SOLICITOR
PROGRAMS HERE WE HAVE AN ACTIVE
PORTFOLIO OF GRANTS REWARDED TO
THE PARENTS RO1 R21 RO 3 AND
SBIR GRANT MECHANISMS.
SO FOR DISCOVERY WE HAVE THE
ADJUVANT DISCOVERY PROGRAM THIS
IS OUR LONGEST RUNNING ADJUVANT
PROGRAM.
BASIC RESEARCH WE HAVE MOLECULAR
MECHANISMS OF COMBINATION
ADJUVANT PROGRAM, THIS IS
RECENTLY RECOMPETED IN A SECOND
ITERATION WHICH LAUNCHED THIS
PAST YEAR.
FOR PRE-CLINICAL DEVELOPMENT THE
FLAGSHIP PROGRAM IS ADJUVANT
DEVELOPMENT PROGRAM AND H IS THE
PROGRAM THAT I'M ASKING THAT WE
RENEW.
WE ARE ALSO IN THE PROCESS OF
LAUNCHING TWO NEW PROGRAMS TO
SUPPORT THE HEAD TO HEAD
COMPARISON OF VACCINE ADJUVANTS.
FINALLY FOR THE EXPANDED --
EXPANDING ACCESS WE HAVE
PUBLISHED THE NIAID STRATEGIC
PLAN FOR RESEARCH ON VACCINE
ADJUVANTS THIS IS AVAILABLE ON
OUR WEBSITE, AND ALSO SHOWS UP
THROUGH WEB SEARCH BUT ALSO
WITHIN THE PAST YEAR WE LAUNCHED
THE VACCINE ADJUVANT COMPENDIUM
WHICH IS ONLINE DATABASE
DESIGNED TO PROVIDE INFORMATION
ON ADJUVANTS THAT IS RAILABLE TO
THE RESEARCH COMMUNITY.
NOW FOR THE NEXT FEW SLIDES I
WILL FOCUS FAR MORE JUST ON THE
ADJUVANT DEVELOPMENT PROGRAM,
THAT IS THE PROGRAM WE ARE
ASKING FOB RENEWED.
SO THE ADJUVANT DEVELOPMENT
PROGRAM IS EXTREMELY PRODUCTIVE
WE HAVE MADE SOME VERY NOTABLE
ACCOMPLISHMENTS THE PAST FEW
YEARS.
WE HAVE SUPPORTED THE
PRE-CLINICAL DEVELOPMENT OF 14
ADJUVANTS SIX ARE ABOUT 40%
CURRENTLY SUPPORTED BY THE
PROGRAM THAT RUNS FROM 2018 TO
2023.
SO YOU CAN SEE HERE THAT WE HAVE
CAST QUITE A WIDE NET OVER THE
ADJUVANT INCLUDES TLR AGONIST
NANO EMULSIONS AND CAR E BOW
HYDRATES AND VERSUS VESICLES.
50% ENTERED PHASE 1 FIRST IN
HUMAN CLINICAL TRIALS.
THE OTHERS ARE WORKING TOWARDS
THE GOALS, SEVERAL ARE PREPARING
TO SUBMIT IND PACKAGES TO THE
FDA IN THE FUTURE SO WE EXPECT
IT TO INCREASE.
THEY ARE TESTED IN OVER 25
CLINICAL TRIALS THAT HAS RANGED
FROM ALLO IMMUNOTHERAPY, TO
INFECTIOUS DISEASE, INFLUENZA,
HIV HEP V E. COLI AND SARS
COV-2.
TWO ADJUVANTS TO HIGHLIGHT.
WHICH ARE BOTH IDENTIFIED
THROUGH DISCOVERY PROGRAM AND
ALSO CURRENTLY BEING SUPPORTED
BY THE DEVELOPMENT PROGRAM OR IN
COVID VACCINE WITH EUA STATUS.
FIRST IS HYDROXYQUINN 2 FROM DR.
DAVID IT IS A TLR 78 AGONIST IN
KOVAXIN.
IT WAS DEVELOPED BY A BIOTECH
APPROVED BY THE WHO AND IS IN
USE IN 13 COUNTRIES.
THE COLLABORATION BETWEEN THAT
AND BROAD BIOTECH WAS CATALYZED
BY OUTREACH EFFORTS WE MADE
UNDER THE ENDOUS VACCINE ACTION
PROGRAM.
SO THE SECOND IS ADVIX CPG FROM
DR. NICK PETROSKI.
A TLR 9 AGONIST USED IN THE
COVID VACCINE SPIKE GENE WHICH
IS ACTIVELY USED IN THE MIDDLE
EAST.
THE ADJUVANT DEVELOPMENT PROGRAM
HAS BEEN VERY -- VERY ACTIVELY
USE THIS TO SUPPORT OTHER NIH
NIAID PROGRAMS.
SO WITH WORK WITH NIAID
COLLEAGUES TO LEVERAGE THE
PROGRAM, TO ADVANCE THERAPEUTICS
AND AL LOW GENE THERAPY AND
DEVELOPMENT OF VACCINES TO TREAT
OR PREVENT DISEASE, WE USE THIS
PROGRAM TO SUPPORT EFFORTS
OUTSIDE OF THE NIAID.
SO WE HAVE A VERY CLOSE
COLLABORATION WITH THE NATIONAL
INSTITUTE OF DRUG ABUSE, OR
ADJUVANT THERE PROGRAM ARE BEING
USED FOR THE DEVELOPMENT OF
VACCINES TO TRY SUBSTANCE USE
DISORDER.
WE ALSO COLLABORATE WITH THE
NATIONAL CANCER INSTITUTE TO
ADVANCE WORK ON THERAPEUTIC
CANCER VACCINES.
FOR THE LAST SLIDE REALLY ABOUT
THE FY 23 INITIATIVE THAT I
WOULD LIKE TO CONTINUE.
THIS IS OUR FLAGSHIP INITIATIVE
FOR THE ADJUVANT DEVELOPMENT
PROGRAM.
ONE CHANGE WE WOULD LIKE TO MAKE
IS HISTORICALLY THE SOLICITATION
IS FOCUSED ON DEVELOPMENT OF
ADJUVANTS WITHIN VACCINES OR
INFECTIOUS DISEASE.
FOR THIS ITERATION WE LIKE TO
OPEN THAT UP TO ALSO ALLOW
PROPOSALS DEVELOP ADJUVANTS
WITHIN CONTEXT OF IMMUNE
MEDIATED DISEASE.
AS BEFORE, WE WOULD LIKE TO
SUPPORT THE PRE-CLINICAL
DEVELOPMENT AND OPTIMIZATION OF
VACCINE ADJUVANTS NO CHANGES
HERE.
WE WOULD ALSO LIKE TO CONTINUE
TO USE CONTRACT MECHANISM ALLOWS
GREATER OVERSIGHT AND INCREASE
FLEXIBILITY.
THE PERIOD OF PERFORMANCE FOR
THE CONTRACTS, FIVE YEARS, SO
THERE'S REALLY NO CHANGE FROM
THE CURRENT PROGRAM.
SO I HOPE WE ARE ABLE TO
CONTINUE WITH THIS PROGRAM, IT
IS HIGHLY SUCCESSFUL AND REALLY
QUITE EXCITED TO SEE WHAT IS
GOING TO HAPPEN WITHIN THE NEXT
FIVE YEARS.
SO I'M HAPPY TO ANSWER ANY
QUESTIONS PEOPLE MIGHT HAVE.
THANK YOU.
MARVELOUS, THANK YOU.
BALI, LOOKED LIKE YOU MIGHT HAVE
BEEN SPEAKING.
>> I WAS SPEAKING TO MYSELF.
>> OKAY.
WE HAVE ANY OTHER COMMENTS OR
QUESTIONS?
>> SEEMS LIKE A WINNER.
>> APPROVE.
>> AGREE.
>> GREAT PROGRAM.
>> OKAY.
IN THAT CASE, IN THE INTEREST OF
TIME LET'S JUST MOVE ON UNLESS
THERE ARE QUESTIONS TO A MOTION
TO APPROVE THIS MOVING FORWARD
IN A SECOND.
>> SO MOVED.
>> SECOND.
>> GREAT.
THANK YOU ALL.
THAT LETS US WRAP UP NOW.
AND I WANT TO ONCE AGAIN THANK
THE SPEAKERS TODAY FOR JUST A
REALLY TERRIFIC SET OF
PRESENTATIONS AND PANEL
DISCUSSION WHICH WAS REALLY
NICE.
>> DAN, IF I COULD ASK THE
COUNCIL MEMBERS TO VOTE IN THE
ELECTRONIC COUNCIL BOOK TO
APPROVE THAT RESEARCH CONCEPT
CLEARANCE.
>> JUST TO ADD IF WE COULD ALSO
APPROVE THE THREE SBIR TOPICS AS
WELL.
>> COULD YOU REMIND US WHERE WE
ACCESS VOTING FOR THOSE?
I DON'T SEE IT.
>> IT SHOULD BE THE VOTING
MATERIALS UNDER THE OPEN SESSION
SECTION.
YOU SEE THAT, VOTE ON DOCUMENTS.
>> OPEN SESSION.
>> UH-HUH.
>> OKAY.
>> WHEN YOU OPEN THE THINGS THAT
CONTAIN IT IS TEXT BUT NOT WHERE
TO VOTE.
>> SHOULD BE TOWARDS TOP OF THE
PAGE.
>> ARE OTHERS SEEING IT?
>> I'M NOT SEEING ALSO.
>> IF THAT CONTINUES TO BE A
PROBLEM CAN WE JUST HAVE EMAILS
SENT TO YVETTE.
>>
>> ABSOLUTELY.
YOU GOT IT.
>> UNDERSTOOD.
ANY COMMENTS YOU HAVE AS WELL,
THOSE COULD ALSO BE CAPTURED BY
EMAIL.
GREAT.
THANK YOU SO MUCH.
>> LET'S JUST PLAN ON EMAIL TO
YVETTE, EVERYONE HAS HER ADDRESS
BUT IF THERE ARE ANY QUESTIONS
YOU CAN SEND REMINDER IF YOU
DON'T HEAR FROM ANYBODY.
>> I WILL.
>> DID YOU SEE APPROVAL OF THE
PRE-SBIRs?
>> THE THREE THAT WAS PREVIOUSLY
MENTIONED?
>> WE WOULD LIKE AN OFFICIAL
VOTE ON THE THREE SBIR TOPICS AS
WELL.
>> RIGHT.
>> MOVE TO APPROVE.
SPEAKER5: (INAUDIBLE).
>>
>> CORRECT.
>> APPROVAL.
>> I HAVE TROUBLE WITH THE
RANKING ONLINE SO I SET MY
RANKING TO (INAUDIBLE).
>> THAT'S FINE.
>> SEND AN EMAIL.
>> I DID AS WELL.
SO I WILL DO THAT NOW.
>> WE SENT FEW MORE TO AMY.
>> YOU CAN ESSENTIAL TO ME, IF
YOU SENT TO AMY, IT IS NOT --
YOU CAN SEND TO ME, IF YOU SENT
TO AMY THAT IS NOT A PROBLEM.
WE ALL WORK TOGETHER.
>> ALL RIGHT.
THAT'S TERRIFIC.
THEN THAT ALLOWS US TO WRAP UP
AND GET ON TO THE REST OF THE
DAY.
THANK YOU SO MUCH.
BYE-BYE
>> THANK YOU.