IT IS A PLEASURE TO INTRODUCE
SHANE CROTTY, REMARKABLY AS AN
UNDERGRAD HE COMBINED THIS
TRAINING AND WRITING AHEAD OF
THE CURVE, A BIOGRAPHY OF DAVID
BALTIMORE.
IF YOU GOOGLE SEARCH FOR CROTTY,
AND BALTIMORE AND CSPAN YOU WILL
FIND A VERY YOUNG SHANE'S 2001
APEERPANCE ON BOOK TV TALKING
ALL ABOUT HIS BOOK FOR 45
MINUTES.
SHANE NEXT DID A Ph.D. WITH
ALSO FANTASTIC PRODUCT OF DAVID
BALTIMORE NAMED [INDISCERNIBLE]
STUDY AT UCSF, STUDYING POLIO
VIRUS, STUDYING THE LONG
STANDING PROBLEM ON HOW THE 1 OF
THE FIRST ANTIVIRAL DRUGS WORKS.
AND SHANE SHOWED THIS WORKS
MOSTLY IN VIVO BY INDUCING ERROR
CATASTROPHE IN RNA VIRUSES
INCLUDING THE POLIO VIRUS WE'RE
STUDYING.
SHANE ALSO SHOWED 1 OF MY
FAVORITE PAPERS OF HIS THAT
QUITE REMARKABLY POLIO VIRUS IS
ABLE TO ESCAPE THE ANTIVIRAL
EFFECTS OF--1 OF MY FAVORITE
DRUGS WHICH TARGETS THE HOST
SECRETORY PATHWAY, PEOPLE SAY
THAT TARGETING THE HOST PATHWAY,
YOU GET AROUND THE PROBLEM OF
VIRAL AVOIDANCE ON THE HOST AND
SHANE SHOWED BRILLIANTLY IN THIS
PAPER WHICH I DON'T THINK A LOT
OF PEOPLE KNOW ABOUT, THIS IS
JUST IS NOT TRUE, VIRUSES ARE
VERY, VERY CLEVER.
I HAD THE PLEASURE OF FIRST
MEETING SHANE WHEN HE APPLIED
FOR A POST DOC IN MY LAB.
HE MIGHT REMEMBER MEETING
DR. HATCHER IN HIS BATH ROBE
WHEN WE KNOCKED ON THE WRONG
DOOR LOOKING FOR HIS SISTER WHO
WAS LIVING ON CAMPUS AT NIH.
IT WAS CLEAR TO ME AT THE TIME
THAT SHANE WAS FULLY CAPABLE OF
BEING A PI AND I THINK I MADE
THAT CLEAR TO SHANE.
I HOPE I DID, THE PROMISE HE
SHOWED WAS JUST ABSOLUTELY
REMARKABLE.
HE CHOSE WISELY CHOSE ON DO A
SHORT AND HIGHLY PRODUCTIVE POST
DOC NOD IN MY LAB, WHERE IN JUST
2 YEARS HE BECAME AN EXPERT IN
VIRAL IMMUNOLOGY, FOCUSING MORE
OR LESS ON THE GENERATION OF
MEMORY B-CELLS BUT I'M SURE HE
GOT GREAT EXPOSURE TO T-CELLS
WHICH [INDISCERNIBLE] LAB IS
ALSO FAMOUS FOR.
SHANE STARTED HIS LAB IN 2003
AND BASICALLY BECAME A WORLD
LEADER IN ADAPTIVE ANTIVIRAL
UMPIRESUNITY, PHOBEUSING ON
T-CELL BIOLOGY, PARTICULARLY IN
THE CONTEXT OF HIV AND
VACCINATION.
WHEN COVID CAME ALONG, SHANE
ALONG WITH HIS CLOSE COLLEAGUE,
ALONG WITH ALEX [INDISCERNIBLE]
PUBLISHED CLASSIC STUDIES OF
HUMAN BNT RESPONSES TO
SARS-COV-2.
MANY OF YOU KNOW SHANE FROM HIS
NUMBER OF APPEARANCES ON THIS
WEEK IN VIROLOGY, IT'S A
FANTASTIC PODCAST FROM
[INDISCERNIBLE].
IF YOU DON'T KNOW IT, JUST
SEARCH FOR TWIV, AND CROTTY AND
SHANE'S APPEARANCES ARE JUST
FANTASTIC.
HOW MANY TIMES HAVE YOU BEEN ON
THERE, 4, 5?
MANY.
A LOT.
IN ANY EVENT THIS IS A FANTASTIC
FORUM FOR VIRUSES AND VIRAL
IMMUNOLOGY AND SHANE IT'S A
GREAT PLEASURE TO WELCOME YOU
VIRTUALLY ANYWAY TO NIH AND I
HOPE TO SEE YOU SOMETIME IN THE
NEAR FUTURE IN PERSON.
>>THANKS FOR THAT INTRO, I
LOVE HOW YOU MENTIONED THE VIRUS
PAPER.
THAT LITERALLY WAS A BET OVER A
BEER WITH ANOTHER GRAD STUDENT
THAT THEY WERE THE CELL
BIOLOGIST IN THE LAB AND DOING
GREAT WORK AND THEY JUST SAID
IT'S IMPOSSIBLE FOR THE VIRUS TO
ESCAPE A CELLULAR PROTEIN
REQUIREMENT AND BET A BEER ON
IT.
[LAUGHTER]
AND IT WAS DETERMINED AND TESTED
OUT.
I WON'T BE TALKING ABOUT THAT
FOR THE REST OF THE DAY.
THANKS FOR HAVING ME AND THIS IS
A GREAT FORUM AND A FANTASTIC
GROUP OF RESEARCHERS TO TALK TO.
I WILL TALK ABOUT PROJECTEDS
WE'VE DONE IN THE CONTEXT OF
COVID, AND SOME RELATED PROJECTS
ACTUALLY THAT REALLY GET AT
INFORMING, SHOWING OW COVID
VACCINE STUDIES AND COVID
IMMUNOLOGY INFORMS OTHER
PROGRAMS.
I'M GOING TO START HERE WITH
SOMETHING YOU ALL KNOW WELL BUT
IT IS CERTAINLY INCREDIBLY
IMPORTANT AND OUR UNDERSTANDING
OF COVID AND OBVIOUSLY THE COVID
VACCINES HAVE REALLY BEEN HUGE
THINGS OVER THE PAST COUPLE OF
YEARS.
OUR WORK IN THIS AREA REALLY
STARTED WITH ALEX
[INDISCERNIBLE] EARLY IN 2020
WHEN THERE WAS A HUGE AMOUNT OF
SPHERE AND UNCERTAINTY ABOUT
MOST EVERYTHING RELATED TO
COVID-19 AND INCLUDING WHETHER
THIS WAS A DISEASE THAT WAS A
CONSEQUENCE OF A FACT THAT
PEOPLE JUST DIDN'T MAKE IMMUNE
RESPONSES OR ADAPTIVE IMMUNE
RESPONSES TO THIS VIRUS AND/OR
THAT PEOPLE MADE VERY UNUSUAL
ADAPTIVE IMMUNE RESPONSES TO
THIS VIRUS AND THOSE WERE THINGS
THAT WE THOUGHT WE COULD
POTENTIALLY HELP OUT WITH IN
UNDERSTANDING AND THAT, SUCH
UNDERSTANDING MAY BE HELPFUL FOR
VACCINE PROGRAMS, WHICH VACCINE
PROGRAMS WERE ALREADY UNDERWAY
INCLUDING AMAZING EFFORTS BY THE
VRC AND MODEL --MODERNA AND THEE
LOTS OF CONCERNS ABOUT WHETHER
SPIKE ALONE WAS A TARGET AND
AGAIN, WHETHER THERE WAS SOME
SORT OF IMMUNO DIVERGENT
RESPONSES RELATED TO THIS VIRUS
THAT MIGHT BE PROBLEMATIC FOR
THIS EXAMPLE, FOR VACCINES OR IF
WE WERE JUST GOING TO THE WRONG
TYPE OF IMMUNE RESPONSES FOR
THIS TYPE OF IMMUNITY.
SO THAT WAS A SIMPLE TOPIC OF
THIS PAPER FROM APRIL, MAY, FROM
MAY 2020 WHERE WE SAID, WELL,
WHAT ARE THE ADAPTIVE IMMUNE
RESPONSES LOOK LIKE IN PEOPLE
WITH AVERAGE CASES OF COVID-19.
SO PEOPLE HAVE GOT INFECTED, DID
NOT REQUIRE HOSPITALIZATION BUT
CLEARED THE VIRUS AND PRESUMABLY
MADE A SUCCESSFUL ADAPTIVE
IMMUNE RESPONSE THAT CLEARED THE
VIRUS, WHAT DID THAT IMMUNE
RESPONSE LOOK LIKE AND IN BRIEF,
WE SAW LIKE MULTIPLE LABS HAD
SEEN AT THAT POINT THAT
ESSENTIALLY ALL OF THOSE
INDIVIDUALS MADE ANTIBODY
RESPONSES DESPITE BUT NOTABLY
THEY ALSO MADE CD4 T-CELL
RESPONSES AND CD-4 T-CELL
RESPONSES TO VIRAL PROTEINS AS
WELL AS MANY PEOPLE HAD
DETECTABLE REACTIONS TO THE
RESPONSES AND THE FUNCTIONALITY
OF THIS CELLS LOOK LIKE 1 WOULD
EXPECT FOR A QUOTE-UNQUOTE OR
JUST AN UNKNOWN NEW RESIRATTORY
VIRAL INFECTION, THE
FUNCTIONALITIES LOOK LIKE THE
TYPES OF THINGS YOU WOULD GET IN
AN ANTIVIRAL RESPONSE AND IN
ADDITION SPIKE WAS AN IMMUNO
DOMINANT TARGET OF THOSE
RESPONSES INDICATING THAT SPHIEK
WAS INDEED A REASONABLE CHOICE
IF YOU WERE GOING WITH A SINGLE
COMPONENT VACCINE AND THESE
STUDIES HAD A VARIETY OF
RAMIFICATIONS, CERTAINLY 1 OF
THEM WAS--IT WAS REALLY
INTERPRETED BY A NUMBER OF
VACCINE MANUFACTURES THAT
ESSENTIALLY THEY WERE ON THE
RIGHT PATH AND THAT THEY COULD
FOCUS THEIR EFFORTS INSTEAD OF
TRYING MANY DIFFERENT VACCINE
STRATEGIES, WHERE I THINK I
COULD FOCUS ON SPIKE ONLY
VACCINES AND TRY AND ILLICIT
CONVENTIONAL CD4 RESPONSES IF
THEIR PLATFORMS ALLOWED.
THE SECOND PROGRAM WE EXPLORED
INTENSIVELY, IN THE FALL OF 2020
THERE WAS LOTS OF FEAR AND
UNCERTAINTY ABOUT WHETHER PEOPLE
WOULD BE PROTECTED FROM
REINFECTION, WERE CORONA VIRUSES
SPECIAL IN SOME WAY AND THAT
PEOPLE JUST DON'T DEVELOP IMMUNE
MEMORY AND THAT WAS 1 OF THE
COMMON TALKS POINTSA THE TIME
AND WE FELT WE COULD CONTRIBUTE
TO THAT, NOT IN TERMS OF
DIRECTLY MEASURING REINFECTION
RATES, RIGHT?
THAT WOULD COME FROM OBVIOUSLY
EPIDEMIOLOGICAL STUDIES BUT BY
DIRECT MEASUREMENTS OF IMMUNE
MEMORY TO A PRIMARY VIRAL
INFECTION IN HUMANS AND SEE WHAT
IT WOULD LOOK LIKE AND THAT WAS
PUBLISHED IN THIS STUDY WHICH
WAS POSTED ONLINE AROUND
THANKSGIVING 2020.
WE HAD A LAB PARTY RECENTLY
WHERE SOMEBODY MADE A VERY NERDY
CAKE FOR THE LAB THAT HAD LAB
PAPER QR CODES PRINTED ALL OVER
IT AND I WAS LIKE, IT WAS REALLY
UNEXPECTED, AND THEY'RE LIKE OH
YEAH, THIS IS A THING NOW, YOU
DO IT WITH YOUR SLIDESSA THE
SEMINAR AND YOU HAVE THE QR CODE
IN SEMINAR AND SO THERE YOU GO
AND I'M TRYING IT OUT AND IT'S
IN QR CODE.
A CRITICAL PROBLEM WITH IMMUNE
MEMORY GOING BACK TO MY DAYS IN
[INDISCERNIBLE] LAB AND MANY
OTHER LABS BEFORE IT SHANKAR IT
IS QUITE HARD TO PREDICT IMMUNE
MEMORY AND SO A FOCUS FOR US WAS
TO WAIT UNTIL 6-8 MONTHS POST
INFECTION SO WE CAN GET A SENSE
OF THE CONNECTED IMMUNE MEMORY
AND REALLY TAKING THE APPROACH
WE'VE TAKEN IN ALMOST ALL OF OUR
STUDIES IS REALLY A WHOLISTIC
LOOK AT THE ADAPTIVE IMMUNE
RESPONSES.
CERTAINLY MEASURING ANTIBODIES
AND ALSO MEASURING THE OTHER
MAJOR COMPONENTS OF ADANTE
FOWLERRIVE IMMUNITY WHICH WOULD
BE MEMORY B-CELLS, MEMORY CD4S
AND MEMORY CD8S AND ACROSS
MULTIPETRESSABLE ANTIGENS AND
WHEN WE DID THAT, WE SAW THAT
PEOPLE DID DEVELOP ENHANCED
MEMORY AFTER INFECTION AND BY
WAITING UNTIL APPROXIMATELY 8
MONTHS POST INFECTION, WE BEING
SEE WHAT THE KINETETTICS OF
THOSE RESPONSES ARE AND ON THE
LEFT HERE WE HAVE ANTIBODY
TITERS AND THESE WERE REPORTED
BY MULTIPLE LABS AT THE TIME
WHICH ARE THAT ANTIBODIES ARE
RELATIVELY LOW AND AFFECT PEOPLE
BUT SOMETHING LIKE 90-98% OF
PEOPLE DO BECOME ANTIBODY
POSITIVE AND THOSE TITERS DROP
OVER A RELATIVELY SHORT TIME
FRAME BUT BY 6 MONTHS ARE REALLY
RATHER STABLE AND INDEED THEIR
DATA IN THE LITERATURE NOW OUT
TO A YEAR AND A HALF OR 2 YEARS
SEEING THESE INFECTION INDUCED
ANTIBODY TITERS ARE TABLELY
MAINTAINED AND WHAT WE WERE
ADDING TO THAT LITERATURE WAS
REALLY THE CELLULAR ASPECTS, THE
MEMORY B-CELLS, THE CD8 T-CELLS
AND CD4 T-CELLINGS AND PROBABLY
THE MOST SURPRISING FINDING WAS
THAT PEOPLE HAVE MORE MEMORY
B-CELLS POST INFECTION AND AT 1
MONTH POST INFECTION TO FOLLOW
THE OPPOSITE KINETICS OF THE
ANTIBODY RESPONSE AND WE SAW
THIS FOR SPIKE RBD AND
NUCLEOCAPSID AND THIS IS
REPRODUCED BY MULTIPLE LABS.
AND THAT THE KINETICS AND T-CELL
MEMORY WAS DIFFERENT FROM THE
KINETICS OF MEMORY B-CELLS AND
OF SERUM ANTIBODIES SO THESE
DIFFERENT COMPONENTS OF IMMUNE
MEMORY DO NOT ALL FOLLOW THE
SAME KINETICS AND THAT FOR CD8S
ABOUT 70% OF PEOPLE HAD
DETECTABLE RESPONSES EARLY,
ABOUT 50% AT 8 MONTHS, BUT OF
THE DETECTABLE RESPONSES THE
HALF LIFE OF THOSE RESPONSES WAS
ABOUT 125 DAYS, WHICH ACTUALLY
MATCHED WHAT [INDISCERNIBLE] HAD
DEFINED EARLIER FOR THE YELLOW
FEVER VIRUS VACCINE WHICH IS A
RESPONSE TO INFECTION LOOKED
LIKE IT WOULD BE QUITE GOOD IN
TERMS OF THE QUALITY OF DURATION
EMPLOY THE CD4 RESPONSE TO THIS
VIRUS ARE QUITE ROBUST, ALMOST A
HUNDRED% OF PEOPLE WERE POSITIVE
INITIALLY AND 98% OF PEOPLE
POSITIVE AT 6-8 MONTHS WITH THE
A SIMILAR HALF LIFE SUGGESTING
THAT THE CD4 AND 8 MEMORY WOULD
BE LONG LASTING.
THERE WAS BT ANY BENCHMARK IN
THE LITERATURE FOR LOOKING AT
KINETICS OF CD4 T-CELL MEMORY TO
A PRIMARY HUMAN INFECTION.
SO THIS IS ACTUALLY NOW A
PRIMARY REFERENCE POINT FOR THE
FIELD FOR WHAT IMMUNE MEMORY
LOOKS LIKE IN THE CD4 T-CELL
COMPARTMENT TO A VIRAL INFECTION
AND IN FACT, OVERALL, THIS WAS A
VERY LARGE STUDY IN TERMS OF
LOOKING AT MEMORY TO ALL OF
THESE COMPONENTS AND PROBABLY
THE LARGEST STUDY BEFORE THAT TO
AN ACUTE INFECTION WAS PROBABLY
ABOUT 3 OR 4 INDIVIDUALS AND IN
THIS STUDY WE HAD 188.
I WILL SAY JULIE [INDISCERNIBLE]
AND [INDISCERNIBLE] HAD A
SIMILAR STUDY PUBLISHED I THINK
6 MONTHS LATER AND I THINK THEY
DID A NICER JOB OF CALCULATING
HALF LIVES, WHERE INITIALLY THE
HALF LIVES LOOK LIKE THIS AND
THEY PROBABLY PLATEAU OR NEARLY
PLATEAU THAT THE HALF LIVES
PROBABLY BECOME MORE LIKE A YEAR
AT THESE LATER TIME POINTS AND
IT WOULD BE GOOD TO SEE FURTHER
FOLLOW UP ON THOSE, BUT
ALTOGETHER, THE RESULTS
INDICATED THERE WAS SUBSTANTIAL
IMMUNE MEMORY AFTER THIS
INFECTION, AND IT WAS PROBABLY
SUFFICIENT IMMUNE MEMORY TO
PROVIDE PROTECTION AT LEAST FROM
SERIOUS SARS-COV-2 INFECTIONS
FOR YEARS INTO THE FUTURE, THIS
IS BEFORE THE EXISTENCE OF
VARIANTS WHICH IS DIRECTLY
LOOKING AT IMMUNE MEMORY AND IN
FACT LOOKING AT EPIDEMIOLOGICAL
STUDIES HAVE SUPPORTED THAT OVER
AND OVER AGAIN AT THIS POINT.
AND JOHN MENTIONED WHAT WOULD
HAPPEN IF YOU GOOGLED MY NAME
AND CSPAN IN BALTIMORE.
IF YOU GOOGLE MY NAME AND CSPAN,
YOU WILL FIND DIFFERENT HITS
INVOLVING INTERESTING DEBATES
RELATING INTERPRETING TO THIS
DATA WHICH INCLUDED SENATOR RAND
PAUL AND TONY FAUCI AMONGST
OTHERS BUT THAT'S A TOPIC FOR
ANOTHER DAY.
WITH ALL OF THAT ESSENTIALLY AS
BACKGROUND, WE THEN MOVE TO
UNDERSTAND IMMUNE MEMORY TO
COVID-19 VACCINES.
AND FOR NOW I WILL TALK THROUGH
THE WORK WE PUBLISHED EARLIER
THIS YEAR WHICH WAS THE FIRST
PUBLICATION TO LOOK AT
HEAD-TO-HEAD COMPARISON TO
IMMUNE MEMORY TO 4 COVID-19
VACCINES, INCLUDING A PROTEIN
VACCINE TO LOOK AT IMMUNE MEMORY
OUT AT LEAST 6 MONTHS WHERE WE
FEEL LIKE WE REALLY DO HAVE TO
WAIT THAT LONG TO GET A SENSE OF
WHAT MEMORY'S LOOKING LIKE AND
TO DO SO AGAIN IN A RELATIVELY
WHOLISTIC WAY OF LOOKING AT ALL
3 MAJOR BRANCHES OF ADAPTIVE
IMMUNITY, THE HUMORAL IMMUNITY
AS WELL AS CD4 AND 8 T-CELLS AND
WE FELT LIKE THESE WERE KEY
COMPARISONS TO DO FOR
UNDERSTANDING WHY ARE THERE
SIMILAR OR DIFFERENT OUTCOMES
WITH DIFFERENT COVID-19 VACCINE
PLATFORMS AND ALSO FOR LOOKING
INTO THE FUTURE, LOOKING TO THE
FUTURE FOR VACCINE DEVELOPMENT
TO OTHER PATHOGENS.
ARE SOME OF THESE PLATFORMS MORE
SUITED TO SOME PATHOGENS THAN
OTHERS FOR EXAMPLE, OR IS--OR
RNA VACCINES ESSENTIALLY
MIRACULOUS, THAT THEY DID
SOMETHING PHENOMENAL THAT REALLY
CONVENTIONAL OR MORE
CONVENTIONAL VACCINE
TECHNOLOGIES COULD NOT.
THOSE WERE STILL OPEN QUESTIONS
FROM AN IMMUNOLOGICAL
PERSPECTIVE BECAUSE IT IS HARD
TO RECRUIT PEOPLE WHOF GOTTEN
EACH OF THESE DIFFERENT VACCINES
AND PARTICULARLY FROM A T-CELL
SIDE, YOU HAVE TO BE DOING THOSE
ASSAYS IN THE SAME LAB FOR THEM
TO BE COMPARABLE AND IN
ADDITION, WE HAD LOCAL INFECTED
INDIVIDUALS SO THAT WE CAN
COMPARE VACCINE ILLICITTED
IMMUNE MEMORY.
SO WHAT DID ALL OF THAT LOOK
LIKE?
HERE'S THE WAY WE STRUCTURED THE
FIGURURES, WE DID ANTIBODIES,
AND THEN EACH OF THESE OTHER
IMMUNE COMPONENTS AND IN HERE
WE'RE SHOWING THE RESPONSES TO
EACH OF THE VACCINES SO MODEL
CITIZEN BERNEA, PFIZER, J& J
AND NOVAVAX, AND AT THE DOSES
AND TIMING AND USE IN THE UNITED
STATES AND I'M SORRY, I SHOULD
HAVE BEEN CLEAR--FOR ANYBODY
WHO'S NOT FAMILIAR WITH THE
NOVAVAX VACCINE, NOVAVAX IS A
RECOMBIN ANT SPIKE PROTEIN WITH
[INDISCERNIBLE] ADJUVANT AND IT
SERVES AS A USEFUL COMPARISON
HERE BECAUSE THERE'S A HUNDRED
YEARS MORE EXPERIENCE WITH
PROTEIN BASED VACCINES THAN RNA
VACCINES AND SO, PROVIDES A
VALUABLE COMPARISON.
ONE, CAVEAT TO THIS IS THAT WE
WERE NOT ABLE TO RECRUIT THESE
INDIVIDUALS IMMEDIATELY AFTER
IMMUNIZATION, SO WE ONLY HAVE
THE MEMORY TIME POINTS FOR THE
NOVAVAX INDIVIDUALS.
T1 WOULD BE PREVACCINATION.
T2 IS AFTER A FIRST VACCINATION
IN THE CONTEXT OF THE RNA
VACCINES, T3 AND 2 WEEKS AFTER
THE SECOND IMMUNIZATION, T4
WOULD BE 3 MONTHS OUT AND T5
WOULD BE 6 MONTHS OUT
APPROXIMATELY FOR EACH OF THESE,
OKAY?
AND THEN THE THICK LINES IN EACH
CASE WHICH YOU CAN FOCUS ON ARE
THE GMEs OF THE ENTIRE COHORT,
AND THEN WE HAVE CONVENIENT
REFERENCE OVER HERE FOR HOW DOES
THIS ALL COMPARE TO INFECTED
INDIVIDUALS.
SO INFECTED INDIVIDUALS ARE
BEING SHOWN IN YELLOW WITH THE
SAME COLOR CODES FOR THE
VACCINES OVER HERE.
SO IN TERMS OF ANTIBODY
RESPONSES THIS WORK WAS DONE IN
THE GROUP BY POST DOCTORAL
FELLOWS ZALI ZHANG, AND
ASSISTANT PROFESSOR AT UCSD GEN
DAN AND WE CAPITULATED THAT THE
VACCINES ARE FANTASTIC AT
ILLICITTING HIGH ANTIBODY TITERS
QUICKLY AND CONSISTENTLY ACROSS
INDIVIDUALS BUT WITH A PRETTY
DRAMATIC DECAY OVER A 6 MONTH
PERIOD OF TIME AND TO ME THE
BEST DAT I'VE SEEN IS THAT THOSE
REALLY CONTINUED TO DECAY FOR 10
MONTHS AFTER 2 DOSES OF RNA
VACCINE.
AND ACTUALLY OUT AT 6 MONTHS THE
NOVAVAX PROTEIN HAS NEUTRALIZING
ANTIBODY TITERS QUITE COMPARABLE
TO MODEL CITIZEN DERNA AND
PFIZER WHICH ARE SIGNIFICANTLY
HIGHER THAN WHAT 1 GETS AFTER
INFECTION OR AFTER A SINGLE DOSE
J& J.
NOW NOTE ABLE I WAS INCREEINGING
ABOUT THE J& J VACCINE AND
OTHER GROUPS HAVE NOTED THIS AS
WELL IS THAT AT A MONTH POST
VACCINATION, IT'S REALLY
RELATIVELY POOR NEUTRALIZING
ANTIBODY TITERS, IT'S ONLY ABOUT
50% OF PEOPLE HAVE TITERS THAT
ARE ABOVE 20 BUT INTRIGUINGLY
THOSE TITERS INCREASE OVER TIME
AND AS A COHORT PEOPLE HAVE
HIGHER AN AVERAGE NEUTRALIZING
TITERS AT 1 MONTH THAN THEY DID
AT 6 MONTHS.
WHICH IS THE TREND YOU GET WITH
RNA VACCINES INDICATING THESE
VACCINE PLATFORMS ARE ENGAGING
DIFFERENT IMMUNOLOGICAL
MECHANISMS OF ACTION.
IF WE LOOK AT CD4 T-CELL
RESPONSES WE SEE THAT THE RNA
VACCINES ARE VERY GOOD AT
ELUCIDATING ROBUST RESPONSES
BOTH ACUTE AND OUT AT MEMORY
TIME POINTS.
SIX MONTHS BOTH VACCINATION,
THERE'S REALLY LESS THAN A 2
FOLD DECLINE IN THE MAGNITUDE OF
THE SPIKE SPECIFIC CD4 T-CELLS
WHICH IS REALLY QUITE IMPRESSIVE
IN MY OPINION FOR THE R NA
VACCINES AND IN FACT, THEY
RECEIVED HIGHER CD4 RESPONSES
THAN INFECTION.
NOW INFECTION ALSO ILLICITS
T-CELL RESPONSES TO OTHER
ANTIGENS, RIGHT?
BESIDES SPIKE, BUT STILL IF YOU
SPECIFICALLY FOCUS ON SPIKE,
THESE ARE STILL PRETTY
IMPRESSIVE RESPONSES AND REALLY
THE RNA VACCINE RESPONSES ARE IN
LINE WITH THE NOVA VAX AND IT
CAN DO WELL AT ILLICITTING
RESPONSES IN COMPARISON TO RNA
AND IN OUR HANDS WITH THESE
TYPES OF ASSAYS ACTUALLY J& J
WAS THE LOWEST OF THE RESPONDERS
WHICH REALLY CONTRAST WITH
INITIAL EXPECTATIONS THAT A
VIRAL VECTOR WOULD BE THE BEST
AT ILLICITTING T-CELL RESPONSES
SO AT LEAST WITH CD4S, WE DID
NOT FIND THAT TO BE THE CASE BY
ANY OF THESE METRICS ALTHOUGH IT
CERTAINLY DID ILLICIT CD4
RESPONSES AT 4 AND 6 MONTHS.
WE DID BREAK THIS DOWN INTO
INDIVIDUAL CYTOKINES AND I WILL
HEIGHT LIGHT WE WERE INTRIGUED
THAT THERE ARE A NUMBER OF
GRANZYME B CD4 CELLS ILLICITTED
BY EACH OF THESE 4 VACCINE
PLATFORMS IN HUMANS WHICH WASN'T
NECESSARILY WHAT WE EXPECTED TO
SEE.
OF KEY IMPORTANCE, IS THE
ABILITY OF THESE VACCINES TO
ILLICIT TFH CELLS, THEY ARE THE
SUBSET OF CD4s THAT ARE
REQUIRED FOR HELPING B-CELLS AND
THEY'RE REQUIRED FOR THE
MAJORITY OF NEUTRALIZING
ANTIBODY RESPONSES TO SARS-COV-2
AND THEY'RE CERTAINLY REQUIRED
FOR ALL OF THE OMICRON
ANTIBODIES HAVE YOU CIRCULATING
IN YOUR BLOOD WHICH ARE THE
SOURCE OF--WHICH ARE THE PRODUCT
OF GERMINAL CENTERS AND AFFINITY
MATURATION WHICH WE WILL COME
BACK TO LATER.
SO THESE CELLS ARE CRITICAL.
THEY'RE NOT GENERALLY AT HIGH
FREQUENCIES IN THE BLOOD BUT
THEY ARE DETECTABLE AND SO WE'RE
ABLE TO SEE THAT THE RNA
VACCINES GENERATE THESE AND
GENERATED THEM WELL, GENERATED
THEM EVEN A BIT BETTER THAN J&
J AND IN LINE WITH NOVA VAX, AND
I WOULD ACTUALLY CONCLUDE THAT I
THINK THAT THE POTENCY OF RNA
VACCINES FOR ILLICITTING
NEUTRALIZING ANTIBODIES AND
BEING SO HAWAIILY PROTECTIVE SO
QUICKLY REALLY COMES DOWN TO
THEIR ABILITY, THEIR IMPRESSIVE
ABILITY TO PRIME CD4 T-CELL
RESPONSES AND DRIVE TFH CELL
DIFFERENTIATION AND I THINK
WE'RE SHOWING THAT HERE.
IN ADDITION TO GENERATING THOSE
TFH CELLS, THESE VACCINES ARE
GENERATING MEMORY TFH CELLS
WHICH IS IMPORTANT FOR BOOSTER
RESPONSES AND SUBSEQUENT TIME
POINTS.
FOR CD8 T-CELLS.
THIS IS WHERE THE LITERATURE WAS
A LOT MORE MIXED IN GOING BACK
TO ACTUALLY EARLY PUBLICATIONS
THAT WE'RE OBSERVING VERY
SIMILAR IMMUNE RESPONSES BETWEEN
THE PFIZER, AND MODERNA VACCINE
EXCEPT IN CD8S WHERE PFIZER
REPORTED RELATIVELY STRONG CD8
RESPONSES AND CONTINUED WORKING
WITH MODERNA GENERALLY REPORTED
LOW TO UNDETECTABLE CD8 T-CELL
RESPONSES.
WE AND OTHER VS WORKED ON THIS
IN A VARIETY OF WAYS, IN
PARTICULAR IN THIS CONSORTIUM,
IT WAS JOSE MATEUS, WORKING WITH
[INDISCERNIBLE].
AND SO A LOT OF THIS PARTICULAR
PROJECT WAS ALEX SETTE, MYSELF
AND DANIEL [INDISCERNIBLE] A
REALLY FANTASTIC ASSISTANT
RESEARCH PROFESSOR HERE, AND
MATEUS HANDLING THE BRUNT OF THE
WORK, WHERE WHAT WE SEE WITH
ESSENTIALLY AN OVERNIGHT
EPITHELIAL RACELLULAR CYTOKINE
STAINING AND THE FOLLOWING THAT
ACTUALLY MODERNA AND PFIZER
VACCINES ARE QUITE GOOD AT
ILLICITTING CD8 T-CELL RESPONSES
TO THE EXTENT THEY ARE
DETECTABLE IN 85-90% OF
INDIVIDUALS AFTER IMMUNIZATION
AND ARE STILL DETECTABLE AND
2/3RDS OF INDIVIDUAL ADDED 6
MONTHS NOT AS GREAT AS I WOULD
LIKE BUT CERTAINLY PRESENT IN
THE MAJORITY OF INDIVIDUALS AND
IN FACT, THOSE RESPONSES ARE
HIGHER OR AS HIGH THAN THE J& J
VACCINE.
WHAT OTHER GROUPS HAVE FOUND IS
THAT IF INSTEAD YOU USE A
SHORT-TERM STIMULATION ONLY A 6
HOUR STIMULATION INSTEAD OF AN
OVERNIGHT STIMULATION, WHAT YOU
SEE IS RESPONSES TO AN ADEN O
VACCINE IN HUMANS AND NOT TO THE
RNA VACCINES SO THIS COMES IN
DOWN GENERAL ASSAYS 1 USES, AND
IN ASSESSING T-CELLS, ICS IS
REALLY MORE IN LINE WITH WHAT
YOU'RE INTERESTED IN BECAUSE DO
YOU WANT TO KNOW ARE THE CELL
SAYS THERE GOOD, THEY DID SEE A
REINFECTION WOULD THEY RECALL,
WHEREAS A 6 HOUR ASSAY IS
TELLING YOU THE CAPACITY FOR
IMMEDIATE EFFECTOR FUMPLEGZS
WHICH IS VERY HIGH, WHETHER CD8
T-CELL RESPONSE WAS ILLICITTED
OR NOT.
WE DO SEE A LITTLE INDICATION OF
THE CD8 RESPONSE AFTER THE IN,
OVAVAX, WE HAVE REPRODUCED THIS
IN A COHORT, 25 INDIVIDUALS HAVE
SOME DETECTABLE RESPONSE, I WILL
NOT FOCUS ON THAT NOW BAH WE DO
THINK THAT'S INTERESTING BECAUSE
IT'S UNCONVENTIONAL FOR A
PROTEIN VACCINE.
AND THE FINAL IMMUNE MEMORY
COMPONENT WE LOOKED AT ACROSS
THESE 4 VACCINES HEAD-TO-HEAD
WERE THE MEMORY B-CELLS WHICH
WERE SPIKE AND RBD, WE FOUND ALL
4 DO ILLICIT MEMORY B-CELLS AND
THOSE DO INCREASE BETWEEN 3
MONTHS AND 6 MONTHS POST
VACCINATION AND I WILL COME BACK
TO THIS AND IT IS INTERESTING
THAT THESE GO UP, WHEREAS THE
ANTIBODY TITERS ARE CLEARLY
GOING DOWN AND THE T-CELL
RESPONSES CERTAINLY AREN'T GOING
UP AND THIS IS SIMILAR TO WHAT
WE SEE IN THE CONTEXT OF
INFECTION AND COMPARING ACROSS
THE 4 VACCINES OTHERS AGAIN
THEY'RE DOING A FANTASTIC JOB OF
GENERATING B-CELL MEMORY, IT
WILL BE ADEN O VIRAL VECTOR OR
EVEN THE PROTEIN VACCINE.
AND HOW DOES ALL THIS CONNECT TO
PROTECT EVALUATION PROCESS
IMMUNITY?
AND I'LL COMMENT JUST A BIT ON
THIS, HAVING TRAINED AS A
VIROLOGIST IT'S ALWAYS CRITICAL
TO THINK OF PROTECTIVE IMMUNITY
IN THE CONTEXT OF THE ANATOMY
AND PATHOGENESIS OF THE
PARTICULAR VIRAL INFECTION THAT
YOU ARE TRYING TO DEAL WITH AND
IN THE CASE OF SARS COV-2 THIS
IS CLEARLY A VIRUS THAT IS RAPID
AT REPLICATING NAISAL CAVITIES
AND ORAL CAVITIES AND VERY RAPID
AT CAUSING ASYMPTOMATIC TO COLD
LIKE DISEASE AND IT'S A RATHER
DIFFICULT VIRUS TO STOP QUICKLY
BUT IN TERMS OF PATHOGENESIS
IT'S A RELATIVELY SLOW INFECTION
IN THE LUNG AND INFECTION IN THE
LUNG IS LOW WITH
HOSPITALIZATIONS, FREQUENTLY 2
WEEKS POST INFECTION OR SYMPTOM
ONSET AND THIS PROTECTIVE
IMMUNITY NEEDS TO KEEP THESE
DIFFERENTIAL CONCEPTS OF
PROTECTION, I. E. PROTECTION
FROM INFECTION, VERSUS
PROTECTION FROM SEVERE DISEASE
IN MIND AS WELL AS THE DIFFERENT
TISSUES IN WHICH THOSE ARE
HAPPENING.
IN BRIEF MY PERSONAL
INTERPRETATION OF THE LITERATURE
IS AS FOLLOWS.
FIRST OF ALL THE SIMPLEST OPTION
FOR ANY VACCINE IS HIGH LASTING
NEUTRALIZING ASPECT BODIES, AND
SARS-COV-2 IS PRIMARY FOR THIS,
I MEAN THIS IS--THIS GENERAL
TOPIC IS LITERALLY WHAT I
FOUNDED MY LAB BASED ON 19 YEARS
AGO WAS GENERATING NEUTRALIZING
ANTIBODY RESPONSES IS KEY FOR
MOST VACCINES AND WHAT WE NEEDED
TO BETTER UNDERSTAND IS THE
FUNDAMENTAL IMMUNOLOGICAL
PRINCIPLES UNDERLYING HOW DO YOU
GENERATE THOSE RESPONSES AND HOW
DO YOU GET THEM TO BE DURABLE.
BUT GIVEN THAT IT WAS CLEAR THAT
INFECTION ITSELF DIDN'T ELICIT
PARTICULARLY HIGH NEUTRALIZING
ANTIBODIES AND THERE WAS LOTS OF
CONCERN ABOUT DURABLE
ANTIBODIES, WE AND OTHERS RAISE
THE ISSUE OF LIF YOU CAN'T
GENERATE HIGH ENOUGH LEVELS OF
NEUTRALIZING ANTIBODIES OR IF
THEY'RE NOT LONG LASTING, ARE
THERE OTHER POTENTIAL MECHANISMS
OF PROTECTIVE IMMUNITY AGAINST
COVID-19 AND ADDITIONAL LAYERS
OF ANTIBODIES.
AND IT HAS BEEN HARD TO MAINTAIN
ANTIBODIES LONG LASTING EITHER
IN THE CONTEXT OF VACCINE BEING
USED OR IN THE CONTEXT OF
VARIANTS AND THE VITRATTURE HAS
VARIOUS LINES OF EVIDENCE
POINTING TO CONTRIBUTION OF
T-CELLS AGAINST COVID-19.
I WON'T GO THROUGH ALL OF THOSE
IN THE INTEREST OF TIME WE CAN
TALK ABOUT THEM IN THE Q&A.
OVER ALL MY PERSPECTIVE OVERALL
WHICH IS THE SAME BACK IN 2020
IS THAT IT'S REASONABLE TO
CONSIDER THAT HOSPITALIZATION
LEVEL COVID-19 IS PREVENTED BY
ANY DESCENT COMBINATION OF
ANTIBODIES, MEMORY B-CELLS, CD4S
AND CD8S.
I HAVE FOUND THAT SOMETIMES
PEOPLE HEAR THIS IN RATHER
DIFFERENT WAYS SO I WILL SAY IT
AGAIN A LITTLE BIT DIFFERENTLY,
I AM NOT SAYING THAT T-CELLS,
THAT ALL THE PROTECTIVE IMMUNITY
AGAINST COVID-19 IS T-CELLS, SO
T-CELLS IS THE MAJORITY OF IT,
WHAT I AM SAYING IS THAT THE
AVAILABILITY DATA POINT TO
CONTRIBUTIONS OF T-CELLS AGAINST
COVID-19 AND IN PARTICULARLY IN
THE CONTEXT OF MORE SEVERE
DISEASE, IT'S REASONABLE TO
CONSIDER THAT THEY DO CONTRIBUTE
AS WELL AS MEMORY B-CELLS
CONTRIBUTING.
AND I LIKE TO THINK OF THIS IN A
LAYERED DEFENSES TYPE OF MODEL
WHERE YOU WOULD LOVE TO HAVE THE
VIRUS STOPPED BY NEUTRALIZING
ANTIBODIES BUT IF YOU DON'T HAVE
ENOUGH, DO YOU HAVE ADDITIONAL
LAYERS OF THE DEFENSE THAT CAN
HELP PREVENT SEVERE COVID-19
FROM OCCURRING.
AND REALLY IF YOU CAN CONSIDER
LAYERED DEFENSES, WE NEED TO
MOVE BEYOND JUST THINKING ABOUT
CIRCULATING IMMUNITY WHICH IS
EVERYTHING THAT I'VE TALKED
ABOUT SO FAR, RIGHT, WERE ALL
MEASUREMENTS IN THE BLOOD TO
ALSO CONSIDERING LOCAL IMMUNITY,
TISSUE RESIDENT MEMORY WHICH
WOULD BE MORE FRONT LINE
DEFENSES AND SO THERE HAVE BEEN
PLENTY OF QUESTIONS ABOUT, WELL,
DID INFECTION ILLICIT TISSUE
RESIDENT MEMORY OR DO THE
VACCINES ILLICIT TISSUE RESIDENT
MEMORY, THOSE ARE MUCH HARDER
QUESTIONS TO ASK BECAUSE YOU
HAVE TO ACCESS HUMAN TISSUE TO
DO SO.
AND SO THOSE ANSWERS HAVE
FOLLOWED BEHIND THE MUCH MORE
COMMON MEASUREMENTS IN THE
CIRCULATION.
AND 1 OF THE FIRST STUDIES TO
SHOW OR TO ASSESS WHETHER OR NOT
THERE WAS TISSUE RESIDENT MEMORY
AFTER SARS-COV-2 INFECTION WHICH
IS THIS 1 LED BY THE WONDERFUL
DONNA FAR BERNEA DEET AND MOST
OF YOU WILL KNOW DONNA FAR
FARBER
HAS DONE AMAZING WORK MAKING USE
OF ORGAN DONOR PROGRAMS IN THE
NEW YORK METROPOLITAN AREA TO
DIRECTLY LOOK AT HUMAN IMMUNE
MEMORY IN TISSUES, IN COMPARISON
TO BLOOD.
AND SO IN THIS PARTICULAR STUDY
WHAT BECAME AVAILABLE JUST
THROUGH THAT--JUST AN EXTENT
RANDOM ENROLLMENT PROCESS WAS
THERE WERE 4 INDIVIDUALS QUHO
DIED FROM COVID UNRELATED CAUSES
AND HAD UNREMARK CALVERT CASINGS
OF COVID-19 AT SOME PREVIOUS
TIME POINTS AND WE COMPARED
WHETHER THOSE INDIVIDUALS, THOSE
4 INDIVIDUALS WHO HAD A HISTORY
OF COVID-19 DID THEY HAVE
DETEBTIBLE B-CELL OR T-CELL
MEMORY IN THEIR LUNGS AND THE
LUNG DRAINING LYMPHNODES.
SO THOSE INDIVIDUALS ARE SHOWN
IN RED HERE.
AND THE SHORT ANSWERS WERE YES,
THEY HAD TISSUE RESIDENT MEMORY
CD4 T-CELLS AND TISSUE MEMORY
CD8 T-CELLS IN LUNGS AND IF
ANYTHING, THERE WERE A HIGHER
FREQUENCY OF VIRUS SPECIFIC CD8
IN THE LUNGS THAN IN THE BLOOD,
AND IT IS NOTABLE HERE BECAUSE
AGAIN, THESE ARE PEOPLE WITH
UNREMARKABLE CASES OF COVID-19
AND THERE STILL WAS ENOUGH
ANTIGEN IN THE LUNGS RIGHT TO
RESULT IN SIGNIFICANT AMOUNTS OF
RESIDENT MEMORY T-CELLS.
WHAT ALEX IN MY GROUP WAS
RESPONSIBLE FOR WAS ASKING THE
QUESTION WERE THERE RESIDENT
MEMORY B-CELLS WHICH IS A MUCH
LESS STUDIED AREA, PARTICULARLY
IN HUMANS SO WE WERE THE FIRST
TO DEMONSTRATE THAT THERE ARE
INDEED ROBUST AMOUNTS OF
RESIDENT MEMORY B-CELLS IN THE
LUNG, SPIKE SPECIFIC AND RBD
SPECIFIC RESIDENT MEMORY B-CELLS
IN THE LUNGS OF PEOPLE WHO HAVE
HAD AGAIN UNREMARKABLE CASES OF
COVID-19 COMPARED TO NEGATIVE
CONTROLS.
THESE PEOPLE WERE ALL ENROLLED
BEFORE THE VACCINES WERE
AVAILABLE SO WE KNOW THESE ARE
ALL INFECTION INDUCED EVENTS,
OKAY.
AND WE DID ALSO SEE MEMORY IN
THE LUNG DRAINING LYMPHNODES,
THAT'S WHAT LLN STANDS FOR AS
WELL AS GUT TRAINING LYMPHNODES
WHICH IS AN IMPORTANT AND
INTERESTING TOPIC.
OTHER LABS HAVE ALSO PUBLISHED
THAT MEMORY T-CELLS ARE
DETECTABLE IN LUNGS OF INVESTED
INDIVIDUALS AND MORE RECENTLY
THERE'S BEEN NICE DATA AVAILABLE
ON NAISAL, NAISAL PHARYNGIAL
MEMORY CELLS, BY UPON J. SUN AND
[INDISCERNIBLE] AMONG RPGHTS
DEMONSTRATING THERE CLEARLY ARE
CDEFICIENCY, 8 AND CD4 MEMORY
T-CELLS IN THESE TISSUES AFTER
INFECTION AND NOT AFTER
VACCINATION WITH R NA VACCINES
WHICH I THINK LARGELY MATCHES
OUR EXPECTATION BUT IS IMPORTANT
TO SEE AND ANYTHINGLY IT LOOKS
LIKE THESE MAY BE RELATIVELY
DURABLE RESPONSES WHICH WARRANTS
MORE INFORMATION BUT AT LEAST
FOR THE MOMENT IT DOESN'T LOOK
LIKE THEY JUST SHOW UP FOR 2
MONTHS AND IN THIS PERSON WHO IS
INFECTED OR IN HYBRID IMMUNITY
IF YOU'VE BEEN INFEBTED OR
VACCINATED AND THEN VACCINATED
AND HAVE A BREAK THROUGH
INFECTION, YOU END UP WITH
HYBRID IMMUNITY WHERE YOU GET
TISSUE RESIDENT MEMORY CELLS,
REALLY AS VERY STRONG
CIRCULATING MEMORY GENERATED BY
VACCINATION.
THERE WAS 1 ADDITIONAL PIECE OF
INFORMATION BY THESE ORGAN DO
DONORS THAT SURPRISED US AND
THAT WAS WHEN WE LOOKED IN THE
LUNG DRAINING LYMPHNODES WE
COULD SEE GERMINAL CENTERS THAT
IN AND OF ITSELF IS
UNSURPRISING, PEOPLE DO GET
OBVIOUSLY EXPOSED TO MANY
THINGS, BUT WE HAD THE CAPACITY
WITH FLUORESCENT PROBE STAINING
TO DEMONSTRATE THERE WERE
SARS-COV-2 SPIKE SPECIFIC
GERMINAL CENTER B-CELLS IN THESE
LUNG DRAINING LYMPHNODES AND THE
PREVIOUS PROBABLY FOR 3 OUT OF 4
OF THESE INDIVIDUALS AND THEY'RE
PREVIOUSLY RECORDED INFECTIONS
WERE 6 MONTHS OR MORE IN THE
PAST AND SO THIS SUGGESTS THAT
THERE WERE ONGOING GERMINAL
CENTERS FOR AT LEAST 6 MONTHS
AFTER AGAIN AN UNREMARKABLE CASE
OF COVID-19 IN THESE LUNG
DRAINING LYMPHNODES.
AND SO NOW, WITH THAT, I'LL
PIVOT TO THESE CONNECTIONS
BETWEEN WHAT WE'VE BEEN
OBSERVING IN THE CONTEXT OF
COVID-19 AND COVID-19 VACCINES
AND WHAT WE'VE BEEN WORKING ON I
WOULD SAY MORE BROADLY IN
VACCINE IMMUNOLOGY, PARTICULARLY
USING--WORKING ON HIV VACCINES
BOTH BECAUSE THE WORLD NEEDS AN
HIV VACCINE AND BECAUSE IT'S A
RATHER FANTASTIC MODEL SYSTEM
FOR VACCINE IMMUNOLOGY BECAUSE
OF THE MANY TOOLS WE HAVE
AVAILABLE.
WE--I MENTIONED TF8 CELLS BEING
IMPORTANT BEING ESSENTIAL FOR
T-CELL AND B-CELLS, AND WE'VE
BEEN STUDYING TFH CELLS FOR A
NUMBER OF YEARS NOW AND AFTER WE
AND OTHERS HOPE TO ESTABLISH
THAT TF8 STYLES WERE REAL AND
IMPORTANT IN 2009, THERE HAVE
BEEN A LOT OF GREAT ADVANCES IN
THAT FIELD BY MANY GROUPS
INCLUDING PAM [INDISCERNIBLE]
GROUP AT NIH AND MANY OTHERS AND
BETWEEN THE ENTIRE WORK OF THE
FEELTD WE HAVE LEARNED MANY
THINGS ABOUT TFH CELLS, AND THEY
HELP THESE CELLS EARLY IN IMMUNE
RESPONSES AS EARLY AS THE FIRST
FEW DAYS, BUT ARE THEN
ABSOLUTELY CRITICAL IN GERMINAL
CENTERS FOR THE ENTIRE PROCESS
OF GERM LINE CENTERS INCLUDING
THE PRODUCTS, THE PRODUCTS
THEMSELVES.
GERMINAL CENTERS ARE ABSOLUTELY
AMAZING IMMUNOLOGICAL EVENTS AND
STRUCTURES.
THESE ARE LITERALLY REALTIME
EVOLUTION WHERE ANY EVOLUTIONARY
PROCESS HAS TO HAVE GENERATIONS
ISSUES RIGHT?
SO THAT'S CELL DIVISION,
MUTATIONS, WHICH ARE SOMATIC
HYPERMUTATIONS THAT OCCUR, IN
THE CENTERS AND A SELECTIVE
PRESSURE OR A LIMITING RESOURCE
AND IN THIS CASE, THE LIMITING
RESOURCE IS ACTUALLY GENERALLY
THE TFH CELLS AND THE TFH CELLS
ARE LIMITED IN NUMBER AND
PROVOID A LIMITED AMOUNT OF HELP
TO THE B-CELLS AND THEY SIGNAL
THE B-CELLS TO UNDERGO MUTATION
AND PROLIFERATION AND THEN
AMONGST THOSE EVENTS, AFTER A
PSYCHOEVENT, THOSE B-CELLS HAVE
TO COME BACK, INTERACT WITH THE
TFH CELLS AGAIN AND OVERALL IN
THE POP IELINGS, THERE'S A
TENDENCY FOR THE B-CELLS TO HAVE
THE HIGHEST AFFINITY TO GET THE
MOST HELP FROM THE TFH CELLS AND
THEIR ADDITIONAL SIGNALS, THAT
GO ON, BEYOND DRIVING THIS
EVOLUTIONARY PROCESS, CAN THEN
DRIVE FURTHER DIFFERENTIATION TO
GENERATE PLASMA CELLS OUT OF
THAT GERMINAL CENTER B-CELLS OR
MEMORY B-CELLS.
AND IT'S VERY CLEAR FROM
BEAUTIFUL WORK FROM A NUMBER OF
LABS THAT REALLY ESSENTIALLY,
ALL--AS I WAS SAYING EARLIER ALL
OF YOUR OMICRON NEUTRALIZING
ANTIBODIES IN THE BLOOD ARE
COMING FROM THIS PROCESS WHERE A
B-CELL THAT STARTED WITH THE
ABILITY TO RECOGNIZE THE
ANCESTRAL STRAIN PRESENT IN YOUR
ORIGINAL MODERNA OR PFIZER OR
OTHER VACCINE, THOSE B-CELLS
UNDERWENT EXTENSIVE MUTATION AND
SELECTION AND A NUMBER OF THEM
BECAME CAPABLE OF BINDING TO
OMICRON, WITH HIGH AFENNITY EVEN
THOUGH THEY'VE NEVER SEEN
OMICRON, AND MAKING ANTIBODIES
THAT COULD DO SO.
OR IN FACT, IN GENERAL, THAT
DIDN'T HAPPEN DIRECTLY AFTER THE
FIRST OR SECOND IMMUNIZATION,
WHAT WAS HAPPENING AFTER THE
FIRST AND SECOND IMMUNIZATION
FOR THE GENERATION OF MEMORY
B-CELLS THAT HAD THE POTENTIAL
TO BIND OMICRON AND REALLY 1 KEY
ASPECT OF GERMINAL CENTERS
THAT'S BECOMING MORE AND MORE
APPRECIATED IS THAT THEY REALLY
ARE A SOURCE OF GENERATING
B-CELL DIVERSITY FROM A TELEIO
LOGICAL PERSPECTIVE OF THE
IMMUNE SYSTEM RECOGNIZING THAT
THE PRESENCE OF 1 VIRUS SLOWING
UP NOW MAY MEAN THAT THEY WOULD
BE RELATED VIRUSES SHOWING UP IN
THE FUTURE AND THUS MAKING A
DIVERSITY OF MEMORY B-CELLS,
MIGHT BE QUITE HELPFUL IN
RECOGNIZING VIRAL VARIANTS IN
THE FUTURE AND INDEED THAT'S
EXACTLY WHAT GETS SEEN.
WE HAVE BEEN TRYING TO
UNDERSTAND THOSE GERMINAL CENTER
PROCESSES FROM OTHER
PERSPECTIVES.
THE SIMPLEST MODEL OF A GERMINAL
CENTER HAS ALWAYS BEEN THAT IT'S
WHERE YOU HAVE RAPID EVOLUTION
AND SELECTION OF THE BEST
B-CELLS AND THE BEST B-CELLS WIN
OUT AND WHAT WE SAID WAS THAT
DIDN'T REALLY MATCH OUR
OBSERVATIONS IN SOME OF THE HIV
VACCINE FIELDS WHERE IT'S BEEN
VERY DIFFICULT TO GENERATE
NEUTRALIZING ANTIBODIES, SO, WHY
WOULD YOU HAVE SITUATIONS WHERE
YOU WOULD IMMUNIZE WITH AN
ANTIGEN THAT HAD NEUTRALIZING
ANTIBODY EPITOPES ON IT BUT YOU
WOULDN'T SEE THOSE NEUTRALIZING
ANTIBODIES COME OUT.
AND WE CONSIDERED THAT IMMUNO
DOMINANCE MIGHT BE A REASON FOR
THAT PROBLEM.
THAT WAS CERTAINLY IN THE HIV
FIELD THAT WAS CONTROVERSIAL AS
WELL AS SOME OTHER FIELDS AND SO
WE TRIED TO LAYOUT SOME CLEAR
CONCEPTS THAT WERE TESTABLE THAT
WOULD ADDRESS THOSE B-CELLS AND
IMMUNO DOMINANCE EXISTS AND IF
IT DID WHAT PARAMETERS DOES IT
ABIDE BY AND SO 1 MODEL WAS THAT
YOU CAN GET IMMUNO RESPONSES
BASED ON INFINITY DISPARITY, AND
IF YOU HAVE FOR EXAMPLE, EASY
EPITOPES ON AN ANTIGEN, LET'S
CALL THESE THE NONNEUTRALLIZING
EPITOPES, IF THESE HAVE A BETTER
AFFINITY THAN THE B-CELLS THAT
RECOGNIZE DIFFICULT NEUTRALIZING
EPITOPES THEN PERHAPS THE
B-CELLS THAT RECOGNIZE THE
NONNEUTRALLIZING EPITOPES, WIN
OUT IN COMPETITION SIMPLY BUZZ
THEY START WITH A BETTER
AFFINITY ON AVERAGE.
OR YOU COULD HAVE A NUMERICAL
DISPARITY WHERE MAYBE THERE ARE
JUST MANY MORE B-CELLS THAT CAN
RECOGNIZE NONNEUTRALLIZING
EPITELOMERES, THAN NEUTRALIZING
EPITOPES AND THAT NUMERICAL
DISPARITY MIGHT BE SO LARGE THAT
YOU FAILED TO GET NEUTRALIZING
ANTIBODY RESPONSES BECAUSE THEY
GET NIEWMERICALLY OUTCOMPETED.
THESE CAN HAPPEN THROUGH
MULTIPLE MECHANISMS, 1ICISMEM
CONCEPT IS GLYCANS SO VIRUSES
LIKE HIV, THIS IS THE ENVELOPE
SHOWN WITH GLYCANS SHOWN IN
BLUE, THESE ARE SELF-GLYCANS SO
HUMAN B-CELLS THAT DEVELOP IN
HUMAN B-CELLS THAT HAVE HIGH
AFFINITY FOR CELL GLYCANS GET
ELIMINATED BECAUSE THEY'RE
AUTOREACTIVE SO YOU
INTRINSICALLY HAVE LOWER
AFFINITY B-CELLS AND RARE
B-CELLS IF THE EPITOPES ARE
GOING TO INVOLVE A SELF-GLYCAN
COMPONENT.
ADDITIONALLY, IT COULD BE THAT
LIMITED T-CELL HELP COULD HELP
IN B-CELL IMMUNE DOMINANCE
BECAUSE AFTER AN INITIAL PRIMING
EVENT THERE ARE VERY FEW CD4
T-CELLS IN THE FIRST FEW DAYS
AND YET WE KNOW THAT MOST IMMUNE
RESPONSES B-CELLS REALLY ONLY
UNDER GO 1 CELL DIVISION BEFORE
THEY SEE T-CELL HELP AND THEN
ALL SUBSEQUENT CELL DIVISIONS
ARE T-CELL DEPENDENT IN A
MAJORITY OF CASES AND IN THAT
SCENARIO WITH A LIMITED NUMBER,
IT'S PRETTY EASY TO IMAGINE THAT
SOME B-CELLS MAYBE JUST THE MOST
COMMON B-CELLS WOULD GET HELP
AND MANY OTHERS WOULD NOT AND
THEN THESE CELLS WOULD START
EXPONENTIALLY DIVIDING, RIGHT
WHICH WHICH MAKES IT VERY
UNLIKELY THAT THESE WOULD EVER
BE ABLE TO CATCH UP.
SO WE PUT THESE OUT THERE AND WE
TESTED THESE IDEAS AND IN BRIEF
AND IN THE INTEREST OF TIME WE
FIRST SHOWED THAT IN HUMAN NAIVE
B-CELLS, THIS DEFINITELY OCCURS,
YOU CAN HAVE SIGNIFICANT
DIFFERENCES IN AFFINITY BETWEEN
NAIVE B-CELLS, AND 2 DIFFERENT
EPITOPE TAUPES AND YOU CAN HAVE
LARGE DIFFERENCES IN
FREQUENCIES, SO FOR A BROADLY
NEUTRALIZING EPITOPE, THE VRC 1
CLASS WHICH IS THE VRC IS VERY,
VERY FAMILIAR WITH, WE FOUND
THOSE ARE FREQUENT AT HIGH
AFFINITY AT 1 AND A MILLION TO
THE HUMAN B-CELLS WHERE IN AN
EASY EPITOPE THERE MIGHT BE 1
AND 5000.
THAT IS A REALEE BIG IN
FREQUENCIES FROM A COMPETITIVE
STANCE.
SO WE THEN TESTED THESE IN
DIFFERENT MOUSE MODELS, USING
PHYSIOLOGICALLY RELEVANT
CONDITIONS AND AGAIN, IN BRIEF,
WE DEMONSTRATED ALL 3 OF THESE
MECHANISMS OF IMOWN O DOMINANCE
DO CONSIDER.
AND CAN RESULT IN ESSENTIALLY NO
NEUTRALIZING ANTIBODIES
DEVELOPING IN SOME CASES AND THE
RESPONSE TO THAT WAS ESSENTIALLY
AT THE OTHER GROUPS HAVE
CONFIRMED THOSE OUTCOMES, THE
RESPONSE TO THAT TO SOME DEGREE
WAS, OKAY, FINE IMMUNO DOMINANCE
IS A REAL PROBLEM, NOW WE'RE
JUST SAD.
AND THE KEY THING THERE IS,
FREQUENTLY TO SOLVE A PROBLEM,
YOU HAVE TO FIRST UNDERSTAND
WHAT THE PROBLEM WAS, SO KNOWING
THAT IMMUNO DOMINANCE WAS AN
ISSUE, WE DID A SERIES OF
STUDIES TO TRY AND SEE IF IMMUNO
DOMINANCE COULD BE MODULATED BY
DIFFERENT IMMUNOLOGICAL EVENTS
AND WAWE HAVE FOUND IS THAT BY
CHANGING THE KINETICS OF THE
DELIVERY OF ANTIGEN, YOU CAN
HAVE MASSIVE IMPACTS ON IMMUNO
DOMINANCE WHERE A CONVENTIONAL
INJECTION OF HIV ENVELOPE INTO
MONKEYS GENERALLY GIVES ONLY
ABOUT 50% OF THE MONKEYS MAKE
NEUTRALIZING ANTIBODIES
APPROXIMATE AND IT'S ONLY ABOUT
AFTER 6 MONTHS OF IMMUNIZATIONS
BUT IF WE CHANGE THAT TO A SLOW
DELIVERY SUCH THAT THE EXACT
SAME AMOUNT OF PROTEIN AND
ADJUVANT IS DELIVERED, BUT IT'S
DELIVERED OVER--IT'S SPREAD OUT
OVER 14 DAYS OR 12 DAYS INSTEAD
OF A SINGLE INJECTION, THOSE
ANIMALS NOW MAKE NEUTRALIZING
EABT BODIES AND THEY MAKE THEM
FASTER AND OUR MEASUREMENT TO
THE B-CELL RESPONSES TESTED 2
IDEAS, 1 WOULD BE THIS HAPPENS
BECAUSE SOMATIC HYPERMUTATION IS
BETTER AND YOU JUST HAVE MORE
AFFINITY MATURATION, MORE
AFFINITY AND THAT'S WHY YOU END
UP WITH NEUTRALIZING ANTIBODIES
OR IT WAS AN IMMUNO DOMINANCE
PROBLEM OF WHICH B-CELLS GOT
RECRUITED AND IT TURNED OUT THAT
THEY ALL POINTED TO THE IMMUNO
DOMINANCE PROBLEM AND UNDER
CONVENTIONAL IMMUNIZATION, THERE
ARE LOW TO NO HIV B-CELLS THAT
GET RECRUITED INTO THE GERM LINE
CENTER RESPONSE AT ALL AND THEN
THEY GET OUTCOME PETEED QUICKLY.
BUT IN THE SLOW DELIVERY CONTEXT
WHERE WE HAVE A RESPONSE WE HAVE
MUCH BETTER RECRUITMENT OF THE
RARER AND LOWER AFFINITY, HIV
NEUTRALIZING ANTIBODY CAPACITY
B-CELLS AND THEN THAT THOSE HAVE
MORE TIME AND MORE ABILITY TO BE
KEPT IN A GERMINAL CENTER AND
NOT BE OUTCOME PETEED AND ATTAIN
ADDITIONAL AFFINITY.
AND SOME OF THAT WE THINK HAS TO
DO WITH ANTIGEN ANTIBODY COMPLEX
FORMATION AND BETTER RETENTION
OF ANTIGEN AND WE CAN TRACK ALL
OF THAT USING LYMPHNODE FINE
NEEDLE ASPIRATES AND IN THE
INTEREST OF TIME, I WILL JUMP TO
THE FINAL PIECE; OKAY WHICH IS 1
OF THE THINGS WE OBSERVED IN ALL
THOSE STUDIES CHES THAT THE
GERMINAL CENTER COULD BEHAVE
DIFFERENTLY THAN THE SIMPLE
MODELS ORIGINALLY IN PLACE AND A
GERMINAL CENTER COULD BE A MUCH
MORE INCLUSIVE ENVIRONMENT AND
ALSO COULD EXIST FOR A
SIGNIFICANTLY LONGER PERIOD OF
TIME THAN WE THOUGHT.
WE THOUGHT GERMINAL CENTERS AM
PEAK AT 2 OR 3 WESTBOUNDS BASED
ON MOUSE MODELS AND OTHER DATA
BUT WE HAD BEEN SEEING GERMINAL
CENTERS STILL AT 8 WEEKS AND
THAT WAS LONGER THAN WE EXPECTED
AND SO WE SET UP A STUDY WHICH
WE JUST RECENTLY PUBLISHED TO
ASK, WELL, HOW LONG CAN THESE
GERMINAL CENTERS LAST AFTER A
PRIMING IMMUNIZATION AND IT USED
TO BE ABOUT ESSENTIALLY NOTHING
HAPPENED AFTER A PRIMING
IMMUNIZATION BECAUSE YOU
COULDN'T MEASURE ANYTHING IN THE
BLOOD AND WHAT YOU SHOWED IS
THAT CERTAINLY THERE ARE THINGS
IN GOING ON IN THE LYMPHNODE AND
MAYBE LOTS OF THINGS ARE GOING
ON IN THE LYMPHNODE.
SO, WE DID A STUDY THAT WAS AN
EXERCISE IN PATIENTS SO HERE I'M
SHOWING YOU LYMPHNODE SAMPLES
FROM THE SAME ANIMALS,
LONGITUDINALLY TRACKED OVER TIME
AND LOOKING AT THE GERMINAL
B-CELLS AND AT 10 WEEKS POST
VACCINATION, WE SAW LOTS OF
GERMINAL B-CELLS THAT WERE
ENVELOPE SPECIFIC STILL AND AT 4
MONTHS, POST VACCINATION, THOSE
GERMINAL CENTERS WERE STILL
THERE, AND AT 6 MONTHS, THOSE
GERMINAL CENTERS WERE STILL
ONGOING EVEN THOUGH WE PROVIDED
NO NEW ANTIGEN IN THE SYSTEM
SINCE DAY 12.
OKAY?
SO I DON'T--THIS IS JUST
FANTASTIC.
THIS WAS REALLY AMAZING THESE
GERMINAL CENTERS WERE GOING ON
THIS LONG AND MY POST DOC SAID
THIS IS TERINCREASE IN BODY,
THIS EXPERIMENT'S GOING ON
FOREVER, AND SO WE DID END IT AT
THAT POINT.
AND FOR COMPARISON, WE IMMUNIZED
ANIMALS WITH HIV ENVELOPE WITH
ALLUM AND WE GOT A PEAK AT ABOUT
WEEK 3 AND THEN THEY WERE GONE
BY WEEK 10 BUT IF WE DID THIS
SLOW DELIVERY IMMUNIZATION,
AGAIN JUST OVER A COURSE OF 12
DAYS WITH AN ADJUVANT WE REALLY
LIKE WHICH WE CAN DISCUSS, WE
SEE AT WEEK TEN-DOLLAR'S OVER A
HUNDRED FOLD DIFFERENCE IN THE
GERMINAL CENTER RESPONSE BETWEEN
THESE 2, IMMUNIZATION APPROACHES
AND A HUNDRED FOLD DIFFERENCE IN
B-CELLS IS A MASSIVE DIFFERENCE
IN THE AMOUNT OF EVOLUTIONARY
SPACE THAT CAN BE EXPLORED
BECAUSE THEY'RE DIVIDING
APPROXIMATELY ONCE EVERY 4-6
HOURS AT LEAST BASED ON MOUSE
MODELS AND HERE'S THE
QUANTIFICATION OF THE DATA OUT
TO 6 MONTHS.
SO 1 CRITICAL QUESTION WAS ARE
THESE ACTUALLY REAL GERMINAL
CENTERS, ARE THESE FUNCTIONAL?
SO WE DID SINGLE CELL
TRANSCRIPTOMICS AND WE CAN SEE
THAT THE GERMINAL CENTER B-CELLS
AT WEEK 3 LOOK SIMILAR TO THE
GERMINAL CENTER B-CELLS IN WEEK
29 INCLUDING PROLIFERATION
MARKERS AND SOMATIC
HYPERMUTATION, SO, TRANSCRIPT
ORDER OF MICRONSICS THESE
B-CELLS LOOK VERY EQUIVALENT
BETWEEN EARLY AND LATE.
THEY ARE STILL FUNCTIONAL, THEY
ARE STILL DIVIDING AND WE SHOW
THAT THEY ACONTINUE TO
ACCUMULATE FUNCTIONS SO THEY
CONTINUE TO ACCUMULATE SOMATIC
HYPERPUTATION FOR 6 FULL MONTHS.
BUT REALLY TO SUMMARIZE IT ALL
IN A SINGLE SLIDE, WE COULD
TRACK LYNNERAGES OVER 6 MONTHS
IN NISSAN MALS, SINGLE B-CELL
LINEAGES BY GOING BACK INTO
THESE GERMINAL CENTERS OVER AND
OVER AGAIN AND WE COULD SEE
THERE WERE LINEAGES THAT STAYED
IN THESE GERMINAL CENTERS FOR 6
MONTHS AND THAT THEY WOULD
UNDERGO AFFINITY MATURATION.
HERE'S 1 THAT'S PRETTY STRIKING
EXAMPLE OF ESSENTIALLY
UNDETECTABLE AFFINITY AT TIME
POINTS AND NOW A THOUSAND FOLD
IMPROVEMENTS IN AFFINITY BY 6
MONTHS LATER.
THAT DOES HAVE PRACTICAL
SMLICATIONS BECAUSE WE CAN
ACTUALLY SEE FOR THE FIRST TIME
EVER, THAT THESE ANIMALS
ACTUALLY DEVELOPED AUTOLOGOUS
BEFORE, THIS INDICATING THE
B-CELLS WERE FUNCTIONAL BEFORE
BOOSTER.
SO IMMUNOLOGICALLY THIS IS
REALLY FASCINATING BECAUSE BACK
TO THE ENVELOPE CALCULATIONS
WOULD BE THAT THAT'S ABOUT 750
CELL DIVISIONS THAT THESE
GERMINAL CENTER B-CELLS ARE
UNDER GOING OVER 6 MONTHS.
SO I THINK THAT MEANS WE DON'T
REALLY UNDERSTAND THE ABILITY OF
THESE CELLS TO PROLIFERATE THE
WAY WE THOUGHT AND THAT THESE
GERMINAL CENTERS ARE FUNCTIONAL
THEY CAN HAPPEN IN RESPONSE TO A
PRIMING IMMUNIZATION AND THAT
ESSENTIALLY PATIENTS IN A
VACCINE STRATEGY CAN HAVE LOTS
OF BENEFITS WHEN YOU'RE TRYING
TO GENERATE RESPONSES TO
DIFFICULT TARGETS, AND THIS WAS
LED BY A FANTASTIC INSTRUCTOR
JMPLET H. LEE WHO IS CAMERA SHY,
AN AMAZING SCIENTIST AND HARRY
SUTTON, DID SOME OF THE WORK,
AND JUST TO TIE IT BACK TO THE
COVID WORK, WE'RE NOT SHOWING
ANYTHING NEW HERE IN OUR
EXPERIMENTAL DATA, I THINK THE
DAILY BASIS AT IS CONSISTENT
WITH GERMINAL CENTERS IN
SARS-COV-2 INFECTED INDIVIDUALS
6 MONTHS LATER SUGGESTING THAT
IS A NORMAL BIOLOGICAL PROCESS
AND I THINK [INDISCERNIBLE] HA
BETA THAT GERMINAL CENTERS ARE
DETECTABLE IN PEOPLE 6 MONTHS
LATER WE THINK YOU DON'T HAVE TO
INVOKE RNA EXPRESSION FOR 6
MONTHS TO EXPLAIN THOSE RESULTS
BUT THEY COULD EXPLAIN WHY
MEMORY B-CELLS ARE INCREASING
OVER A 6 MONTH PERIOD.
IT MAY ALSO BE TRUE FOR ADEN O
VIRAL VECTORS BUT THESE KINETICS
ARE DIFFERENT FROM THESE
KINETICS SUGGESTING THAT THESE
DIFFERENT PROCESSES IN THE
GERMINAL CENTER, RIGHT AND LUNG
GERMINAL CENTERS MAY HAPPEN IN
DIFFERENT WAYS WITH DIFFERENT
PLATFORMS SO EVERYTHING I SHOWED
ABOUT THE HIV STUFF IS
COLLABORATIVE SO I DID JUSTMENT
TO HIGHLIGHT THAT THAT'S OUR
CHILD CONSORTIUM LED BY DENNIS
BURREDON, ALL OF THE ANTIGENS
ARE PROVIDED BY BILL
[INDISCERNIBLE] AND MOST OF OUR
WORK IS IN CLOSE COLLABORATION
BILL AND ADAPTED RUE AND WITH
THAT I WILL STOP AND TAKE ANY
QUESTIONS, I KNOW I WENT A SMIJ
LONG, YEAH, THANKS IF ARE YOUR
ATTENTION.
>>GREAT, THAT WAS WONDERFUL
SHANE AND I DO WANT TO EMPHASIZE
FOR PEOPLE IN THE AUDIENCE THAT
PART OF THE REASON WHY SHANE AND
ALEX AND OTHERS ON THE TEAM
THERE HAVE BEEN ABLE TO REALLY
UNCOVER THESE AND STUDY THESE IS
JUST BECAUSE OF THE FUNDAMENT
AMILLIO WORK ON TFH AND GERMINAL
CENTER BIOLOGY THAT HE DESCRIBED
AT THE END AND WE HAVE A LOT OF
QUESTIONS, I WILL TRY TO GET
THROUGH THEM.
THERE WERE A COUPLE OF QUESTIONS
YOU PROBABLY--SOME ADDRESSED AT
THE END ON WHY--WHAT IS IT ABOUT
MRNA VACCINES THAT YOU THINK
THAT GIVES THIS LONG RESPONSE
PARTICULARLY.
IS IT THAT THEY'RE BETTER AT TFH
CELLS OR CD4 CELL RESPONSES AND
WHY IS IT OR WHY DO YOU THINK?
>>IT'S DEFINITELY--THEY ARE
FANTASTIC AT PRIMING CDFOUR
RESPONSES AND FOR EXAMPLE, RBD
ALONE IS QUITE SMALL AND DIDN'T
HAVE GREAT T-CELL EPITOPES IN IT
AND YET BIOENTECH USING RBD WAS
ABLE TO ILLICIT QUITE ROBUST CD4
RESPONSE AND THAT'S 1 KEY PIECE
OF DATA FROM ME DEMONSTRATING
THAT.
AND IN TERMS OF KINETICS, WE
THINK THAT RNA VACCINES ARE
PROBABLY MIMICKING THESE TYPES
OF KINETICS WHERE THERE IS
ANTIGEN EXPRESSION FOR AT LEAST
A PERIOD OF A COUPLE OF WEEKS
AND THAT THAT IS INVOKING THESE
TYPES OF MECHANISMS THAT WE'RE
TALKING ABOUT THAT THEN ALLOW
FOR SUSTAINED GERMINAL CENTERS
AND I THINK REALLY WHAT WE'RE
DEALING WITH HERE ARE THE IMMUNE
SYSTEMS EVOLVE FOR MILLIONS OF
YEARS TO TRY AND RECOGNIZE
PATHOGENS SO IT'S NOT--LET'S SEE
IF I CAN--IT'S REALLY USED TO
NOT BEING EXPOSED TO A BOLUS
IMMUNIZATION, RIGHT?
BUT INSTEAD SEEING IT OVER TIME
MECHANISMS GET INVOKED AND I
WILL--GET INVOKED AND I THINK
RNA RACK SEENS ARE EXPRESSING
ANTIGEN OVER SOME PERIOD OF
TIME.
SCOTT BOYD HAS DATA ON HA AND
THAT THOSE RESULTS IN THE
ABILITY TO SUPER THESE LONGER
GERMINAL CENTERS IN OUR CASE,
THEY WILL SHOW, THE RESULTS IN A
DRAMATIC ANTIGEN CAPTURE AND
IT'S A BEAUTIFUL IMAGES FROM
DALE URBAN'S LAB WHERE WE LOOK
AT WHOLE CLARIFIED LYMPHNODES IN
THE MONKEYS WITH A FLUORESCENT
ANTIGEN 2 KAYS AFTER
CONVENTIONAL SYRINGE.
THIS IS A VIDEO, THERE ARE BITS
OF ANTIGEN THERE COMPARED TO
SLOW DELIVERY OF THE EXACT SAME
TOTAL AMOUNT OF ANTIGEN ASK
THERE'S ENORMOUS DIFFERENCE IN
THE ANTIGEN TO BE CAPTURED AND
GO TO GERMINAL CENTERS IF YOU
GET THE IMMUNE SYSTEM AHEAD
START AND SOME ADDITIONAL TIME.
YEAH, GO AHEAD, PAM.
>>OH, NO, I WAS REMINDED TO
TELL PEOPLE THAT THE CME CODE IS
44465 AND JUST A LOT OF
QUESTIONS COMING IN.
SO 1 FROM AMANDA HENNING, ARE
YOU CONCERNED AT ALL ABOUT
INCREASED RISK OF LYMPHOMA
DEVELOPMENT WITH LONG GERMINAL
CENTER ACTIVITY AND AWLINGS FROM
STEPHEN [INDISCERNIBLE] 2 PEOPLE
WITH THE SAME QUESTION.
>>HMM, YOU KNOW THAT GOT BUMPY
THERE SO I WILL PAUSE, CAN YOU
ASK THE QUESTION AGAIN?
>>YES, SORRY.
ARE YOU CONCERNED ABOUT A
POSSIBLE RISK OF INCREASE
DEVELOPMENT OR AUTOIMMUNITY WITH
MORE PROLONGED GERMINAL CENTER
ACTIVITY.
>>YEAH, WE ABSOLUTELY HAVE TO
KEEP THAT IN MIND.
CLEARLY THESE RESPONSES CAN GO
ON DRAMATICALLY LONGER THAN WE
WERE GENUINELY THINKING AND
AGAIN, I THINK WHAT WE'RE DOING
IS ACTUAL NORMAL BIOLOGY AND I
THINK THIS IS PRETTY COMMON IF
NOT NORMAL EVEN AFTER VIRAL
INFECTIONS AND OTHER EXPOSURES,
AGAIN GOING BACK TO SEEING THESE
LUNG GERMINAL CENTERS AFTER
REMARKABLE CASES OF COVID-19.
I THINK THIS IS PROBABLY A
PRETTY NORMAL BACKGROUND EVENT
IN HUMANS AND THAT VACCINES MAY
BE ABLE TO ENGAGE THIS IN A
BETTER WAY SO THAT AGAIN, YOU
GET THINGS LIKE OMICRON
RECOGNITION FROM A VACCINE THAT
DOESN'T ACTUALLY INCLUDE OMICRON
SEQUENCES BUT YEAH, IT'S A GOOD
POINT.
>>OKAY.
ANOTHER QUESTION, MOST OF YOUR
WORK, THIS IS FROM
[INDISCERNIBLE] ON SARS-COV-2
INDICATES THAT THE IMMUNE
RESPONSE TO THE VIRUS IS
EXPECTED AND EXPECTED WITH TB
INTERACTIONS BUT THIS
INFECTION'S BEEN UNLIKE ANY
INFECTION WE HAVE.
DO YOU THINK IT'S
IMMUNOLOGICALLY DIFFERENT OR IS
IT THE VIRUS THAT'S DIFFERENT?
>>I THINK IT'S MORE THAN 1
THING.
ANY SITUATION WHERE YOU HAVE A
PROBLEM THAT'S BECOME AS VAST AS
COVID-19.
IT'S NOT JUST 1 THING.
I ALWAYS--SO, I SAID FOR QUITE A
WHILE LOOK THIS VIRUS' SUPER
POWER IS THAT IT'S INCREDIBLY
GOOD AT EVADING INNATE IMMUNITY.
IT'S VERY SILENT ANYBODY THAT
CAN HAVE CAUSE AND EFFECT OF
DISEASE HAS TO HAVE SOME GOOD
IMMUNE EVASION TRICK AND THIS
VIRUS IS UNUSUALLY GOOD AT BEING
SILENT TO THE INNATE IMMUNITY.
RIGHT?
THAT'S WHY YOU HAVE ASYMPTOMATIC
AND PRESYMPTOMATIC AND PEOPLE
ARE TRANSMITTING LARGE AMOUNTS
OF VIRUS WITHOUT KNOWING THEY'RE
SICK, THAT'S BECAUSE THIS VIRUS
AVOIDS TRIGGERING INNATE
IMMUNITY FOR I LONG TIME AND
THAT DOES HAVE IMPLICATIONS ON
THE ADAPTIVE IMMUNE RESPONSE AND
THE AABILITY OF THE ADAPTIVE
IMMUNE RESPONSE TO REPLY AND IN
A PAPER I DIDN'T TALK ABOUT, YOU
KNOW WE TRIED--WE COMPARED
HOSPITALIZED VERSUS
NONHOSPITALLIZED PATIENTS AND
OUR INTERPRETATION OF THE DATA
WAS THAT IT'S PROBABLY PEOPLE
WHO HAVE A RELATIVELY LATE AND
SLOW INNATE IMMUNE RESPONSE THAT
ARE THE PEOPLE ARE AT HIGHEST
RISK FOR HOSPITALIZATION BECAUSE
WHAT WE'RE SEEING IS PEOPLE IN
THE HOSPITAL WITHOUT DETECTABLE
CD4 OR 8 T-CELL RESPONSES
SUGGESTING THAT YOUR ADAPTIVE
IMMUNE RESPONSE DOESN'T JUST
START UNTIL THE INNATE IMMUNE
RESPONSE, RIGHT?
YOU NEED THAT INNATE IMMUNE
SIGNAL SO THIS DELAY IN THE
INNATE HAS THIS DOWN STREAM
LARGE IMPACT ON THE WAY IN THE
ADAPTIVE WHICH THE OLDER YOU
ARE, IS MORE LIKELY TO HAPPEN
AND CAN PROBABLY BE A MAJOR
CAUSE OF MUCH OF THOSE PROBLEMS.
CERTAINLY NOW I THINK WE ALL
FINALLY RECOGNIZE THAT THE OTHER
SUPER POWER OF THIS VIRUS IS
VARIANTS AND IT'S ABILITY TO
MUTATE AND IT'S INCREDIBLY
FRUSTRATING.
I THINK SOME OF THAT WASN'T
APPARENT EARLY ON BECAUSE IT
DOESN'T SHOW THAT MUCH DIVERSITY
BUT IT'S SHOWN THAT IF IT
DOES--GIVEN THE ABILITY TO
IBT--INTEGRATE FECT OVER A
BILLION PEOPLE, RIGHT?
YOU ROLL THE DICE THAT MANY
TIMES WITH SEQUENCE EVOLUTION OF
THE VIRUS AND IT CAN COME UP
WITH WAYS TO EVADE QUITE A
VARIETY OF NEUTRALIZING
ANTIBODIES.
>>I THINK THIS IS A RELATED
QUESTION BUT IT'S ON YOUR
INTERPRETATION OF WHY THE
VACCINES DON'T HAVE A
SIGNIFICANT IMPACT ON
TRANSMISSION AS OPPOSE TO SEVERE
ILLNESS.
>>THEY DO HAVE A SIGNIFICANT
IMPACT ON TRANSMISSION, I MEAN
TRANSMISSION IN THE
EPIDEMIOLOGICAL STUDIES I'M
FAMILIAR WITH, TRANSMISSION WAS
REDUCED 50-75% IN VACCINATED
COMPARED TO UNVACCINATED WHICH
YOU KNOW WE START MULTIPLYING
THAT ACROSS POPULATIONS, THAT IS
SUBSTANTIAL.
I DO THINK THE VIRUS, THERE'S
BEEN PLENTY EVALUATION PROCESS
EVIDENCE THAT THE VIRUS EVOLVED
TO BE MOAGHT MORE INFECTIOUS AND
HAVE HIGHER TITERS, IT IS HARDER
AND HARDER AS TIME HAS GONE ON
TO PREVENT TRANSMISSION IS
BECAUSE IT'S BECOME AN EVEN
FASTER VIRUS AT TRANSMITTING.
FOR THE ANCESTRAL STRAIN IT WAS
REASONABLE TO EXPECT SOME IMPACT
ON TRANSMISSION BECAUSE THERE
WAS A SEVERAL DAY WINDOW THERE
FOR THAT TO HAPPEN AND THAT'S
GOTTEN COMPRESSED MORE OVER
TIME.
>>SOMEONE'S ASKED, DO YOU KNOW
ANYTHING ABOUT THE ENZYME
PATHWAYS THAT CLEARS THE
MODIFIED RNA IN THE COVID
VACCINES?
>>NO, IT'S A GREAT QUESTION.
I MEAN, THE STANDARD STATEMENTS
BY BOTH MODERNA AND PFIZER HAVE
BEEN THAT THE RNA IS DETECTABLE
1 OR 2 DAYS POST IMMUNIZATION.
THERE HASN'T BEEN GREAT
LITERATURE PUBLISHED BY THEM,
WELL THERE HASN'T BEEN
LITERATURE PUBLISHED BY THEM ON
THOSE TOPICS AND I THINK THE
DATA FROM SCOTT BOYD WHERE HE
SHOWS IN CORE LYMPHNODE BIOPSIES
IN HUMANS DETECTABLE RNA 2 WEEKS
AND 4 WEEKS POST IMMUNIZATION
SUGGESTS AND PROTEIN SUGGESTS
THERE MAY BE FUNCTIONAL RNA FOR
AT LEAST THAT AMOUNT OF TIME AND
AND MAY SUGGEST THAT THE
DEGRADATION OF THE RNA, THE
MODIFIED RNA IS SLOWER THAN
INITIALLY THOUGHT, YEAH.
BUT I DON'T KNOW WHAT THE
PATHWAYS ARE.
THATYA A GOOD QUESTION.
>>I THINK IT REALLY HIGHLIGHTS
THE CHALLENGES OF LOCAL TISSUE
RESPONSES, RIGHT?
THIS IS CLEARLY A VIRUS THAT
DOES HAVE ORAL INFECTIONS AND SO
YOU WOULD LOVE TO KNOW WHAT ARE
THE B-CELL AND T-CELL RESPONSES
IN THAT TISSUE, RIGHT?
THAT'S A HARD QUESTION, THAT IS
NOT A HUMAN SITE THAT'S EASY TO
SAMPLE AND THERE IS SOME ABILITY
TO START SAMPLING, NAISAL
TISSUES AND SO I'M HOPING
THERE'S MORE AND MORE DATA THAT
GET ACCUMULATED FOR EVEN WITH
THE KINETICS OF RESPONSES LOOK
LIKE, THAT'S HARD TO DO THOUGH,
RIGHT?
YOU HAVE TO CAPTURE PEOPLE
DURING ACUTE INFECTION,
PREFERABLY SUPER EARLY DURING
THE INFECTION SO YOU KNOW WHAT
THE BASE LINE IS BUT WE--PEOPLE
WOULDN'T SHOW UP UNTIL
SYMPTOMATIC.
SO THOSE ARE REALLY IMPORTANT
QUESTIONS FOR US TO BED
UNDERSTAND WHAT MECHANISMS OF
PROTECTIVE IMMUNITY REALLY OCCUR
IN THESE TISSUES BECAUSE I DO
THINK IT'S QUITE HARD TO
EXTRAPOLATE FROM ANIMAL MODELS,
ANIMAL MODELS ARE AWESOME BUT
YOU NEED SOME DIRECT EVIDENCE IN
PEOPLE.
I REALLY--I DO--I AM QUITE
IMPRESSED BY THE HUMAN CHALLENGE
MODELS BOTH FOR SARS-COV-2 AND
FLU, FOR EXAMPLE IN HUMAN
CHALLENGE MODELS IN FLU,
INFECTED PEOPLE, PEOPLE WHO GOT
INFECTED PEOPLE WHO HAD CD8
T-CELLS IN THEIR LUNG, THAT'S
WHAT CORRELATED WITH LOWER
OVERALL VIRAL LOAD DURING YOU
KNOW WHEN THEY GOT CHECKED FOR
VIRAL LOAD OVER 7 DAYS AND I
JUST DON'T THINK YOU CAN FIND
THOSE THINGS UNLESS YOU GET
TISSUE SAMPLES WHERE YOU FIND
[INDISCERNIBLE] HAD IS A HIGH
BAR.
IT'S ACTUALLY AMAZING, WHAT THE
STUDIES ARE BEING DONE NOWADAYS.
SO 1 PERSON WANTED TO ASK YOU TO
SPEAK TO THE IDEA OF THE
ORIGINAL ANTIGENIC SIN AND HOW
COVID AND COVID VACCINES HAVE
CAUSED THE FIELD TO UPDATE OR
MODIFY THIS IDEA IF AT ALL.
>>YEAH, WE DON'T--SO WE HAVE A
STRONG INTEREST IN THAT TOPIC,
WELL FIRST AS HUMAN BEINGS WE
WANT TO BE PROTECTED AGAINST
COVID BUT WE HAVE A STRONG
INTEREST IN THE TOPIC IN THE
CONTEXT OF HIV VACCINES AND SORT
OF TRYING TO EXTEND UPON WHAT I
TALKED ABOUT TODAY WHERE TO
GENERATE BROADLY NEUTRALIZING
ANTIBODIES WE HAVE A SHEPHERDING
APPROACH AND THEN YOU'RE COMING
BACK WITH A RELATED BUT
DIFFERENT IMMUNO GENERATED AND
THEN ANOTHER DIFFERENT BUT
RELATED IMMUNOGEN SO YOU HAVE TO
HAVE A RECALL RESPONSE THAT YOU
CAN BUILD UPON AND HOW DO THINGS
LIKE IMPRINTING OR CLINICAL
GENETICSINAL [INDISCERNIBLE]
IMPACT THAT.
I THINK LIKE MOST OF THE FIELD,
I TRIED TO MOVE AWAY FROM THE
TERM ORIGINAL [INDISCERNIBLE]
BECAUSE IT INVOKES QUITE A
VARIETY OF EMOTIONAL RESPONSES
FROM PEOPLE AND I THINK
IMPLINTING IS A LITTLE MORE
NEUTRAL.
I CAN JUST COMMENT ON THE STATE
OF THE LITERATURE WHICH IS THERE
ARE BEAUTIFUL PREPRINTS FROM
LAURA WALKER AND [INDISCERNIBLE]
BETTY SHOWING THAT WHEN A PERSON
SEES OMICRON OR ANOTHER FAIRLY
DIVERGENT VARIANT, ALMOST ALL
THE RESPONSE TO THAT IS MEMORY
B-CELLS TO THE ORIGINAL AND
WHILE EVERYBODY WAS ABLE TO
DETECT NAIVE B-CELLS, THEY WERE
LESS THAN 1 PERCENT OF THE
RESPONSE AND SO THERE IS A VERY
STRONG IMPRINTING.
NOW I THINK IT'S EASY TO
ELECTRIC AT THAT AS A PRETTY
POSITIVE THING.
THIS IS ESSENTIALLY WHAT I WAS
TALKING ABOUT EARLIER OF IN THE
GERMINAL CENTER RESPONSE IS,
PART OF A GOAL OF THAT PROCESS
IS TO GENERATE MEMORY B-CELLS,
THAT HAVE DIVERSE RECOGNITION
CAPACITY AND DON'T NECESSARILY
RECOGNIZE THE CURRENT ANTIGEN
THE BEST BUT MIGHT RECOGNIZE A
RELATED ANTIGEN I. E. OMICRON
MUCH BETTER THAN WHAT I NAIVE
B-CELL COULD STARTING FROM
SCRATCH SO THERE MIGHT BE
MUTATIONS ON OMICRON THAT ARE
AFFECTING AN EPITOPE BUT IF HAVE
A B-CELL IT'S BINDING NOT JUST
TO THE BINDING OF THE CENTER OF
THE EPITOPE BUT BESIDE THE CELL,
THE B-CELL CAN STILL HANG ON AND
BE A GOOD RESPONDER TO THAT AND
I THINK THAT'S WHAT REALLY THE
FLU FIELD SEES IN A LOT OF ITS
LITERATURE HAS JUST BEEN MORE
DIFFICULT TO INTERPRET THE FLU
LITERATURE BECAUSE PEOPLE HAVE
SUCH INTENSE COMPLEX HISTORIES
WITH FLU.
YEAH, I GUESS I WILL STOP THERE.
THOSE ARE MY MAIN THOUGHTS.
>>YEAH, I THINK WE'RE GOING TO
HAVE TO STOP BECAUSE OF THE
TIME.
>>COOL.
>>THIS IS REALLY WONDERFUL AND
YEAH, WE ARE--YOUR COMMENTS ON
THE FLU AND THE HISTORY, IT DOES
BRING HOME HOW WE ARE LIVING IN
THE WORLD'S BASED EXPERIMENT AND
WE ARE THE SUBJECTS.
AND I THANK YOU FOR PROVIDING
YOUR INSIGHT, SO, THANKS
EVERYONE AND WE WILL SEE YOU IN
2 WEEKS.
>>YEAH, THANKS IF YOUR TIME AND
ALL THOSE EXCELLENT QUESTIONS.