>> I'M DAN ROTROSEN, DIRECTOR OF
THE DIVISION.
IT'S MY PLEASURE TO WELCOME YOU
TO OPEN SESSION OF THE COUNCIL
SUBCOMMITTEE.
WE HAVE FOUR TERRIFIC SPEAKERS
WHO ALL ARE FUNDED BY AND WORK
THROUGH OUR VACCINE ADJUVANT
PROGRAM, SO VERY TIMELY UPDATE
FROM THEM.
BUT BEFORE WE BEGIN WITH THAT,
WOLFGANG LIGHTNER IS GOING TO
GIVE BACKGROUND ON THAT PROGRAM
AND ITS EVOLUTION, AND SOME
THOUGHTS ON NEW OPPORTUNITIES.
WOLFGANG WILL INTRODUCE EACH OF
THE SPEAKERS AND FOLLOWING THOSE
PRESENTATIONS WE WILL HAVE THREE
RESEARCH CONCEPT CLEARANCES FOR
COUNCIL APPROVAL.
AND AS WE ORDINARILY DO, WE
REALLY WELCOME YOUR COMMENTS,
SUGGESTIONS, AND THE LIKE.
AND I HAVE TWO REMINDERS.
ONE IS IF YOU'RE ONLINE DO NOT
USE THE CHAT FUNCTION.
THAT WILL CREATE A FACA
REQUIREMENT, WHICH WE REALLY
DON'T WANT.
AND SECOND, IF YOU ARE SPEAKING
REMEMBER TO USE THE MICS, AND
IDENTIFY YOURSELF SO THE RECORD
CAN BE ACCURATE.
WOLFGANG, IT'S ALL YOURS.
>> GOOD AFTERNOON.
THE MAKE FOCUS WILL BE
ADJUVANTS, I'M THE CHIEF OF THE
SECTION THAT OVERSEES THE
ADJUVANT PROGRAM.
NOW, BEFORE I TELL YOU A LITTLE
MORE ABOUT THE PROGRAM, I WANT
TO GIVE YOU A HISTORIC SUMMARY
OF HOW WE GOT THERE.
DATA HAS BEEN SUPPORTING THE
ADJUVANT RESEARCH FOR TWO
DECADES NOW, AND ACCORDING TO
DR. HACKETT WHO CREDITS THE
PROGRAM HE CREDITS CHARLIE
CHAINWAY WITH INSPIRING THE
PROGRAM, HE PRESENTED THE FIRST
RESULT OF A HUMAN TOLL RECEPTOR
AT ACTUALLY AT AN OPEN COUNCIL
MEETING, THIS FORUM WE'RE HERE
TODAY, IN 1997.
A YEAR LATER, HOSTED AN EXPERT
PANEL ON BASIC IMMUNOLOGY OF
VACCINES, THIS ALSO PROVIDED
FOUNDATIONAL INSIGHT INTO WHAT
LED TO THE FIRST DATE ADJUVANT
PROGRAM, THE FIRST SOLICITED
PROGRAM.
A YEAR LATER ADJUVANT RESEARCH
WAS INCLUDED IN THE NIAID
STRATEGIC PLAN FOR THE FIRST
TIME, AND THE FIRST PROGRAM THAT
WAS THE ADJUVANT DISCOVERY
PROGRAM WAS LAUNCHED IN 2003.
WE'RE NOW STARTING FIFTH
ITERATION OF THAT PROGRAM.
IN 2011, ADJUVANT RESEARCH
BROUGHT ITS OWN STRATEGIC PLAN
FOR THE FIRST TIME, THIS PLAN
WAS RENEWED IN 2019 JUST IN TIME
FOR THE PANDEMIC.
AND THE INVESTIGATORS THAT ARE
SUPPORTED BY THIS PROGRAM HAVE
BEEN EXCEPTIONALLY PRODUCTIVE
AND INNOVATIVE AND THIS PROGRAM
HAS LED TO TWO ADJUVANTS THAT
ARE USED IN LICENSED COVID
VACCINES.
TOGETHER WITH MANY, MANY OTHER
CLINICAL TRIALS OFF VACCINES
INCLUDING ADJUVANTS THAT HAVE
COME OUT OF THE PROGRAM.
NOW, THE PROGRAM STARTED WITH
ADJUVANT DISCOVERY.
IN THE MEANTIME OVER THE LAST
TWO DECADES, A LOT OF ADDITIONAL
SOLICITED PROGRAMS HAVE BEEN
ADDED TO COVER THE RANGE OF
ACTIVITIES NEEDED TO GET NOVEL
ADJUVANTS TOWARDS THE CLINIC.
WE'RE SUPPORTING ADJUVANT
DISCOVERY, RESEARCH ON
COMBINATION ADJUVANTS TO
DETERMINE WHAT'S THE RIGHT
COMBINATION, HOW COMBINATIONS
WORK, AND THERE'S A LOT OF FOCUS
ON BRINGING NOVEL ADJUVANTS
TOWARDS THE FIRST CLINICAL
TRIAL, TOWARDS IND-ENABLING
STUDIES.
SO OUR ADJUVANT DEVELOPMENT
PROGRAM HELPS NOVEL ADJUVANTS
TOWARDS IND-ENABLING STUDIES.
NOW, WHILE THE PROGRAM DOES NOT
DIRECTLY SUPPORT CLINICAL
TRIALS, THESE ARE MANAGED BY
EITHER OTHER DIVISIONS AT NIAID
OR OTHER AGENCIES.
THE ADJUVANT PROGRAM HAS BEEN
INVOLVED IN DEVELOPMENT OF NOVEL
ADJUVANTS FOR OPIOIDS, PART OF
THE NIH "HEAL" PROGRAM.
AS YOU'RE AWARE OF, IT IS NOT IN
THE MISSION TO DEVELOP.
THEY ARE THE MOTE IMPORTANT
COMPONENT OF VACCINES AND THERE
ARE ISSUES WITH RESEARCH, NAMELY
WHAT IS AVAILABLE FOR VACCINE
RESEARCH.
THE NUMBER OF ADJUVANTS THAT ARE
AVAILABLE TO ACTUALLY BE TAKEN
INTO THE CLINIC IS VERY SMALL,
BUT THE NEED CONTINUES TO
INCREASE.
MOST ADJUVANTS OUT THERE ARE
ONLY AVAILABLE FOR PRE-CLINICAL
STUDIES.
ADJUVANTS USED IN LICENSED
VACCINES ARE NOT ACCESSIBLE TO
MOST RESEARCHERS.
SO AS A RESULT, THE WAY ADJUVANT
SELECTION WORKS IN REAL LIFE IS
THE VACCINE DEVELOPERS TEND TO
GO WITH THE ONES THAT ARE
ACCESSIBLE, NOT THE ONES MOST
SUITABLE FOR PARTICULAR VACCINE.
AND SO AS A RESULT YOU MAY END
UP WITH SUBOPTIMAL COMBINATIONS
OF ADJUVANT AND VACCINE.
NOW, CHARLIE CHAINWAY FAMOUSLY
CALLED ADJUVANTS THE DIRTY
LITTLE SECRET OF VACCINES, THAT
REFERS TO THE FACT THAT WE'VE
BEEN ADDING ADJUVANTS OR WITH
KNOWN THAT ADJUVANTS ARE
CRITICAL FOR VACCINES FOR THE
LONGEST TIME WITHOUT
UNDERSTANDING WHY.
THIS WAS CERTAINLY TRUE AT THE
TIME, STILL TRUE.
IF YOU THINK ABOUT ALUM, ADDED
TO HUMAN VACCINES FOR A CENTURY,
WE STILL DON'T UNDERSTAND HOW
ALUM WORKS.
SO VACCINE DEVELOPMENT REALLY
REQUIRES MORE DETAILED INSIGHTS
INTO IMMUNE MECHANISMS, DAIT
SUPPORTS THESE.
SYSTEMATIC SEARCH FOR NOVEL
ADJUVANTS, NOVEL ADJUVANTS THAT
ARE HIGHLY DEFINED, AND I'M NOT
ONLY TALKING ABOUT CHEMICALLY
DEFINED SO VERY SPECIFIC
MOLECULES, NOT JUST MIXTURE OF
MOLECULES, WHOSE FUNCTIONS WE
DON'T UNDERSTAND, BUT ALSO
DEFINED IN TERMS OF THE
MECHANISM OF ACTION.
SIDE-BY-SIDE COMPARISON, GETTING
AT THE PROBLEM I JUST MENTIONED,
THE SELECTION OF ADJUVANT SIMPLY
BASED ON AVAILABILITY, NOT BASED
ON THEIR BEING THE BEST CHOICE
FOR PARTICULAR VACCINE.
WE'RE ABLE TO ADD TWO NEW
PROGRAMS TO THE PORTFOLIO IN
2022, TO LOOK AT DIFFERENT
ADJUVANTS AND ESTABLISH IMMUNE
PROFILES, IMMUNE FINGERPRINTS OF
DIFFERENT ADJUVANTS THAT WILL
HELP US GET AT -- GAIN
MECHANISTIC INSIGHTS INTO
CORRELATES OF PROTECTION.
THE ULTIMATE GOAL OF THE PROGRAM
IS TO CREATE A COMPREHENSIVE
TOOLBOX OF NOVEL ADJUVANTS
AVAILABLE FOR VACCINE
DEVELOPMENT.
NOW, GETTING BACK TO THE THEME
OF THIS AFTERNOON, OPPORTUNITIES
AND NEW DIRECTIONS, WE COULD
SPEND A LOT OF TIME TALKING
ABOUT NEW DIRECTIONS, A LOT HAS
HAPPENED IN THE ADJUVANT
RESEARCH FIELD, ESPECIALLY IN
THE LAST COUPLE YEARS.
NOW, THE FOUR TOPICS I WANT TO
ADDRESS, THOSE WILL BE COVERED
BY THE SPEAKERS, FIRST OF ALL
WHAT IS AN ADJUVANT.
TRADITIONALLY AGONISTS OF IT
NATURE IMMUNE RECEPTORS BUT SO
MANY MORE MOLECULES CAN GIVE
ADJUVANT EFFECT.
FROM THE UNIVERSITY OF CHICAGO,
HE'S BEEN WORKING ON IDENTIFYING
NOT ACTIVATORS BUT INHIBITORS,
SPECIFICALLY INHIBITORS OF
SELECTIVE OF NF-kappaB, AS
CO-ADJUVANTS, CHALLENGING THIS
NOTION OF INFLAMMATION HAS TO BE
ASSOCIATED WITH IMMUNITY, AND IN
ORDER TO BE EFFECTIVE.
ONE OF THE OBSTACLES IN THE
FIELD HAS BEEN THE READOUTS.
SO IF YOU'RE LOOKING AT
INDIVIDUAL IMMUNE PARAMETERS, IT
IS VERY HARD TO UNDERSTAND HOW
AND ADJUVANT WORKS, WHAT IS
REQUIRED IS A BROAD LOOK AT THE
PROFILE IMMUNE RESPONSE INDUCES,
AND DR. PULENDRAN WILL TALK
ABOUT SYSTEMS IMMUNOLOGY TO
UNDERSTAND HOW ADJUVANTS WORK.
HOW TO USE THE RIGHT ADJUVANT
FOR THE JOB.
WE'VE BEEN THINKING OF ADJUVANTS
AS ENHANCERS, INCREASING IMMUNE
RESPONSE.
BUT ADJUVANTS DO MUCH MORE.
THEY ARE NOT JUST RAMPING UP
IMMUNE RESPONSES BUT ALSO
DRIVING IN A CERTAIN DIRECTION,
THEY ACT AS IMMUNE MODULATORS.
DR. JAY EVANS FROM UNIVERSITY OF
MONTANA WILL BE JOINING US
ONLINE.
HE'S BEEN PART OF -- HIS TEAM
HAS BEEN PART OF THE PROGRAM
SINCE THE BEGINNING, SINCE 2003.
HE WILL BE TALKING ABOUT A NOVEL
SYNTHETIC TLR 4 AGONIST AS
IMMUNE MODULATOR TO ALTER
EXISTING ALLERGIC RESPONSE TO IN
THIS CASE (INDISCERNIBLE)
ADJUVANTS, DELIVERY THROUGH THE
NASAL ROUTE.
AND FINALLY, ONE OF THE
RECOGNITIONS IN THE FIELD HAS
BEEN THE TARGETING A SINGLE
PATHWAY, SINGLE RECEPTOR, SIMPLY
NOT ENOUGH TO GET AN OPTIMAL
IMMUNE RESPONSE TO VACCINE, MAY
BE NECESSARY TO COMBINE MULTIPLE
PATHWAYS AND TO DEVELOP
COMBINATION ADJUVANTS.
THERE ARE AT LEAST TWO MAJOR
CHALLENGES WHEN COMBINING IMMUNE
MODULATORS.
NUMBER ONE, WHAT'S THE RIGHT
COMBINATION?
WHICH ONES ARE ACTING
SYNERGISTICALLY, TRULY, WHICH
ARE ONLY ADDITIVE, AND WHICH
ONES MAY ACTUALLY INTERFERE WITH
EACH OTHER.
THAT'S CHALLENGE NUMBER 1.
NUMBER TWO, HOW DO YOU DELIVER
IN ORDER TO GET OPTIMAL EFFECT.
DR. NICOLAS CHEVRIE FROM
UNIVERSITY OF CHICAGO WILL TALK
ABOUT THAT PROBLEM AND HOW TO
SOLVE THIS ISSUE OF DEVELOPING
OPTIMAL COMBINATION ADJUVANTS.
I'LL HAND OVER TO THE FIRST
SPEAKER, AND I'LL FINISH WITH A
SNAPSHOT OF THE DAIT ADJUVANT
WEBSITE.
HERE WE GO.
>> GREAT.
I'LL JUST START TALKING WHILE MY
TITLE -- THERE IT GOES.
THANK YOU FOR THE INVITATION TO
COME TALK, THANK YOU, WOLFGANG,
FOR THE INTRODUCTION AND SUPPORT
OF THIS WORK FOR MANY YEARS.
SO, IT'S REALLY MY PLEASURE TO
COME AND TALK TO YOU GUYS ABOUT
THIS.
I THOUGHT I WOULD -- YOU
MENTIONED THAT WE'RE FROM
CHICAGO, YOU'RE GETTING A
CHICAGO SANDWICH TODAY.
AS YOU'RE SORT OF MAYBE YOU'VE
SEEN, YOU KNOW, THE ITALIAN BEEF
SITUATION HERE, I WANTED TO
EXPLAIN THE PROGRAM WE'RE FROM,
IT'S A UNIQUE THING, PRITZKER
SCHOOL OF MOLECULAR ENGINEERING,
FOCUSED IN IMMUNOENGINEERING
AREA ON SOCIETAL PROBLEMS BUT
BRINGING VERY BASIC TECHNOLOGY
IN ENGINEERING TO SOCIETAL
PROBLEMS.
SO VACCINES AND ADJUVANTS SIT
SQUARELY IN THIS AREA, THERE'S
WHY THERE'S TWO OF US IN THE
ROOM FOCUSED ON THIS TOPIC.
IN PARTICULAR I'M INTERESTED IN
THIS IDEA OF UNDERSTANDING HOW
TO BALANCE KIND OF
REACTOGENICITY.
THE PANDEMIC BROUGHT THIS TO A
FORE, AND THERE'S THAT GREAT
QUOTE FROM PHIL DORMIZZER
TALKING ABOUT CHALLENGES OF
PICKING A DOSE VERSUS RESULTING
AT VERSE EVENTS THAT MIGHT CROP
UP, THE QUIET PART SAID OUT
LOUD, THE WAY VACCINES GET
DEVELOPED.
AND SO THIS IS -- I MADE THIS
FOR A VARIETY OF REASONS,
THERE'S A HERO'S JOURNALY WHEN
YOU TRY AND DEVELOP A VACCINE,
FROM A CORE NEW IDEA, TRY AND
GET EFFICACY, TRY TO BATTLE
REACTIVE GENICITY, THERE'S ALL
THESE THINGS YOU HAVE TO
CONSIDER, DIFFERENT AREAS THAT
COME TOGETHER.
PART IS THAT WE SORT OF LACK A
NUMBER OF TOOLS TO NAVIGATE THE
SPACE.
WE DON'T HAVE A WAY TO BALANCE
OUT ALL THESE AREAS.
WE HAVE THINGS WE'D LIKE TO
ACHIEVE, AND YET WE DON'T HAVE A
LOT OF THE TOOLS WE NEED MY
GROUP IS INTERESTED IN BRINGING
NEW TOOLS, BETTER FRONT ENDS TO
THE INNATE IMMUNE SYSTEM, THE
THING WE'RE FOCUSED ON.
ADJUVANTS ARE A FUNDAMENTAL TOOL
FOR INNATE IMMUNE MANIPULATION,
FRONT END TO THE BACK END
DEVELOPING OVER A FEW YEARS TO
STUDY AND CHARACTERIZE IMMUNE
SYSTEM IN GREAT DETAIL.
WE HAVE INCREDIBLE ADVANCES IN
SYSTEMS IMMUNOLOGY WHICH DR.
PULENDRAN WILL TELL US A
FRACTION OF.
WE HAVE INSIGHTS INTO
COMPUTATIONAL IMMUNOLOGY.
WE HAVE ALL THIS ABILITY TO
STUDY EVERY CELL IN IMMUNE
RESPONSE, YET HAVE FEW TOOLS FOR
MANIPULATING AND CHANGING THE
RESPONSE ON THE FRONT END.
I SEE ADJUVANTS AS A BASIC TOOL
FOR PUTTING INPUTS IN AND
CHANGING THEM IN DIFFERENT WAYS.
I WANTED TO HIGHLIGHT ONE OF THE
THINGS THAT WE GLOSS OVER ABOUT
THE NOBEL PRIZE FROM LAST YEAR
MORE mRNA TECHNOLOGY WASN'T
GIVEN FOR THE mRNA TECHNOLOGY
ITSELF, IT WAS FOR ABILITY TO
REDUCE INFLAMMATION FROM mRNA
VACCINE, THE MANIPULATION OF THE
IMMUNE RESPONSE.
IT'S A GOOD IDEA TO DELIVER
mRNA, GREAT IDEA IN THE '90s,
BUT ABILITY TO MODIFY INNATE
IMMUNE RESPONSE THAT WAS GAME
CHANGING.
A LESSON TO LEARN.
WHAT CAUSES EFFECTS, THE HOST OF
THINGS THAT OCCUR WHEN YOU
INJECT VACCINE INTO -- DO AN
I.M. INJECTION INTO A MUSCLE.
I CALLED THESE THINGS THE DIRTY
HALF DOZEN, THE THREE CYTOKINES
THAT SHOW UP IN PARTICULAR TNF,
ILL
IL-AND IL-1 BETA, WHEN WE'RE
HAVING HOW TO MODIFY A RESPONSE.
WHEN CONSIDERING BALANCING
ADVERSE EVENTS BETWEEN ABILITY
TO BOOST ADJUVANTICITY AND
REMOVE INFLAMMATION, DIFFERENCE
BETWEEN A NORMAL DRUG WITH
BALANCE BETWEEN ABILITY TO DOSE
AND THE ABILITY TO INDUCE
ADVERSE EVENT, LET ME HIGHLIGHT
THIS, VERSUS THE WAY A VACCINE
WORKS WHERE YOU NORMALLY HAVE AN
INCREASING DOSE, SIDE EFFECTS,
AND EFFICACY, AND THESE TWO ARE
COUPLED.
THIS IDEA WE COULD UNCOUPLE,
HAVE INDEPENDENT CONTROL OVER
INFLAMMATION WHILE MAINTAINING
ABILITY TO DOSE.
WE COULD CREATE TYPES OF CURVES
WHERE TNF, IL-6, IL-1 BETA,
MAINTAIN ABILITY TO INDUCE
DIFFERENT RESPONSES.
I MADE THIS METAPHOR, THAT WHEN
WE ADD A TRADITIONAL VACCINE TO
A SYSTEM, IT'S LIKE SHOUTING
INTO A MEGAPHONE.
ALL OF THE SIGNALS INCREASE AT
THE SAME VOLUME.
YOU HAVE TNF IL-6, GO UP AT SAME
RATE, DON'T HAVE ROLE OVER THE
PROCESS.
THIS IS JUST THE WAY YOU THINK
ABOUT TRADITIONALLY, YOU
ACTIVATE A SIGNAL THROUGH
NORMALLY TOLL LIKE RECEPTOR OR
PATTERN RECOGNITION RECEPTOR,
GOES DOWNSTREAM, THE CELL DOES
WHAT IT DOES.
MY KIDS WERE IN KINDERGARTEN
WHEN WE STARTED THIS PROJECT,
THE KINDERGARTEN TEACH HER A
GREAT LINE.
YOU GET WHAT YOU GET, YOU DON'T
GET UPSET.
THIS IS EXACTLY HOW VACCINATION
WORKS, RIGHT?
AND SO WE WERE THINKING, YOU
KNOW, OUR IDEA IS CAN WE KIND OF
CREATE SIX-BAND EQUALIZER FOR
THIS SYSTEM, BE ABLE TO TUNE OR
MODIFY VERY SPECIFIC PARTS OF
THE RESPONSE SO WE CAN CHANGE
THE SIGNAL IN A DESIRED FASHION.
AND SO WHAT IF WE COULD MAKE
SOMETHING THAT LOOKED LIKE THIS
I'M IN AN ENGINEERING
DEPARTMENT, WHAT IF WE COULD
MAKE A HIGH PASS/LOW PASS
FILTER, ABLE TO TUNE DOWN N TNF
AND IL-6, AND CONTROL FACTORS
WITHIN THE CELL.
WHAT IF WE COULD DO THAT FOR
INNATE SIGNALING?
THE APPROACH WAS TO ALTER THE
SIGNAL BY ALTERING THE SIGNAL
PROCESSING WITHIN THE CELL.
RATHER THAN ACTIVATE RECEPTOR ON
THE OUTSIDE WE TOOK THIS IDEA OF
CHANGING THE SIGNALING WITHIN
THE CELL, SO THERE'S A LOT KNOWN
ABOUT WHAT TARGETS, WHAT CAN YOU
DO TO CHANGE RESPONSE.
THE FACT THAT OF NF-kappaB IS
HUNDREDS OF PROTEINS TALKING TO
EACH OTHER, CORE TRANSCRIPTION
FACTOR, SIMPLIFYING THIS ARROW
WITH HUNDREDS OF PROTEINS THAT
PERFORM THIS PROCESS DECIDING
HOW MUCH TNF OR MHC TO PRODUCE
AND HOW TO TRANSCRIBE THEM.
THEN YOU CONTROL WITH A SECOND
MOLECULE THAT GOES IN THE
INHIBITION PROCESS, WE STARTED
AS THE PANDEMIC WAS BEGINNING
BUT DID THIS HIGH-THROUGHPUT
SCREEN, TOOK 15 PRR AGONISTS,
EVERYTHING THAT WOULD ACTIVATE
INNATE IMMUNE SYSTEM CROSSED
WITH 4,000 OR 5,000 DIFFERENT
SIGNAL-MODIFYING MOLECULES KNOWN
TO INTERACT WITH THE NETWORK,
FIRST LOOKED FOR ANYTHING THAT
WOULD MODIFY THE SIGNAL,
DOWN-SELECTED IN A CRITERIA I'LL
EXPLAIN, AND EVENTUALLY ENDED UP
WITH VERY SPECIFIC COMPOUNDS
THAT WE KNEW MODIFIED THE
NF-kappaB SIGNAL IN A SPECIFIC
WAY.
HOW DO YOU FIND AN IDEAL
MOLECULE AMONGST MANY THINGS
THAT LOOK SIMILAR?
I'LL MAKE THIS ANALOGY AGAIN,
YOU CAN TELL I HAVE CHILDREN.
IT'S LIKE DOING WHERE'S WALDO,
YOU HAVE THIS BIG CHALLENGE,
EVERYTHING LOOKS SIMILAR BUT
SOMEWHERE IN THE GIANT FIELD OF
SIMILAR THINGS IS ONE THING YOU
WANT.
I WON'T TELL YOU WHERE HE IS YET
BUT I'LL SHOW YOU BY THE END OF
THE PRESENTATION WHERE WALDO IS.
THIS WAS THE CHALLENGE, A HUGE
LIBRARY OF MOLECULES, WE WERE
LOOKING FOR DO THESE MOLECULES
JUST CHANGE THE WAY THESE THINGS
WORK, THEN WE ASKED DO THEY
CHANGE THE SPECIFIC CYTOKINES,
DO THEY CHANGE TNF, IL-6, IL-1
BETA, AND HOW MUCH DO THEY
CHANGE CELL SURFACE MARKERS, WE
CREATED THIS INDEPENDENTLY
WEIGHTED SCORE WE CALL A VACCINE
SCORE TO PICK THOSE MOLECULES,
TESTED ON HUMAN CELL LINES TO
MAKE SURE WE COULD VALIDATE THEY
WOULD WORK IN A PERSON AT SOME
POINT.
WE'RE BEGINNING TO TEST ON
SPECIFIC PATIENTS AND THEN
LOOKING FOR ONES THAT WORK VERY
WELL WITH DIFFERENT INDIVIDUAL
SYSTEMS, mRNA VACCINES,
COMMERCIAL VACCINES.
I'LL SHOW YOU THE VACCINE SCORE
IN MORE DETAIL.
THIS IS ONE AXIS.
TWO AXES, YOU CAN SEE IMPROVED
PERFORMANCE, BETTER AT ANTIGEN
PRESENTATION AND REDUCE TNF AND
IL-6 BUT MAINTAIN CYTOKINES THAT
CAUSE CELL MIGRATION AND
INTERFERENCE.
THERE'S A SWEET SPOT IN BETWEEN
THE TWO.
THIS MOLECULE, PME-564, IS LEAD
CANDIDATE, BALANCING THE TWO
PERFECTLY WHERE IT'S ABLE TO
INCREASE ABILITY TO PRESENT
ANTIGENS WHILE MINIMIZING THE
AMOUNT OF THOSE CYTOKINES
INVOLVED IN REACTOGENICITY, TO
TUNE DOWN REACTIVE CYTOKINES AND
INCREASE REACTOGENICITY.
THIS SHOWS THE POINT WE
CORRELATED ALL OF THESE THINGS
TOGETHER AND WHEN YOU HAVE A
TRADITIONAL VACCINE YOU HAVE
INHERENT CONTRAST BETWEEN WHERE
WHEN YOU ADD MORE VACCINE, YOU
GET MORE PROTECTION, BUT WHEN
YOU -- THEN YOU HAVE A DROP IN
THE TOLERABILITY SCORE.
THERE'S AN AN AXIS.
WHEN YOU ADD MODIFYING COMPOUNDS
YOU MOVE TO THE AREA MORE SAFE
AND MORE PROTECTIVE
SIMULTANEOUSLY.
THAT'S WHAT WE'VE BEEN LOOKING
FOR.
I WANTED TO HIGHLIGHT SOME OF
THE OTHER THINGS WE'VE BEEN
DOING IN THIS SPACE, TRYING TO
APPLY NEW METHODS OF SIFTING
THROUGH THE DATA.
AND SO ONE OF THE THINGS WE PUT
IN THIS PROPOSAL WAS USING
MACHINE LEARNING AS A WAY TO
PRIORITIZE AND OPTIMIZE.
THE OTHER QUESTIONS PEOPLE SEEM
TO HAVE A LOT OF DISCUSSION
WHETHER A.I. IS GOING TO BE A
USEFUL TOOL, I WANT TO HIGHLIGHT
AND EMPHASIZED AT THE WORLD
VACCINE CONGRESS IT WON'T TAKE
ANYBODY'S JOB, JUST A BETTER
VERSION OF A TOASTER, AN
APPLIANCE YOU PLUG IN AND LEARN
HOW TO USE IT.
SO THINK ABOUT IT THAT WAY WHEN
YOU'RE THINKING ABOUT A.I., NOT
AS SORT OF THIS THING THAT'S
GOING TO RISE UP AND, YOU KNOW,
MAKE EVERYBODY'S LIVES MORE
DIFFICULT.
THE REASON IT MIGHT BE VALUABLE,
WHY WE THOUGHT IT WOULD BE WORTH
CONSIDERING, IS THAT IN A
TRADITIONAL DISCOVERY PROJECT
YOU GO FROM THIS HUGE NUMBER OF
COMPOUNDS, WINNOWING DOWN LIKE I
SHOWED, ALL THESE SELECTION
CRITERIA.
AND WHAT THE MACHINE SYSTEMS CAN
DO IS GIVE THEM INFORMATION
ABOUT HOW TO SUBSELECT FROM THAT
MUCH LARGER LIBRARY, AND THEN
THEY CAN MAKE INFORMED GUESSES
BY JUMPING ALL OVER THIS SPACE.
I'LL SHOW AN EXAMPLE OF THAT.
AND THEN THEY CAN FORECAST MORE
ACCURATELY THE MORE INFORMATION
THEY HAVE TO UNDERSTAND HOW TO
REDUCE THAT DOWN AND GIVE YOU
SORT OF MORE HITS WITH LESS
INFORMATION.
AND I'M GOING TO SHOW YOU AN
EXAMPLE OF HOW THAT MIGHT WORK
WITH SORT OF CARTOON FROM THE
WHERE'S WALDO.
WE USE THIS VERSION OF MACHINE
LEARNING, BAYESIAN OPTIMIZATION.
WHICH IS WE FED THE DATA FROM
THAT ORIGINAL SCREEN AND THEN
THE BAYESIAN OPTIMIZER BUILDS A
SURROGATE MODEL, CREATES
INFERENCE, ORIGIN FRIENDS MODEL,
A FUNCTION THAT BASES OFF OF ALL
THE DATA BEFORE, MAKES GUESSES
AND THEN TRIES AGAIN.
WE GAVE IT ANOTHER ROUND OF DATA
TO TRY AGAIN.
IT KEEPS ITERATING THIS PROCESS.
THIS IS WHERE THE WHERE'S WALDO
CARTOON COMES BACK IN BECAUSE
WHAT WE DID IS BASICALLY WHAT
THE BAYESIAN OPTIMIZER DOES IS
LOOKS AT THIS PICTURE AND PUTS
RANDOM SPOTS DOWN AND SAYS,
OKAY, ARE THESE RANDOM SPOTS
WALDO OR NOT WALDO?
THAT'S ALL IT KNOWS, CREATES A
FUNCTION, THIS IS WHAT A
BAYESIAN OPTIMIZER DOES, CREATES
A FUNCTION AND THESE ARE THE
RANDOM POINTS ALONG THE
FUNCTION.
OKAY, I'VE LEARNED FROM THESE
OBSERVED DATA THAT THESE ARE
EITHER CLOSE TO WALDO OR THEY
ARE NOT WALDO.
AND THEN IT REVISES THAT DATA,
SECOND TIME, THAT'S A WALL,
THAT'S THE SKY, THOSE ARE NOT
WALDO, THESE DON'T LOOK LIKE
WALDO, ET CETERA.
IT CAN BLOT OUT PORTIONS OF THE
DATA VERY QUICKLY BECAUSE IT CAN
MAKE INFERENCES ABOUT WHAT'S
AROUND THERE USING STATISTICAL
PROBABILITY TO GUESS WHAT IS OR
ISN'T IN THAT SPACE.
IT DOES IT AGAIN, SECOND GUESS,
SAMPLES AGAINST, REVISES ITS
FUNCTIONAL GUESS, USES
ACQUISITION FUNCTION, KEEPS
ROUNDING THE CURVE DOWN TO GET
CLOSER TO WHAT MIGHT BE WHAT WE
CALL THE TRUE FUNCTION, WHAT THE
OPTIMIZED VERSION OF THE
FUNCTION WOULD LOOK LIKE.
IT'S BOUNDING IT WITH CONFIDENCE
INTERVAL EACH TIME.
WE DON'T KNOW WHERE WALDO IS YET
BUT WE KNOW WHERE HE ISN'T IN
THIS EXAMPLE.
IT KEEPS DOING THIS.
I'M NOT GOING TO BELABOR THE
POINT MUCH BUT YOU CAN KEEP
REFINING YOUR FUNCTION, KEEP
GUESSING.
AND SO EVENTUALLY YOU GET CLOSER
TO THE GUESS WITH EACH GUESS
THAT YOU GET.
I'LL JUST SHOW YOU HE'S DOWN
HERE IN THIS LITTLE CORNER HERE,
FOR EVERYBODY'S SATISFACTION.
BUT HE'S HIDING IN THIS YELLOW
POCKET.
THIS IS WHAT WE DID WITH THE
MOLECULES, WE TOOK THIS LARGE
TRAINING SCREEN AND THEN SET OF
DATA, FED IT TO THE BAYESIAN
OPTIMIZER, IT ITERATED AND WENT
OVER A LIBRARY OF 140,000
MOLECULES AND SAID I HAVE A
GUESS OF 720 MOLECULES.
AND WE DID THAT EXPERIMENT.
AND GUESSED AGAIN.
DID ANOTHER 720 MOLECULES,
GUESSED AGAIN, REPEATED SEVERAL
TIMES.
YOU CAN SEE HOW IT'S MOVING
AROUND THIS ENTIRE LARGE SPACE
OF MOLECULES AS IT TRIES TO FIND
NEW THINGS THAT IT CAN LOOK FOR.
THIS IS HOW WE REPRESENT THAT IN
THIS SPACE, AND YOU'LL SEE IT'S
COVERING THAT SPACE RELATIVELY
EFFECTIVELY BUT ENDS UP WITH
SETTLING ON VERY SPECIFIC AREAS,
THESE HIGH RED POINTS, LOG FOLD
CHANGE WHERE IT'S WORKING WELL.
TURNS OUT IN PARTICULAR IT FOUND
REALLY GOOD HITS FOR THINGS THAT
WERE GOOD AND MODIFYING C DAMPER
OR STING, ITS BEST HITS.
I WANT TO HIGHLIGHT ONE, AN
INTERESTING STORY.
WE FOUND THIS MOLECULE THAT VERY
SMALL MOLECULE WORKING IN
COMBINATION WITH TRADITIONAL
AGONIST WAS ABLE TO BOOST
INTERFERON ALMOST TO THE SAME
LEVEL AS THIS COMPOUND MERCK
DISCOVERED, AND TRIED TO
HIGHLIGHT THE FACT MERCK'S
LIBRARY WAS 204 MILLION
COMPOUNDS IN SIZE, WE ONLY HAD
TO DO 2,000 COMPOUNDS, TRYING TO
HIGHLIGHT THE CONTRAST IN TERMS
OF THE AMOUNT OF SIZE OF A
LIBRARY SPACE YOU WOULD HAVE TO
EXPLORE.
s SO WHAT DO WE DO WITH THESE
MOLECULES ONCE WE FIND THEM?
WHAT'S THE POINT OF SEARCHING
AND LOOKING IF YOU'RE GOING TO
EXPLORE?
I WANT TO HIGHLIGHT THINGS YOU
CAN DO WITH THESE AFTERWARDS.
THIS WAS A COVID VACCINATION
EXPERIMENT IN SYRIAN GOLDEN
HAMSTERS, A PRIME AND BOOST,
WE'RE USING CpG AS ADJUVANT,
PROTEIN BASED EXPERIMENT,
CHALLENGE ON DAY 42 WITH THE
ACTUAL VIRUS, AND I'M GOING TO
HIGHLIGHT THE MOST RELEVANT DATA
HERE WHICH IS THAT WHEN WE TOOK
THE NASAL WASH FROM THIS, FOR
THOSE NOT FAMILIAR, THAT'S THE
NASAL CAVITY OF A HUMAN, THE
CAVITY OF THE HAMSTER IS SMALLER
OF COURSE.
YOU'RE LOOKING FOR AMOUNT OF
VIRUS STILL IN THAT CAVITY AFTER
A DAY OR TWO POST-INFECTION
BECAUSE YOU CARE MOST ABOUT HOW
MUCH THAT VIRUS RESIDES THERE,
THAT'S HOW RELATED IT IS TO
INFECTIVITY.
YOU'LL SEE THAT HERE WITH THE
FULL S PROTEIN WE HAVE CpG,
NORMAL ADJUVANT, OR OUR MOLECULE
ON DAY 2, ALREADY HALF OF THE
HAMSTERS HAVE NO DETECTABLE
VIRUS IN THE NASAL WASHES.
BY DAY 3 ALMOST ALL COMPLETELY
CLEARED, IN TRADITIONAL VIRUS
MORE THAN HALF STILL HAVE VIRUS
RESIDING IN THEIR NASAL PHARYNX.
SO THE POINT IS THAT, YOU KNOW,
WITH THE MODULATORS YOU CAN WORK
QUICKLY, DECREASE AMOUNT OF
VIRUS, SOME HAD COMPLETE
STERILIZING IMMUNITY TO THE
INFECTION AS FAR AS WE CAN
DETECT.
THESE ARE THE THINGS YOU CAN
ACHIEVE BY TWEAKING AND
ADJUSTING THE RESPONSE.
IT DOESN'T JUST REDUCE
REACTOGENICITY, AFFECTS POTENCY
OF THE VACCINE.
THE OTHER THING PEOPLE ARE
INTERESTED IN INCREASING
DURABILITY OF IMMUNE RESPONSE,
PLEASED TO SEE THIS WAS THE
OTHER EFFECT COMPOUNDS HAD.
WE TOOK THE SEASONAL FLU
VACCINE, IN THIS CASE THE
PRODUCT FROM SANOFI, THIS HAS NO
ADJUVANTED MOLECULE ON ITS OWN,
BECAUSE IT'S AN INACTIVATED FLU
VIRUS THERE ARE SEVERAL PRRs
INSIDE, SELF-ADJUVATING VIRUS.
WHAT IT'S GOOD AT ACCEPTING
INPUTS IN A GENERAL FASHION.
WE DID A SIMILAR EXPERIMENT,
BOOST AND PRIME, BOOST TO DAY
21, MEASURE HOW MANY ANTIBODIES,
AND DO A CHALLENGE ON DAY 35.
I'M NOT GOING TO SHOW YOU ALL OF
THE DATA BECAUSE IT'S A LOT.
WE DON'T HAVE THAT MUCH TIME BUT
THE MOST IMPORTANT AND RELEVANT
FACT WAS THAT EVEN AS WE TRACK
THESE ANIMALS OVER TIME, WE SAW
AT THAT EARLY TIME POINT THEY
HAD MUCH HIGHER LEVELS OF
ANTIBODY, WHEN WE ADDED THIS PME
564, AND TRUE FOR LOTS OF
COMPOUNDS, HIGH LEVELS OF
ANTIBODIES STAYED OVER A LONG
PERIOD OF TIME, MAINTAINED THIS
KIND OF MUCH HIGHER LEVEL OF
DURABLE RESPONSE, AND WE LEVEL
SET THEM AT HIGHER LEVEL, THEY
CONTINUED TO HAVE THAT HIGHER
LEVEL BASICALLY UNTIL WE FACT
THEM OUT AT DAY 110.
SO, AND THEN WE DID A CHALLENGE.
THIS WAS KIND OF AN INTERESTING
IDEA, TYPICALLY THIS STRANGE OF
2019 IS NOT LETHAL, BUT WE
WANTED TO SEE HOW EFFECTIVE IT
WAS AT PROTECTION AND SO WHAT WE
DID WAS ADDED REGULAR FLU ZONE
AND MODULATORS AND GAVE THEM
JUST INCREDIBLY HIGH DOSE OF
VICTORIA 2019.
YOU'LL SEE THE MICE PARTICULARLY
ONES JUST INOCULATED WITH FLU
ZONE ABOUT SUCCUMB, TO
INFECTION, SOME.
AND MICE WITH COMPOUND WILL
BOTH, YOU KNOW, EXPERIENCE SOME
BODY WEIGHT LOSS AND THEN
EVENTUALLY REBOUND AND SO THEY
WILL ALL SURVIVE EVEN AT THIS
HIGH LEVEL OF VIRUS.
AND THEN DO MUCH BETTER.
WE DO SEE INTERESTING THINGS
WHERE THERE'S A SPLIT BETWEEN
THE NUMBER OF MICE THAT ARE SORT
OF EXPERIENCING NO EFFECT AT
ALL, BASICALLY STERILIZED FROM
THE VERY BEGINNING, SOME MICE
ARE EXPERIENCING INFECTION MORE
SEVERELY.
SO WE'RE STILL LOOKING AT HOW
THAT WORKS RIGHT NOW.
SO WITH THAT, I'VE TOLD YOU A
LITTLE BIT ABOUT THIS KIND OF
AREA THAT WE'RE WORKING IN, SO
TO SUMMARIZE, YOU KNOW,
ADJUVANTS ARE THIS I THINK VERY
PROBLEM-DRIVEN TECHNOLOGY,
ULTIMATELY THIS FRONT END FOR
INNATE IMMUNE SYSTEM, A THING
WE'RE REALLY STUDYING SO WE CAN
UNDERSTAND HOW TO BETTER
MANIPULATE INNATE IMMUNITY.
I TALKED ABOUT POTENTIATORS AND
IMMUNE MODULATORS THAT ALLOW YOU
TO TUNE AND TWEAK IMMUNE
RESPONSE, MACHINE LEARNING AS A
DIFFERENT WAY TO SUBSELECT AND
MOVE THROUGH HIGH-THROUGHPUT
SCREEN MORE EFFICIENTLY.
AND COOL THINGS THESE MOLECULES
CAN DO ONCE YOU FIND THEM, PLUG
THEM INTO COMMERCIAL PRODUCTS,
IMPROVE COMMERCIAL PRODUCTS.
WE'RE BEGINNING TO EXPLORE HOW
TO MAKE A COMPANY AROUND THIS
IDEA SO WE CAN TRANSITION THAT
OUT INTO THE REAL WORLD,
HOPEFULLY.
WITH THAT I WANT TO ACKNOWLEDGE
ALL THE PEOPLE WHO HAVE DONE ALL
THIS HARD WORK, IN PARTICULAR
JEREMIAH AND MATT, LEADS ON THE
DISCOVERY PROJECT, DROVE A LOT
OF THIS WORK, █AND THEN OLIVER
LED THE MACHINE LEARNING WORK,
AND ANDY FERGUSON, MY PARTNER IN
DOING THE MACHINE LEARNING WORK
AS WELL.
OF COURSE, I'D LIKE TO THANK
WOLFGANG AND KENTNER,
INSTRUMENTAL IN SUPPORTING THIS
WORK.
I'D BE HAPPY TO ANSWER QUESTIONS
AND THANK YOU VERY MUCH FOR THE
OPPORTUNITY TO TALK.
>> YOU INCREASE ANTIGEN
PRESENTATION, DOWNREGULATE THE
TNF AND IL-6.
BUT IF YOU LOWER THAT TOO MUCH
THEN YOU SKEW IMMUNE RESPONSE
FROM CELL-MEDIATED IMMUNITY MORE
TOWARD PERHAPS Th2 IMMUNITY.
DO YOU SEE THAT WHEN YOU USE
YOUR LEVERS TO THE POINT WHERE
IF YOU DOWNREGULATE THE TNF AND
IL-6 TOO MUCH YOU SEE A Th2
RESPONSE OR HAVE YOU LOOKED AT
THAT YET?
>> WE HAVE.
SO I THINK THIS IS OFTEN THE
INTERESTING THING THINKING ABOUT
CYTOKINES, THERE'S A DIFFERENCE
BETWEEN SYSTEMIC LEVELS OF
CYTOKINES AND WHAT YOU NEED IN
THE LYMPH NODE FOR INDUCING
Th1 AND Th2 RESPONSE.
WHEN WE DO THIS WE'RE MEASURING
SYSTEMIC CYTOKINES IN THE BLOOD,
WHAT CAUSES REACTOGENICITY AND
SIDE EFFECTS.
WE'RE TRYING TO LOWER ENOUGH SO
YOU DON'T DETECT THEM IN THE
BLOOD BUT THE CELLS PRODUCE TNF
AND IL-6, NOT ENOUGH TO DUMP
THEM INTO THE BLOOD IF THAT
MAKES SENSE.
>> THE QUESTION IS RECHALLENGE,
AT THE RECHALLENGE STAGE, WHEN
YOU TOGGLE DOWN, WHEN YOU
RECHALLENGE TO WHATEVER YOUR
TARGET IS, THAT YOU SEE Th2
IMMUNITY IN WE SAW WITH THE
FIRST RSV VACCINE IN THE
1960s, YOU SAW THIS THC
RESPONSE, THAT WOULD KILL KIDS
RATHER THAN PROTECT THEM.
>> WHEN WE LOOK AT BOTH THE
ANTIBODY SUBTYPES AND LOOK AT
THE RATIOS, THEY BASICALLY
MAINTAIN THE SAME LEVEL, WHEN WE
LOOK AT THE T CELLS THEY DON'T
APPEAR VERY DIFFERENT.
SO, AGAIN, THERE'S KIND OF THE
ABILITY TO MODULATE ALLOWS YOU
TO INTERMEDIATE BETWEEN THINGS.
IF WE DID ADD TOO MUCH OF THIS
WE WOULD END UP IN THAT
SITUATION, BUT THERE'S THE
ABILITY TO DOSE.
SO WE'VE DONE A DOSE CURVE WHERE
YOU CAN SORT OF ADD JUST ENOUGH
TO START SEEING TNF AND IL-6
COME BACK IN THE BLOODSTREAM AS
WELL AS CONTINUING DOWN THAT
PATH.
IN THE LYMPH NODE YOU SEE THEY
ARE STILL PRODUCING CYTOKINES
AND INDUCING A DIFFERENT -- A
SORT OF REGULAR T-CELL RESPONSE.
BUT TO ANSWER THE LARGER
QUESTION AS WELL, WE'RE VERY
INTERESTED IN BEING ABLE TO
DIRECTLY FORECAST, PREDICT, AND
THEN CONTROL T-CELL RESPONSE AS
WELL, THAT'S THE NEXT PHASE OF
THIS, WE'RE HOPING WE GET THE
CHANCE TO KIND OF DO THAT AND
DESIGN THINGS THAT WILL GIVE YOU
EXACTLY THE TYPE OF T-CELL
RESPONSE YOU WANT.
AND SO THAT'S WHAT WE'RE LOOKING
FOR.
>> A FOLLOW-UP FROM YOUR
QUESTION, IN YOUR TARGETS, YOUR
SCREENS, YOU IDENTIFIED
NF-kappaB AND MENTIONED LIN AS
TARGET MOLECULES.
>> IN OUR EARLIER CONVERSATION.
>> SHOULD I HAVE SAID THAT BUT
BOTH OF THEM ARE TERRIFIC
TARGETS.
YOU'VE SHOWN NICE DATA.
THEY ARE ALSO SO IMPORTANT IN
ADAPTIVE IMMUNE RESPONSE SO THAT
IF YOU INHIBIT THEM, IT GOES
BACK TO THRESHOLD AT WHICH YOU
WOULD LIKE TO INHIBIT THEM.
IN YOUR SCREEN HAVE YOU BEEN
ABLE TO IDENTIFY A TARGET THAT
PLAYS NO ROLE BUT SEEMS TO BE
SOLELY MEDIATING THE EARLY
INFLAMMATORY RESPONSE, BECAUSE
THAT WOULD BE A MORE -- THAT
WOULD ADDRESS THIS ISSUE OF
COMPROMISING IMMUNOGENICITY BY
INHIBITING.
>> THIS WAS A REALLY GOOD
QUESTION.
ONE THAT WE HAVEN'T
INTENTIONALLY SEARCHED FOR WHERE
WE SORT OF HAVE DONE EXCLUSION
CRITERIA AND NOW WE COULD LOOK
AT NOW THAT WE LOOKED AT TARGETS
MORE.
WHAT I'LL EXPLAIN, THAT'S
HELPFUL FOR CONTEXT, BECAUSE
THESE ARE ADMINISTERED AT THE
SITE OF INJECTION, ALL SMALL
MOLECULES, WE ALSO MODIFY THE
MOLECULES TO BE LOCALIZED, THEY
ARE NOT MOVING INTO THE REST OF
THE SYSTEM, SO BY LOCALIZING IT
WE CAN SEE THEY ARE ONLY
INHIBITING INNATE RESPONSE AND
NOT AFFECTING.
UNDERSTANDING HOW TO MANIPULATE
ONLY THE INNATE RESPONSE IS
FUNDAMENTALLY INTERESTING
QUESTION BECAUSE WE'D LIKE TO
SEE HOW THE TWO SYSTEMS OPERATE
DIFFERENTLY, RIGHT?
I THINK WE HAVE THE OPPORTUNITY
TO MINE THE DATASET FOR THAT,
FOR SURE.
>> HI.
JIM BURN, UNIVERSITY OF
WISCONSIN.
I HOPE YOU CAN HEAR ME.
>> YES.
>> TERRIFIC TALK.
WHEN YOU STARTED OFF WITH WHAT
LOOKS LIKES EXPERIMENTS USING
DIFFERENT COMBINATION OF SMALL
MOLECULES TO FIND OUT HOW THEY
WORK TOGETHER AND SO FORTH, AND
YOU'VE DONE WORK WITH INJECTED
VACCINES, BUT ALSO SHOWED WORK
WITH MUCOSAL VACCINES LIKE FLU
ZONE OR I THINK IT WAS MUCOSALLY
APPLIED FLU VACCINE YOU SHOWED.
WHEN YOU DO THAT IS IT IMPORTANT
TO CONSIDER WHAT SMALL MOLECULES
ARE DOING TO EPITHELIAL CELLS
AND DO YOU HAVE A PARALLEL
DATASET WHERE YOU'VE DONE ALL
DIFFERENT COMBINATIONS TO SEE
WHAT THAT DOES TO EPITHELIAL
CELL RESPONSES?
>> THAT'S A GREAT QUESTION.
WE -- JUST TO BE CLEAR THAT WAS
DONE WITH AN I.M. INJECTION.
BUT WE'RE ACTIVELY IN THE
PROCESS OF DOING MUCOSAL
VACCINATION, AND SO THAT'S
SOMETHING WE CAN LOOK AT IN MORE
DETAIL.
SO ASAKÉ'S LAB REACHED OUT, TO
THE SURPRISE OF NOBODY, RUNNING
INTO THE SAME PROBLEM THAT
EVERYBODY ELSE IN THE
VACCINATION WORLD IS RUNNING
INTO, WHICH IS IT'S NOT SO EASY
TO ADMINISTER ADJUVANTS TO THE
LONG, SO THEY ARE LOOKING FOR
SIMILAR SOLUTIONS.
I THINK WE CAN START EARLY IN
THAT PROCESS LOOKING AT
EPITHELIAL RESPONSE.
WE'VE ADMINISTERED COMPOUNDS
INTRANASALLY, INTRATRACHEALLY,
BOTH.
WHEN WE LOOK AT INNATE RESPONSE
IN THE LUNG WE DON'T SEE MASSIVE
CHANGE WITH MODULATOR OR THE
ADJUVANT ON ITS OWN BUT WE'VE
NEVER LOOKED AT THE EPITHELIAL
RESPONSES.
THAT'S A REALLY INTERESTING
QUESTION THAT WE SHOULD DIVE
INTO.
>> THANK YOU.
>> THANK YOU VERY MUCH.
>> OH, YES.
>> SORRY, ONE MORE QUESTION.
>> ONE QUICK QUESTION ABOUT THE
TRAINING FOR YOUR IN SILICO
EXPERIMENTS, SO USING YOUR WALDO
ANALOGY, WHAT IF WALDO CHANGES
CLOTHES, FOR EXAMPLE MOLECULE
YOU'RE LOOKING FOR WHAT ABOUT
POST TRANSCRIPTIONAL CHANGES,
FOR EXAMPLE GLYCOSYLATION, ET
CETERA, WHAT IF THE PARAMETERS
THAT YOU ARE TRAINING THE SYSTEM
WITH ARE DIFFERENT?
>> YEAH, SO I THINK THIS IS THE
SORT OF CAUTIONARY TALE ABOUT
USING A.I. AND MACHINE LEARNING
APPROACHES, YOU HAVE TO BE VERY
CLEAR ABOUT EXACTLY WHAT YOU
WANT FROM THE TRAINING AND THE
SCREENING SYSTEM.
SO WHAT I'VE BEEN TRYING TO
EMPHASIZE AS WE GO INTO THIS
PROCESS IS THAT, YOU KNOW, YOU
CAN'T JUST SET THE MACHINE OFF
AND LET IT GO SEARCH FOR
SOMETHING.
YOU HAVE TO HAVE AN EXPERT THAT
UNDERSTANDS EVERY PART OF THE
PROCESS.
SO THAT YOU KNOW EXACTLY WHAT
PARAMETER TO OPTIMIZE FOR.
AND THEN YOU HAVE TO HAVE A LOT
OF SANITY CHECKS ALONG THE WAY.
SO EACH TIME WE DID THIS WE WERE
SORT OF LOOKING FOR MAKING SURE
THE MOLECULES MADE SENSE, MAKING
SURE THEY WERE REASONABLE, IT
WASN'T OPTIMIZING FOR SOMETHING
KILLING THE CELL, FOR INSTANCE.
SO WHENEVER YOU GIVE A SYSTEM
THE CHANCE TO OPTIMIZE A
PARAMETERS IT WILL ALWAYS FIND
THE EASIEST SOLUTION, MAYBE NOT
THE SOLUTION YOU WANT.
YOU HAVE TO BE THOUGHTFUL IN
THAT PROCESS MAKING SURE YOU'RE
DOING THAT CORRECTLY.
THAT'S THE ANSWER.
IT REQUIRES HUMAN EYE TO KIND OF
MAKE SURE THAT IT'S GOING IN THE
PATH YOU WANT, IF THAT MAKES
SENSE.
>> THANK YOU VERY MUCH.
WE'LL TRANSITION FROM A
DISCUSSION OF BIG DATA FOCUSED
ON MOLECULES THAT INDUCE IMMUNE
RESPONSES TO THE BIG DATA OF THE
MOLECULES THAT ARE INDUCED BY
THESE IMMUNE RESPONSES.
DR. PULENDRAN?
>> THANK YOU, WOLFGANG.
I THANK YOU FOR INVITING ME.
IT'S A PLEASURE TO BE HERE.
THE NEXT 20 MINUTES OR SO I'D
LIKE TO TALK WITH YOU ABOUT SOME
WORK WE'RE DOING TO UNDERSTAND
MECHANISMS OF ACTION OF
ADJUVANTS USING SYSTEMS
IMMUNOLOGY APPROACH.
THE MODEL SYSTEMS WE'RE USING
HUMANS, NON-HUMAN PRIMATES AND
MICE TO DO SYSTEMATIC COMPARISON
HOW IMMUNE SYSTEMS SENSES
ADJUVANTS IN RESPONSE IN THREE
SPECIES, IT'S IMPORTANT TO DO
SIDE-BY-SIDE COMPARISON BECAUSE
CLINICAL VACCINE FOLLOW THE
WELL-TRODDEN PATH OF MICE TO
MONKEYS TO HUMAN, GREAT
ATTRITION RATE WITH THIS, VERY
FEW THINGS WORK BEAUTIFULLY IN
MICE SEEM TO WORK WELL IN
MONKEYS AND THEN EVEN FEWER IN
HUMANS.
WE'D LIKE TO UNDERSTAND WHY THIS
IS THE CASE.
SO, ALL RIGHT.
OKAY, GOOD.
THIS SLIDE NEEDS NO INTRODUCTION
BUT TO REMIND YOU ADJUVANTS
STIMULATE INNATE AND ADAPTIVE
IMMUNE RESPONSES, INNATE WORKS
QUICKLY, AND THIS IS THE BASIS
OF VACCINATION.
NOW, ADJUVANTS, CURRENT THINKING
IS THEY TARGET INNATE IMMUNE
SYSTEM, TO STIMULATE THESE
EVENTS THAT HAPPEN DURING IMMUNE
RESPONSE.
THE OTHER IMPORTANT THING TO
REALIZE, AARON TOUCHED UPON
THIS, ADJUVANTS ARE WONDERFUL,
YOU MIGHT WONDER WHY WE EVEN ARE
DISCUSSING ADJUVANTS.
WELL, BECAUSE ADJUVANTS BRING TO
THE TABLE MANY INTERESTING
FEATURES SUCH AS ENHANCING
MAGNITUDE, BREADTH, AND
DURABILITY OF IMMUNE RESPONSES.
WE'VE BEEN INTERESTED, HERE'S A
PAPER THAT CAME OUT FROM OUR
GROUP TWO WEEKS AGO, A HUMAN
STUDY IN WHICH HUMANS WHO
RECEIVED A RECOMBINANT SPIKE
PROTEIN FOR COVID WITHOUT OR
WITH ADJUVANT, ASO3 DEVELOPED BY
GLAXOSMITHKLINE, A SQUALINE OIL,
THE IMMUNE RESPONSE INDUCED WITH
ADJUVANT WAS MUCH HIGHER IN
TERMS OF THE LEVEL OF
ANTIBODIES, BUT THE BREADTH OF
ANTIBODIES AND THEIR CAPACITY TO
NEUTRALIZE NOT JUST THE PARENT
WUHAN STRAIN BUT ALSO VARIANTS
WAS SUBSTANTIALLY HIGHER.
MECHANISM BY WHICH THIS HAPPENED
WAS TO REPROGRAM MEMORY B CELLS
SO YOU WOULD NOW ILLICIT MEMORY
B CELLS THAT EXPRESSED
IMMUNOGLOBULIN PROTEINS FAR
BROADER IN THEIR CAPACITY TO
NEUTRALIZE.
SO THAT WAS AN EXAMPLE OF HOW
ADJUVANTS CAN INDUCE ENHANCED
BREADTH BUT AT CLONAL LEVEL.
THEY CAN INDUCE HIGHLY DURABLE
RESPONSE.
THIS IS A STUDY PUBLISHED A
COUPLE YEARS AGO, NON-HUMAN
PRIMATE STUDY IN WHICH WE WORKED
WITH THE SYNTHETIC PLR 7 LIGAND,
DEVELOPED BY 3M.
WE FOUND THAT THIS HAD A
REMARKABLE PROPERTY TO ENHANCE
DURABILITY OF ANTIBODY RESPONSE
AND LONG LIVED PLASMA BONE
MARROW CELLS IN MONKEYS LASTING
MORE THAN A YEAR.
ALONG WITH THIS WE SHOWED HIGHLY
DURABLE IMMUNE RESPONSES WERE
EFFICIENT AT PROTECTING A YEAR
LATER WHEN THESE ANIMALS WERE
CHALLENGED WITH THE SARS-COV-2
STRAIN.
ADJUVANTS ARE EXTREMELY
IMPORTANT, THEY INCREASE
MAGNITUDE, DURABILITY, AND
BREADTH OF IMMUNE RESPONSES.
SO IT IS EXTREMELY IMPORTANT
THAT WE DEVELOP NEW ADJUVANTS
AND UNDERSTAND THE MECHANISMS OF
HOW SOME EXISTING ADJUVANTS
WORK.
SPEAKING OF MECHANISMS, YOU
HEARD FROM WOLFGANG AND CHUCK,
BASED ON THE PIONEERING WORK
CHARLIE JANEWAY AND OTHERS IN
THE FIELD WHO CONTRIBUTED SO
MUCH IN TERMS OF HOW ANCIENT
INNATE SYSTEM WE ALL HAVE CAN
SENSE A VIRUS OR MICROBE OR
ADJUVANTS.
THE DISCOVERY OF TOLL-LIKE WE
RECEPTORS GIVEN THE NOBEL PRIZE
HIGHLIGHTED THIS.
MANY ADJUVANTS IN THE CLINIC,
I'VE HIGHLIGHTED A FEW THERE,
THESE ARE ADJUVANTS DEVELOPED BY
GLAXO SMITHLINE, CONTAIN
COMPONENTS THAT ARE TRIGGERING
TOLLLIKE RECEPTOR 4.
THERE'S A DIFFERENT ADJUVANT
CpG 1018 IN HEPATITIS B
VACCINE BY DYNAVAX, AND ANOTHER
USED IN THE CONTEXT OF COVID
VACCINE IN INDIA.
SO, CLEARLY ADVANCING KNOWLEDGE
OF INNATE IMMUNITY HAS BEEN
FUNDAMENTAL IN CATALYZING
DEVELOPMENT OF NEW ADJUVANTS
THAT TARGET THESE INNATE
RECEPTORS.
BUT I SHOULDN'T LEAVE YOU WITH
THE IMPRESSION THAT WE NOW
UNDERSTAND EVERYTHING ABOUT HOW
ADJUVANTS WORK BECAUSE OF THE
HANDFUL OF ADJUVANTS WE
CURRENTLY HAVE, ALUM THE MOST
PROMINENT EXAMPLE IN USE FOR
DECADES, NEARLY 100 YEARS OR SO,
IF YOU ASK AN IMMUNOLOGIES DO E
UNDERSTAND THE MOLECULAR
PATHWAYS, NOT AT ALL.
ANOTHER LICENSED IN EUROPE, NOW
IN THIS VACCINE FOR FLU IN THE
ELDERLY, MF59, AGAIN SQUALINE
BASED, AND ASO3, USED WITH THE
H1N1, ANOTHER SQUALINE BASED,
AND ANOTHER ONE ASO1 IN
SHINGRIX, WE DON'T HAVE A FULL
UNDERSTANDING HOW IT WORKS.
IT'S USED IN THE RTS MALARIA
SCREEN, AND MATRIX M, USED BY
NOVAVAX IN THE COVID VACCINE WE
DON'T KNOW HOW IT WORKS.
I'M AN IMMUNOLOGIST STANDING IN
FRONT OF YOU, THE FIELD
DISCOVERED TOLLLIKE RECEPTORS
AND THEY HAVE CATALYZED
ADVANCEMENTS, BUT ALL THESE
WONDERFUL ADJUVANTS MILLIONS OF
PEOPLE HAVE BEEN IMMUNIZED WITH
WE DON'T REALLY UNDERSTAND HOW
THEY WORK, OKAY?
THE REASON YOU MIGHT THINK, WHY
IS IT IMPORTANT TO UNDERSTAND,
SO THAT WE COULD HAVE A MORE
RATIONAL UNDERSTANDING OF INNATE
IMMUNITY SO LIKE WHAT AARON
MENTIONED YOU COULD USE THOSE
SAME PATHWAYS TO DESIGN NEW
ADJUVANTS.
NOW, THIS TREE IS WHAT'S CALLED
THE QUILLAJA SAPONAA FOUND IN
CHILE ONLY.
ASO1 IS ESSENTIALLY THIS WITH A
LITTLE BIT OF CHOLESTEROL.
IT'S BEEN THIS VERY EMPIRICAL
PROCESS BY WHICH ADJUVANTS HAVE
BEEN DEVELOPED.
THIS CAME OUT IN "SCIENCE," THE
OTHER IN "NATURE BIOTECHNOLOGY,"
CHEMICALLY ABLE TO SYNTHESIZE,
ELUCIDATE PATHWAY FOR THE
BIOSYNTHESIS OF THESE MYSTERIOUS
ADJUVANTS, VERY EXCITING BECAUSE
FOR THE FIRST TIME BY
UNDERSTANDING THE CHEMICAL BASIS
OF THIS SAPONIN ADJUVANT, COME
UP WITH SMALL MOLECULE THAT
COULD SERVE POTENTIALLY AS NEXT
GENERATION OF ADJUVANTS.
THE OTHER PROBLEM IN THE FIELD
AS I MENTIONED EARLIER ON IS
THAT LOTS AND LOTS OF ETHICS
THAT WORK AMAZINGLY WELL IN MICE
SIMPLY DO NOT TRANSLATE INTO
HUMANS.
THE REASON FOR THAT IS MICE, AND
WE HUMANS, HAVE EVOLVED IN A
DIVERGENT WAY FROM 100 MILLION
YEARS AGO.
SO ALTHOUGH IN BROAD PRINCIPLES,
THE IMMUNE SYSTEMS IN MICE AND
HUMANS ARE QUITE SIMILAR, WE
BOTH HAVE T CELLS AND B CELLS
AND DENDRITIC CELLS AND
MACROPHAGES, THERE'S VERY
IMPORTANT DETAILS THAT ARE
DIFFERENT.
YOU MIGHT BE WONDERING WHY
SHOULD ONE WORRY ABOUT MINOR
DETAILS?
WELL, IT COMES INTO PLAY IF YOU
INJECT AN ADJUVANT THAT TRIGGERS
A CERTAIN RECEPTOR, LET'S SAY
TOLL-LIKE RECEPTOR 7, AND IN
HUMANS WE KNOW THAT THIS IS
HIGHLY RESTRICTED TO ONE TYPE OF
DENDRITIC CELL, PLASMACYTOID,
BUT IN MICE IT'S MORE BROADLY
EXPRESSED IN MANY TYPES OF
DENDRITIC CELLS.
WHEN YOU INJECT A MOLECULE THAT
ACTIVATES ONE RECEPTOR YOU'LL
GET DIFFERENT RESPONSES IN MICE
AND HUMANS, THAT'S ONE EXAMPLE
BUT THERE ARE COUNTLESS OTHERS.
HOW ABOUT MONKEYS?
MONKEYS ARE CLOSER TO HUMANS BUT
ARE STILL 35 MILLION YEARS AWAY,
OKAY?
SO, THIS HIGHLIGHTS THE NEED FOR
US TO DO A COMPARATIVE ANALYSIS
IN THESE THREE DIFFERENT SPECIES
TO SEE WHAT WORKS, WHAT'S
COMMON, WHAT'S DIFFERENT.
AND SO HOW MIGHT YOU LOOK AT
THIS IMMUNE RESPONSE AND I THINK
AARON MENTIONED THIS BRIEFLY IN
HIS TALK.
TRADITIONALLY WE'VE ALWAYS
MEASURED ONE MEASURE OF THE
IMMUNE RESPONSE, ANTIBODY LEVELS
OR T CELL LEVELS.
THAT SERVED US WELL.
THAT'S A VERY GOOD FIRST STEP.
BUT YOU KNOW THE IMMUNE SYSTEM
IS SO MUCH MORE COMPLICATED THAN
JUST ANTIBODIES AND T CELLS.
THERE'S ALL THESE SUBSETS OF
DENDRITIC CELLS, MACROPHAGES,
MONOCYTES.
HOW DO YOU GET A COMPREHENSIVE
LOOK AT HOW THE IMMUNE SYSTEM IS
RESPONDING TO ADJUVANT OR
VACCINE?
SO HERE'S WHERE THE FIELD OF
SYSTEMS IMMUNOLOGY COMES IN
BECAUSE IT IS A SYSTEMATIC WAY
OF LOOKING AT IMMUNE SYSTEM.
THAT'S AN EXAMPLE WHERE A HUMAN
CANP BE IMMUNIZED HAVE ADJUVANT
OR VACCINES, COLLECT LYMPH NODE
SAMPLES, OTHER TISSUES, YOU
COULD USE TOOLS OF EPIGENOMICS,
TRANSCRIPTOMICS, METABOLOMICS,
SO FORTH TO LOOK AT CHANGES IN
RESPONSE TO VACCINATION.
AND REALLY THE FIRST EXAMPLE OF
THAT CAME FROM A STUDY WE HAD
DONE ABOUT 15 YEARS AGO, WHERE
WE DECIDED THAT WE WOULD TAKE A
VACCINE WHICH WAS REALLY A
TERRIFIC VACCINE, HAD BEEN IN
USE IN HUMANS FOR DECADES, AND
600 MILLION PEOPLE HAD RECEIVED
THIS VACCINE.
IT'S A SORT OF GOLD STANDARD
VACCINE BECAUSE ONE SHOT OF THIS
VACCINE GIVES YOU LIFELONG
IMMUNITY.
YET WE DIDN'T REALLY UNDERSTAND
THE BASIS OF HOW THIS VACCINE IS
WORKING.
WELL, I HAVE TO BE PRECISE HERE.
WE DO UNDERSTAND THAT IT USES
ANTIBODIES AND T CELLS BUT THESE
MOLECULAR MECHANISMS BY WHICH
THIS VACCINE WAS TARGETING THE
IMMUNE SYSTEM WAS SHROUDED IN
MYSTERY.
WHAT WE DID WAS A STUDY IN
HUMANS, IMMUNIZED WITH VACCINE,
COLLECTED BLOOD SAMPLES AT ALL
TIME POINTS, AND APPLIED THE
TOOLS OF GENOMICS OR
TRANSCRIPTOMICS TO MEASURE THE
CHANGE IN THE EXPRESSION OF
GENES IN THE BLOOD OF THESE
PEOPLE IN RESPONSE TO
VACCINATION.
AND THEN USING MACHINE LEARNING
TOOLS WE WERE ABLE TO COME UP
WITH A GENE LIST, A PREDICTIVE
SIGNATURE, THAT COULD PREDICT IN
A COMPLETELY INDEPENDENT TRIAL
THE STRENGTH OF THE T-CELL
RESPONSE AND STRENGTH OF THE
ANTIBODY RESPONSE.
THIS WAS THE FIRST EXAMPLE OF A
STUDY IN WHICH WE CAN LOOK
BROADLY, COMPREHENSIVELY, AT
IMMUNE RESPONSE TO VACCINE USING
TOOLS OF SYSTEMS BIOLOGY AND
IMPORTANTLY TO USE THE TOOLS OF
MACHINE LEARNING TO PREDICT
VACCINE IMMUNITY.
SO, THERE'S NO QUESTION WE WERE
GENERATING LOTS OF DATA.
THE QUESTION WAS WHAT PARTICULAR
INSIGHT ABOUT THE PATHWAYS THIS
VACCINE WAS TRIGGERING COULD WE
DISCERN FROM THIS VOLUMES OF
DATA.
OF COURSE IT'S IMPORTANT IN
BIOLOGY TO GO FROM
DATA-TO-KNOWLEDGE TO
UNDERSTANDING.
I'LL JUST GIVE YOU ONE EXAMPLE.
HERE'S THE EXAMPLE I'D LIKE TO
MENTION, YOU CAN SEE ON THE LEFT
THE HEAT MAP, ON THE TOP YOU CAN
SEE THE T-CELL RESPONSE ACROSS
15 OR 20 VOLUNTEERS.
THESE ARE PEOPLE WHO HAVE THE
YELLOW FEVER VACCINE BUT ALL
RESPOND DIFFERENTLY.
SOME HAVE VERY LOW LEVELS OF T
CELLS, OTHERS HAVE VERY HIGH
LEVELS OF T CELL.
WE ASK A SIMPLE QUESTION, WHAT
IS PATTERN OF GENE EXPRESSION IN
USE IN A DAY OR THREE DAYS OR
SEVEN DAYS, VERY EARLY AFTER
VACCINATION, THAT WOULD
CORRELATE WITH THE LEVEL OF T
CELLS.
YOU CAN SEE THERE WERE GENES
THAT POPPED OUT, AND I WAS
STRUCK BY THE FACT THAT ALL OF
THESE GENES BELONG TO WHAT WE
CALL THE INTEGRATED STRESS
RESPONSE.
THIS IS ANOTHER ANCIENT SYSTEM,
A HOMEOSTATIC SYSTEM THAT
MAMMALIAN CELLS EVOLVED TO SENSE
ALL KINDS OF STRESSES.
YOU SEE FOUR MAJOR PROTEINS,
KNOWN THERE, GCN 2, HRI, PERK,
PKR.
GCN 2 IS KNOWN AS EIF 2AK 4 IN
RED.
THAT IS A MOLECULE THAT WE ALL
HAVE IN OUR BODIES, INSIDE
CELLS, THAT CAN SENSE AMINO ACID
CHANGES.
WHEN INSIDE YOUR BODY, IN YOUR
CELL, THE LEVEL OF AMINO ACID
DROPS DOWN, THIS GCN 2 MOLECULE
BECOMES ACTIVATED, THEN IT SENDS
A SIGNAL TO THE RIBOSOMES WHICH
ARE THE PROTEIN TRANSLATION
MACHINERY, TO STOP MAKING ANY
MORE PROTEIN.
OKAY?
WE WERE AMAZED HOW WOULD THE
ANCIENT STRESS RESPONSE PATHWAY
BE LINKED TO VACCINE IMMUNITY?
WHAT HAPPENED IN THE ENSUING FEW
YEARS WHICH I'M SUMMARIZING IN
ONE SLIDE IS WE WERE ABLE TO
WORK OUT MOLECULAR DETAILS OF
THE PATHWAY AND SHOW THAT IN
FACT THIS VIRAL VACCINE, YELLOW
FEVER VACCINE, WAS TRIGGERING
GCN 2 PATHWAY THROUGH PROCESS
KNOWN AS AUTOPHAGY IN DENDRITIC
CELLS, ENHANCING PRESENTATION TO
T CELLS.
I MENTION THIS TO YOU BECAUSE
ORDINARILY, NEITHER WE, NONE OF
MY COLLEAGUES, WERE JUXTAPOSING
VACCINE IMMUNITY WITH INTEGRATED
STRESS RESPONSE.
TWO COMPLETELY DISPARATE THREADS
OF BIOLOGY COULD NOW BE UNITED
THROUGH DEEP MINING OF THE DATA
AND COMING UP WITH NEW
BIOLOGICAL HYPOTHESES WHICH YOU
COULD MECHANISTICALLY DISSECT.
SO, THIS REALLY LEADS ME TO THIS
PARTICULAR ADJUVANT CONTRACT
THAT WOLFGANG MENTIONED WE'RE
SO
THRILLED TO BE PART OF.
I'D LIKE TO SHOW SOME EARLY
RESULTS THAT WE'RE GETTING WITH
THIS KIND OF SYSTEMS APPROACH.
OUR ADJUVANT COMPARISON AND
CHARACTERIZATION ACC PROGRAM, AT
STANFORD, GOALS TO USE SYSTEMS
BIOLOGY APPROACH TO PRE-FILE
INNATE AND ADAPTIVE IMMUNE
RESPONSE INTRODUCED BY
ADJUVANTATED SUBUNIT VACCINES,
IN MICE, MONKEYS, HUMANS.
A COLLABORATION WITH MARK AND
HIS LAB.
WE'D LIKE TO ESTABLISH
COMPARATIVE IMMUNE FINGERPRINT
OF EACH ADJUVANT.
WHY?
WE'D LIKE TO DEFINE MOLECULAR
TICKETS, -- SIGNATURES, GENERAE
MOLECULAR ATLAS OF ADJUVANT.
IF YOU HAVE ABCD, EACH ADJUVANT
HAS A CERTAIN MOLECULAR ATLAS.
WHO CARES?
WELL, I THINK THIS WOULD BE
HELPFUL IN BENCHMARKING NEW
ADJUVANTS SO WHEN AARON COMES UP
WITH THIS NEW ADJUVANT OR IMMUNE
REGULATOR, HE WOULD BE ABLE TO
LOG INTO THE AT ATLAS, AH, THIS
LOOKS LIKE SOMETHING ELSE, AND
COULD CLASSIFY ADJUVANTS.
I THINK THIS IMPORTANTLY FOR
BIOLOGISTS IS A GUIDE POST FOR
HYPOTHESIS-DRIVEN RESEARCH INTO
THE MECHANISMS OF ACTION OF
ADJUVANTS.
SO, LET ME SHARE WITH YOU A FEW
SLIDES ON WHERE WE ARE WITH
THIS.
AND THE SORT OF FOUNDATIONAL
STUDY FOR THIS PROGRAM COMES
FROM A STUDY THAT WE HAD DONE A
FEW YEARS AGO BACK IN 2020,
DURING THE COVID HAND WHEN WE
WORKED WITH DR. NEIL KING AND
DR. DAVID BUTLI AT UNIVERSITY OF
WASHINGTON.
THEY DESIGNED THIS, THIS IS NOW
APPROVED FOR USE IN CLINIC SOUTH
KOREA.
WE WORKED WITH THEM AND WITH A
NUMBER OF DIFFERENT VACCINE AND
ADJUVANTS MANUFACTURERS THAT ARE
SHOWN HERE WITH GLAXOSMITHKLINE,
DYNAVAX AND THIS COMPANY SEPPIC
TO TEST FIVE ADJUVANTS.
ASO 3 IS A SQUALINE BASED,
ANOTHER IS SQUALINE BASED, AS37,
IT'S BASICALLY A TLR7 LIGAND
WITH ALUM.
CPC 1058 MIXED WITH ALUM, AND
STANDARD ALUM.
IN THE CONTEXT OF THAT STUDY
WHERE WE'RE DOING IS EXTENSIVE
IMMUNE PROFILING TO BEGIN TO
DEFINE THE MOLECULAR
FINGERPRINTS OF EACH ADJUVANT.
WE'RE LOOKING AT SINGLE CELL RNA
SEQUENCING, EVERY CELL IN THE
BLOOD IN A DROP OF BLOOD OF A
MONKEY BEFORE IT GOT THE
IMMUNIZATION, ONE DAY AFTER,
SEVEN DAYS, SO ON, YOU CAN ASK
EVERY SINGLE CELL IN ITS GENOME,
THERE ARE SOME 30,000 GENES,
WHAT ARE THEY DOING, GOING UP,
COMING DOWN?
AND YOU CAN THEN MAP THE
TRAJECTORY.
IN THE BEAUTIFUL U-MAP CLUSTER
YOU CAN SEE MAJOR CELL TIMES YOU
CAN DEFINE IN A DROP OF MONKEY
BLOOD.
YOU CAN SEE DIFFERENT TYPES OF
MONOCYTES AND SO ON.
WITH THE FIVE ADJUVANTS, WHAT
HAPPENS WITH TIME?
WHEN YOU IMMUNIZE THESE MONKEYS?
AND YOU CAN SEE HERE IN RED I'M
POINTING TO THESE CLUSTERS WHERE
THERE'S SOME GREEN COMING UP.
SO, THOSE ARE -- ON THE FOCUS ON
THE TREE, THE ALUM, THE ONE
BELOW THE PENULTIMATE ROW, DAY 1
YOU CAN SEE LOTS OF INTERFERON
STIMULATED GENES THAT ARE BEING
STIMULATED.
AND THIS PERSISTS FOR DAY 7.
LOOK AT DAY 22, ONE DAY AFTER
THE SECOND REIMMUNIZATION.
AGAIN, YOU SEE BURST OF GENE
ACTIVITY, PERHAPS NOT
SURPRISING, THAT'S WHAT
ADJUVANTS DO.
BUT WHAT WAS VERY INTERESTING
WHEN YOU ZOOMED INTO THE
MONOCYTE POPULATION ON THE RIGHT
THERE, YOU SEE MANY, MANY
DIFFERENT CLUSTERS OF MONOCYTES.
TRADITIONALLY IF YOU ASK HOW
MANY TYPES DO YOU KNOW?
THE IMMUNOLOGIST WOULD SAY
CLASSICAL, INFLAMMATORY
MONOCYTES, PATROLLING MONOCYTES.
SURE ENOUGH WE CAN SEE THEM.
WE CAN SEE AT THE BOTTOM IN
BROWN ARE THE PATROLLING OR
NON-CLASSICAL.
IN THE MIDDLE IN PINK ARE
INFLAMMATORY.
AT THE TOP YOU SEE ALL THOSE
COLORS.
THOSE ARE ALL DIFFERENT TYPES OF
MONOCYTES, CLASSICAL MONOCYTES.
WHAT ARE THOSE DIFFERENT TYPES?
YOU CAN SEE IN ORANGE THOSE ARE
MONOCYTES OF CLUSTER 1, ISG.
THAT IS INTERFERON STIMULATED
GENES.
IN BLUE YOU CAN SEE WHAT'S
CALLED VCAN HIGH MONOCYTES, IN
GREEN, TRANSCRIPTIONAL PROFILE
IS VERY DIFFERENT.
SO, WE ASK WHAT HAPPENS WITH
EACH OF THESE ADJUVANTS?
LET'S TAKE A LOOK AT, FOR
EXAMPLE, THE 3M 052, HOW DO THEY
CHANGE IN IMMUNE RESPONSE?
ON THE LEFT YOU CAN SEE THIS
DIAGRAM WHERE IF YOU TRAVERSE
PERIPHERY, BOTTOM IS BASELINE,
DAY 1, DAY 7, DAY 18, DAY 22 ONE
DAY AFTER, AND SO ON.
CLUSTERS ARE CHANGING.
TO SIMPLIFY, SEROTIME TRAJECTORY
ANALYSIS, A FANCY WORD, IT MEANS
COMPUTATIONALLY YOU CAN INFER
THE SEQUENCE OF EVENTS THAT
HAPPENED DURING IMMUNE RESPONSE.
SO YOU CAN SEE WITH THIS
PARTICULAR ADJUVANT THE MONOCYTE
RESPONSE GOES FROM HIGH
POPULATION IN BLUE TO S100A9,
CUTS ACROSS INTERFERON
STIMULATED GENES AND GETS INTO
THE INTERMEDIATE AND
NON-CLASSICAL PATROLLING
MONOCYTES.
BUT DIFFERENT ADJUVANT,
TRAJECTORY FOLLOWS TO ORANGE
INTERFERON STIMULATED GENES BUT
DON'T PROGRESS TO THE
INTERMEDIATE OR NON-CLASSICAL.
LOOPS BACK TO THE MIDDLE WHICH
IS A SUBSET OF MONOCYTES WHICH
IS ENRICHED IN NF-kappaB AND
TARGET GENES.
IF YOU DO THIS ANALYSIS BROADLY
ACROSS DIFFERENT ADJUVANTS WHAT
YOU CAN SEE IS THAT THERE ARE
TWO BROADLY DIFFERENT
TRAJECTORIES, THIS SEEMS TO
DRIVE CELLS THROUGH TO THE
INTERMEDIATE, BUT ALUM SO 3, S
37 AND CpG COME HALFWAY THERE
BUT LOOP BACK TO NF-kappaB
HIGH POPULATION.
WHY IS THIS IMPORTANT?
WHAT IS THE FUNCTIONAL RELEVANCE
OF THIS IN TERMS OF INNATE
IMMUNITY, CYTOKINES AND THE
NATURE OF THE ADAPTIVE RESPONSE?
THIS IS SOMETHING THAT WE'RE
LOOKING AT NOW.
LET ME CONCLUDE BY SAYING I'VE
SHOWN MONOCYTES ACTIVATE --
SORRY, ADJUVANTS ACTIVATE
MONOCYTES, THAT'S THE INNATE
SYSTEM.
THE CARTOON AT THE FRONT.
SURPRISE FOR US WAS THAT WHEN
YOU LOOK AT THE DATA IT'S NOT
JUST THE INNATE CELLS ACTIVATED.
YOU CAN SEE, FOCUS ON
PENULTIMATE ROW, 3M-052, THERE'S
A CLUSTER OF T CELLS ON THE LEFT
PANEL, YOU CAN SEE THE
JUXTAPOSED TO YELLOW IS RED
CELLS THAT EXPRESS INTERFERON
STIMULATED GENES AT DAY 1, NOT
ANTIGEN SPECIFIC T CELLS THAT
HAVE BECOME ACTIVATED.
THEY TAKE A LONGER TIME.
THESE ARE SOME SUBSET OF T CELLS
QUICKLY RESPONSING BUT NOT
INTERFERON STIMULATED GENES.
SAME DAY AT DAY 22, ONE DAY
AFTER SECOND IMMIZATION, WHAT IS
THE FUNCTIONAL BASIS?
THEY ARE GUIDING SUBSEQUENT
MONOCYTE RESPONSE, WHAT'S THE
LINK?
WE DON'T KNOW, WE'RE EXPLORING.
YOU CAN SEE KINETICS HERE.
IN THE LAST TWO OR THREE SLIDES
WHAT I WANT TO TELL YOU IS THAT
WE'RE NOW DOING
CROSS-COMPARATIVE ANALYSIS
BETWEEN MONKEYS AND MICE, SAME
ADJUVANTS NOW USED IN MICE.
ALREADY YOU CAN SEE VERY MAJOR
DIFFERENCES.
FIRST OF ALL LOOK AT THE RATIO
OF B CELLS TO T CELLS IN A
MONKEY, .33.
LOOK WHAT HAPPENS IN A MOUSE,
1.39.
THIS INTERFERON STIMULATED
SIGNATURE IN T CELLS THAT I
MENTIONED WHICH ARE SO PROMINENT
IN MONKEYS, WE DON'T SEE THAT IN
MICE.
IF YOU TAKE MOUSE BLOOD, ISOLATE
MOUSE PBMCs LIKE WHAT YOU DO
IN MONKEYS, YOU SIMPLY DON'T SEE
THAT.
BUT YOU DO SEE IT IN THE
DRAINING LYMPH NODES, YOU CAN
SEE THE CLUSTER THERE.
AND SO FINALLY, ALL THESE
CHANGES THAT ARE HAPPENING WITH
ADJUVANTS IS DIFFERENT
TRAJECTORIES, HOW LONG DO THEY
LAST?
IS THERE A CHANGE IN THE
EPIGENOME OF THESE?
WE'VE BEEN LOOKING AT THIS.
THIS IS AN EXAMPLE IN HUMANS.
WHERE WE WERE GIVING THESE
HUMANS THE PANDEMIC FLU VACCINE
WITH ASO 3, IN THAT STUDY
MONOCYTES UNDERGOING INCREDIBLE
EPIGENETIC PROGRAMMING THAT
LASTED FOR ABOUT TWO MONTHS.
SO IN OTHER WORDS, AFTER TWO
MONTHS, THE CHROMATIN LOCI
TARGETED BY INTERFERON FACTORS
STAT1 AND STAT2 WERE MORE
ACCESSIBLE THAN BEFORE VACCINE.
IN CONTRAST TARGETED BY API
TRANSCRIPTION FACTORS WERE LESS
ACCESSIBLE THAN BEFORE YOU GAVE
THE ADJUVANT.
SO THAT WAS PUBLISHED BUT NOW
WHAT WE'RE DOING IS DOING A
CROSS-COMPARATIVE ANALYSIS OF
SIX VACCINES INCLUDING THE
SHINGRIX ASO-1, ALSO PFIZER
mRNA, AND SO ON.
WHAT I CAN TELL YOU IS WE'RE
BEGINNING TO DEFINE WHAT WE CALL
MOTIF SUPER CLUSTERS, SINGLE
CELL LEVEL THAT SEEM TO BE
DIFFERENTIALLY INDUCED BY
DIFFERENCE VACCINES.
SOME ARE CO-REGULATED.
IF YOU LOOK WITH IRF CHROMATIN
ACCESSIBILITY ON X-AXIS IN
MACHINEOCYTES VERSUS AP 1
ACCESSIBILITY THERE'S MOST
DEFINITE INVERSE CORRELATION
ACROSS ALL THESE VACCINES H1N1,
WITHOUT ADJUVANT, SEASONAL FLU
VACCINE, PFIZER mRNA, YELLOW
FEVER, SHINGRIX.
THESE ARE DISTANT REGIONS IN THE
CHROMATIN, HOW IS THIS
EPIGENETIC COORDINATION
HAPPENING, WHAT DOES THIS MEAN
FOR ADJUVANT BIOLOGY?
WE DON'T KNOW.
THERE'S LOTS OF QUESTIONS.
LET ME END WITH THIS SLIDE.
LET ME REITERATE MICE ARE
WONDERFUL TOOLS AND YET THEY
SEEM TO BE SO DIFFERENT FROM
HUMANS.
THIS IS A VERY SIMPLE ASSAY.
THIS IS THE SAME VACCINE, ASO 3
ADJUVANTED GIVEN IN HUMANS,
MONKEYS, MICE.
WE'RE MEASURING IN SERUM
INTERFERON GAMMA AND IL-5.
LOOK WHAT HAPPENS IN HUMANS.
A VERY NICE INTERFERON GAMMA
Th1 RESPONSE.
LOOK AT RHESUS MACAQUES, THE
OPPOSITE, A Th2 RESPONSE.
LOOK AT MICE, MORE LIKE A Th2
RESPONSE.
AGAIN, WE'RE SEEING MANY, MANY
SPECIES DIFFERENCES THAT, AGAIN,
HIGHLIGHT IMPORTANCE OF ACTUALLY
LOOKING AT THESE ACROSS SPECIES
PARTICULARLY IN HUMANS.
THAT'S THE PURPOSE OF THE
PROGRAM THAT WE'RE EXCITED TO BE
PART OF.
THIS IS REALLY THE CONCLUSION,
BASICALLY THE IDEA THAT YOU
COULD DEVELOP ADJUVANTED
VACCINES OR ANY VACCINES BY
GOING THROUGH THE STANDARD PHASE
1, PHASE 2, PHASE 3.
IF YOU'RE SUCCESSFUL LICENSE, OR
YOU'RE SCRATCHING YOUR HEAD WHAT
SHOULD WE DO.
TOOLS SHOULD GO INTEGRATED INTO
THE VACCINE TESTING PIPELINE TO
DO IN VITRO ANIMAL MODELS, IT'S
A VIRTUAL CYCLE OF UNDERSTANDING
THE BASIS OF IMMUNOGENICITY.
WITH THAT I'D LIKE TO CONCLUDE
THESE ARE THE AMAZING PEOPLE WHO
DID THE WORK.
AND OF COURSE HUGE THANKS TO
NIAID AND NIH FOR ALL THEIR
SUPPORT THROUGHOUT THE LAST FEW
YEARS.
THANK YOU.
>> I WAS INTRIGUED BY THE PAPER,
IN YOUR TALK WHEN YOU SHOWED THE
DATA, YOU SUGGESTED THERE WAS
INCREASED -- OF COURSE
DURABILITY, WHICH YOU WOULD
EXPECT FROM VACCINE BUT ALSO
THERE WAS A CHANGE IN THE
ANTIBODY REPERTOIRE THAT THERE
WAS EXPANDED
DO YOU THINK ADJUVANT THAT YOU
WERE USING IN THAT, DOES THAT
HAVE EFFECT ON SOMATIC
RECOMBINATION IN SOME RESPECT OR
AFFINITY MATURATION OR BOTH?
IF IT'S SOMATIC RECOMBINATION
THAT WOULD BE A HUGE PARADIGM
SHIFT I WOULD THINK.
>> THANK YOU FOR THAT.
THAT WAS REALLY THE CRUX OF THE
PAPER.
ON THE ONE HAND, EVERYONE AGREED
THAT ADJUVANTS INCREASE
MAGNITUDE AND SO THROUGH THAT
RISING TIDE RAISES ALL BOATS
MODEL, IF THE MAGNITUDE IS
HIGHER, OF COURSE YOU WOULD
PREDICT SEROLOGICALLY BREADTH
WOULD BE HIGHER BECAUSE THERE
ARE MANY CLONES EMERGING.
WE SHOWED THESE ARE INDUCING
GERMINAL RESPONSES WHICH LEADS
TO PERSISTENT ACQUISITION OF
SOMATIC MUTATIONS OVER SIX-MONTH
PERIOD, COULD YOU ISOLATE CLONES
BEFORE, SHORTLY AFTER
VACCINATION, A MONTH AFTER
VACCINATION, OR SIX MONTHS AFTER
VACCINATION, IN ESTABLISHED
CLONAL LINEAGES TRAJECTORY AND
SHOW THE SAME CLONE HAD ACQUIRED
A THOUSAND-FOLD MORE AFFINITY
AND ALSO ACQUIRED BREADTH.
WE THINK ONE PATHWAY BY WHICH
ADJUVANT IS PROMOTING BREADTH AT
CLONAL LEVEL IS AS YOU SAY
THROUGH THE ACQUISITION,
CONTINUOUS ACCUMULATION OF
SOMATIC MUTATION THAT GIVES THE
OPPORTUNITY TO BIND NOT JUST THE
PARENT STRAIN BUT ALSO OTHER
VARIANTS.
THERE'S ANOTHER PATHWAY THAT'S
NOT THE ONLY PATHWAY, WHAT WE
CALL THE -- IT'S EPITOPE MASK,
INITIAL RESPONSE GENERATES
ANTIBODIES THAT ARE HIGHLY
SPECIFIC TO THE PARENT STRAIN,
WHICH THEN BLOCKS THE DOMINANT
EPITOPE ON THE RBD, LEAVING
EXPOSED THE OTHER SUBDOMINANT
EPITOPES WHICH THE CLONES THAT
RECOGNIZE THOSE EPITOPES NEVER
HAD A CHANCE TO COMPLETE IN THE
FIRST PLACE WITH DOMINANT CLONES
BUT NOW DOMINANT UP -- EPITOPE
IS BLOCKED.
>> DAY 1 ISG POPULATION THAT YOU
SEE IN HUMANS, NOT IN MICE, IS
THIS AN EXPANSION OF BASELINE IN
T CELL COMPARTMENT OR IS THIS
RESPONSIVE POPULATION TO THE
VACCINE AND ADJUVANT, AND DOES
IT CORRELATE WITH ANY OF THE
RESPONSES?
>> GREAT QUESTION.
WE DON'T KNOW IF IT IS AN
EXPANSION OF PREEXISTING ISG
CELLS IN MONKEYS BECAUSE OF
THEIR PRIOR EXPOSURE TO SO MANY
OTHER PATHOGENS, RIGHT?
BUT WHAT WE ARE PLANNING TO DO
IS LINEAGE TRACING USING MITO
Seq, MITOCHONDRIAL MUTATIONS,
YOU CAN SEE WHETHER THE SAME
CELL, SAME LINEAGE, IS CONVERTED
TO THE OTHER TYPE.
WE DON'T HAVE THAT DATA YET BUT
WE'RE DOING THAT.
YOUR QUESTION DOES IT MEAN
ANYTHING IN TERMS OF IMMUNE
RESPONSES, DURABILITY, LONGEVITY
AND SO ON, WE'RE WORKING ON
THAT.
WE DON'T HAVE ANY DATA ON THAT
YET.
>> HI, JIM BURN, JUST A TERRIFIC
TALK.
THANKS SO MUCH.
ONE QUESTION THOUGH WITH THE
ADJUVANTS THAT MARKEDLY INCREASE
BREADTH OF THE ANTIBODY RESPONSE
IS THERE ANY WORRY THERE THAT
YOU'LL START TO INCREASE TO THE
POINT WHERE YOU GET OFF TARGET
ANTIBODIES?
>> YEAH, THERE'S ALWAYS A WORRY
WITH OFF TARGET EFFECTS.
HOWEVER, I THINK THERE'S A LIMIT
TO HOW MUCH BREADTH AND ADJUVANT
CAN INCREASE.
WE'RE VERY LUCKY IN THE CONTEXT
OF WHAT WE'RE SEEING WITH COVID
ANTIGENS.
BUT IT IS FAR -- FALLS FAR SHORT
OF WHAT HIV VACCINE PEOPLE WOULD
LIKE.
I THINK ALTHOUGH IT'S AN
ENCOURAGING STEP TO INCREASING
BREADTH WE'RE FAR SHORT OF
INCREASING TO SUCH A DEGREE IT
GOES TO OFF-TARGET ANTIGENS.
>> THANK YOU.
>> NEXT SPEAKER WILL TALK ABOUT
THE EVALUATION OF NOVEL ADJUVANT
IN A CLINICAL TRIAL.
DR. EVANS, THE FLOOR IS YOURS.
>> CAN YOU HEAR ME OKAY?
>> YES.
>> AND THE SCREEN IS ON THE
RIGHT PRESENTER MODE?
>> YES, IT IS.
>> GREAT.
THANK YOU.
THANKS FOR THE OPPORTUNITY TO
TALK TODAY.
I'M SORRY I COULDN'T BE THERE IN
PERSON.
I'M ACTUALLY FLYING OUT THERE
FOR THE ADJUVANT COMPARISON
MEETING, I'LL BE THERE ON
WEDNESDAY AND THURSDAY OF THIS
WEEK, SO IF PEOPLE WANT TO MEET
IN PERSON AND ASK QUESTIONS.
SO I'M GOING TO TELL YOU A
LITTLE BIT ABOUT THE ADJUVANT
RESEARCH AT UNIVERSITY OF
MONTANA.
I'M JAY EVANS, DIRECTOR AT
UNIVERSITY OF MONTANA, AND A
UNIQUE PUBLIC/PRIVATE
PARTNERSHIP IN 2016.
SO OUR FOCUS IS THE DISCOVER AND
DEVELOPMENT OF NOVEL
DISEASE-MODIFYING THERAPIES,
ADJUVANTS ARE AT THE CORE.
WE DEVELOPED NOVEL ADJUVANTS FOR
VACCINE INDICATIONS, AND THEN
EXPAND INTO OTHER INDICATIONS
SUCH ONCOLOGY, AUTOIMMUNE
DISEASES, ALL ABOUT THE
MODIFICATION.
WE FORMED THIS UNIQUE
PUBLIC/PRIVATE PARTNERSHIP IN
JANUARY OF 2016.
WE WERE FORMERLY THE GSC
DISCOVERY TEAM, NONE OF US WERE
THERE IN 1980, BUT WE'VE BEEN
DOING THIS FOR WELL OVER 20
YEARS AND WE HAVE A STRONG TRACK
RECORD WITH NIAID, PROGRAMS WITH
PATENTS.
WE'RE FULLY INTEGRATED TEAM,
UNIVERSITY OF MONTANA AND DO
SYNTHETIC SMALL MOLECULE DESIGN,
FORMULATION, ANALYTICS FOR DRUG
DELIVER, IMMUNOLOGY.
WE HAVE 70 PEOPLE HERE IN
MISSOULA, COLLABORATORS.
WE HAVE HUNDREDS OF PEOPLE WE'RE
WORKING WITH NOW ADVANCING NOVEL
IMMUNE MODULATORS.
SO THIS IS THE PIPELINE
CURRENTLY.
AGAIN, ALL BASELINE ADJUVANTS
THAT CAME OUT OF THE NIAID DRUG
DISCOVERY DEVELOPMENT PROGRAM,
I'LL TALK MORE, PHASE 1 CLINICAL
TRIAL CANDIDATES, HANDLING PHASE
2, SYNTHETIC TRL 7/8 IN PHASE 1,
SOON ADVANCED INTO PHASE 1 FOR
VACCINE ACCESS, AND NEXT BOX
DOWN BELOW PRE-CLINICAL PROGRAM,
LATE STAGE IND, AND IN
2024-2025, OPIOID VACCINE.
[AUDIO DISTORTION]
NOW I'M GOING TO CHANGE GEARS A
LITTLE BIT ON THE ADJUVANT SIDE
AND TALK ABOUT LATE STAGE
ADJUVANT PROGRAMS, ALL OF THESE
PROGRAMS WERE ORIGINALLY FUNDED
FROM NIAID.
WE HAVE A LONGSTANDING HISTORY
IN TLR 4 AGONIST STARTING IN
EARLY
[AUDIO DISTORTION]
WE HAVE A NEW PATENTEDDED FAMILY
OF SYNTHETIC CONSTRUCT.
WE HAVE A LONGSTANDING WORK IN
TLR7, NOW HAVE A LEAD COMPOUND,
IN PHASE 1 CLINICAL TRIALS RIGHT
NOW, THEY WERE DESIGNED FOR
FORMULATION IN MICE, THEY CAN BE
FORMULATED WITH AQUEOUS WITH
ALUM, REPLACEMENT FOR
[AUDIO DISTORTION]
ALONG THE SAME LINES WE HAVE
MANUFACTURING cGMP MOVING TO
PHASE 1 CLINICAL TRIALS.
MOUNT SINAI.
AS I MENTIONED EARLIER WE HAVE A
SYNTHETIC VERSION.
WE ALSO HAVE A NUMBER OF MID-AND
EARLY STAGE PROGRAMS, PARTNER
WITH BOSTON CHILDREN'S, OHSU,
EXPANDED THIS PUBLIC/PRIVATE
PARTNERSHIP ORIGINALLY
ESTABLISHED WITH UNIVERSITY OF
MONTANA, WE WORK ON THE SCALE
HELPING THEM GET ADJUVANTS, THEY
SPAN FROM LIGAND TARGETING
Th17 RESPONSE, ADJUVANT
DEVELOPMENT PROGRAM, STING
LIGAND PARTNERED WITH OHSU,
PARTNERING WITH AARON NOW,
MODIFIERS.
AND SO THIS HELPS GENERATE
ADJUVANT, BASED ON NEEDS OF
ANTIGEN OR TARGETING, IN
FORMULATION NOW READY TO WORK
THAT DRIVE A BROAD Th1
RESPONSE.
TLR 4 AGONIST, ASO 1 OR ASO 4,
SYNTHETIC SAPHONIN.
[AUDIO DISTORTION]
ONE OTHER ASPECT THAT HAS COME
TO OUR ATTENTION, SOMETIMES IT'S
EASIER TO TAKE ADJUVANTS TO
PHASE 1 TO STAND ALONE,
ESTABLISH A SAFETY PROFILE.
THE PROGRAM WE HAVE NOW, PHASE 1
CLINICAL TRIALS WITH, SEASONAL
ALLERGIC RHINITIS, EVERYONE IN
THE AUDIENCE WILL RECOGNIZE
NEARLY 1 IN 3 ADULTS, 1 IN 4
CHILDREN HAVE SEASONAL ALLERGY,
GROWING INCIDENCE.
WE'VE KNOWN THIS FOR MANY YEARS,
INTRANATIONALLY DELIVERED TRL
AGONIST CAN DRIVE RESPONSE.
WE'RE USING INI-2004, IF YOU USE
GOA INTRANASALLY, YOU FIND YOU
NEED A MORE ACTIVE --
[AUDIO DISTORTION]
THIS IS BEING DELIVERED IN
UNIQUE LIPO SO MANY FORMULATION,
INTRANASAL, DISEASE MODIFYING,
CHANGE UNDERLYING T-CELL
RESPONSE.
POTENTIAL CURATIVE, NOT JUST
TREATING SYMPTOMS.
THIS IS AN ADJUVANT-ONLY
DELIVERED INTRANASALLY, THE
ANTIGEN DOESN'T COME ON BOARD,
YOU DON'T GET THE DISEASE
MODIFYING RESPONSE.
YOU DON'T HAVE TO NECESSARILY
IDENTIFY --
[AUDIO DISTORTION]
GIVEN IN ALLERGY SEASON OR PRIOR
TO EXPOSURE, AND THEN YOU'LL
NATURALLY --
[AUDIO DISTORTION]
MOST PEOPLE ARE WELL AWARE,
TYPICALLY SYNTHESIZED TO
ALLERGEN.
HERE WHEN YOU'RE REEXPOSED
[AUDIO DISTORTION]
PATIENTS SEE ALLERGEN, MORE OF A
Th1 PROFILE, ALLERGEN IgG,
UPON REEXPOSURE YOU ARE GET NO
RESPONSE, REPROGRAMMING IMMUNE
SYSTEM, Th2, Th1 RESPONSE,
DESENSITIZING.
SO THIS IS SOME DATA IN MICE.
THESE ARE MICE THAT WERE
PRE-SENSITIZED WITH ALUM AND
ALLERGEN, A THERAPEUTIC MODEL.
WE TREAT WITH 2004
INTRANATIONALLY, AND 48 HOURS
LATER WITH ALLERGEN.
WINDOW OF INFECTION HERE, WEEK
TO 14 DAYS, THEN YOU WOULD NEED
ANOTHER DOSE.
SO HERE ON THE LEFT-HAND
TIMELINE YOU SEE RESPONSE,
NORMAL CHALLENGE IN MOUSE,
INTERFERON GAMMA.
IF YOU HAVE THIS SENSITIZED
MOUSE, TREAT WITH 2004
INTRANASALLY, THEN TREAT WITH
ALLERGEN YOU SEE THIS RESPONSE.
IF YOU HAVE A NORMAL MOUSE
CHALLENGED WITH ALLERGEN, YOU
IL-5.
A MOUSE THAT'S ALLERGIC AND
SENSITIZED, CHALLENGED, HIGHER
IL-5 RESPONSE.
IN FACT, IT'S THE SAME MOUSE,
TREATED WITH 2004, THEN
CHALLENGED YOU COMPLETELY
EXPRESS IL-5 RESPONSE.
YOU CAN SEE THIS SHIFT IN THESE
MICE.
SO ANOTHER HALLMARK OF BIOLOGY
IN THESE MICE, SENSITIZED TO
ALLERGEN AND THEN CHALLENGE
NORMAL MOUSE, IF YOU SENSITIZE
THE MOUSE TO ALLERGEN, YOU COME
BACK AND CHALLENGE THEM YOU GET
A REALLY STRONG ROBUST.
SAME MOUSE THEN TREATED WITH
2004, CHALLENGED 48 HOURS LATER,
YOU CAN SEE THIS.
SO WE'VE SWITCHED FROM Th2,
Th1 PHENOTYPE.
THE PANEL ON THE RIGHT HERE IS
AIRWAY RESISTANCE INDUCED BY
ALLERGEN CHALLENGE.
RED BARS ON TOP WOULD BE THOSE
MICE THAT WERE ALLERGIC AND THEN
CHALLENGED WITH ALLERGEN, YOU
CAN SEE HIGH LEVELS OF AIRWAY
RESISTANCE.
COMPARED TO IN GOLD A NORMAL
MOUSE, CHALLENGED WITH ALLERGEN,
DOESN'T SEE THAT AIRWAY
RESISTANCE.
IN BLUE BAR A MOUSE TREATED WITH
2004, THEN CHALLENGED WITH THE
ALLERGEN TWO DAYS LATER, AND YOU
CAN SEE EVEN BETTER THAN THE
NORMAL MICE THAT WERE
CHALLENGED.
AGAIN SHOWING IMPROVEMENT.
AND SO THIS PAST YEAR WE
COMPLETED TWO PHASE 1 CLINICAL
TRIALS.
FIRST WAS A PHASE 1A ASCENDING
DOSE STUDY, FOUR COHORTS,
HEALTHY VOLUNTEERS, UP TO 500
MICROGRAMS INTRANASALLY, WELL
TOLERATED, NO SAD.
MOVED TO PHASE 1B, MULTI-DOSE
STUDY, PATIENTS WERE GIVEN THREE
DOSES OVER WEEKS, END TONIGHTS
OF SAFETY AND PK, ADHERENCE.
WE DID A CHALLENGE.
WE START BY PRE-SCREENING VISIT,
CHALLENGED, MAKE SURE PATIENTS
WERE SENSITIVE TO RAGWEED, TWO
WEEK WAITING PERIOD.
WE THEN TREATED WITH 2004, HERE
ON DAY 14 AND 21, A WEEK APART,
THEN CHALLENGED WITH RAGWEED TWO
DAYS LATER.
FOLLOWED BY TWO MORE TREATMENTS
WITH 2004 A WEEK APART PART,
CHALLENGED AGAIN.
REST FOR TWO WEEKS.
CHALLENGED AGAIN AT DAY 51 TO
SEE IF RESPONSE HAD DESENSITIZED
PATIENTS FOR RAGWEED OR GAINED
SENSITIVITY.
YOU'LL SEE WITH THIS STUDY ONLY
DONE IN COHORTS OF NINE ACTIVE,
THREE PLACEBO.
AND SO HERE YOU'LL SEE THE
RESULTS FOR THE GRADE 1, FOR
SAFETY.
WE DID 125, 250, AND
500-MICROGRAM DOSES IN PHASE 1B
STUDY AS WELL AS EACH OF THE
COHORTS, YOU CAN LOOK AT
PLACEBO, JUST AS MANY MINOR
ADVERSE EVENTS AS ACTIVE
COMPONENTS, MOST RELATED TO
NASAL CONGESTION .
TO PUT IN PERSPECTIVE THIS
COMPOUND T 2004 A THOUSAND MIMES
MORE ACTIVE THAN MPL, EQUIVALENT
OF 50 MILLIGRAMS OF MPL, 2004,
INTRANASAL 2004 WAS WELL
TOLERATED.
THIS IS ANOTHER SUMMARY OF THE
CHARACTERISTICS OF THE PEOPLE IN
THE TRIAL, MEAN AGE 36.
AND WITH MOST HAD 10-YEAR
HISTORY.
50% OF PATIENTS AT LEAST ONE
MILD ADVERSE EVENT, MOST WERE
RELATED TO NASAL SYMPTOMS,
CONGESTION, THINGS YOU MIGHT
EXPECT FROM NASAL SPRAY, ALL
GRADE 1/MILD.
AND WE ALSO DID SYNTHETIC PK,
YOU DON'T WANT PERCENT OF
INFLAMMATION, IN THESE SUBJECTS,
GIVEN THIS, ALL PK VALUES OF ALL
DOSES IN SAD AND MAD BELOW LEVEL
OF QUANTIFICATION, NO SYSTEMIC
ABSORPTION OF 2004 WHEN GIVEN
INTRANASALLY.
HERE IS THE SECONDARY ENDPOINT,
DOSE DEPENDENT IMPROVEMENT
CONGESTION COMPARED TO PLACEBO,
WE WERE SURPRISED TO SEE 250 AND
500-MICROGRAM DOSE LEVELS, 34%
AND 53% IMPROVEMENT.
ALSO GOOD TO SEE AT LATER TIME
POINT TWO WEEKS FOLLOWING
TREATMENT, THEY WERE REDOSED
WITH RAGWEED.
AND WE WERE EXCITED TO SEE
INITIAL EFFICACY SIGNAL FROM
THIS TRIAL, SOME OTHER CLINICAL
MEASURES RESULTED --
[AUDIO DISTORTION]
SO CONTINUING EVALUATION OF
COURSE, THESE ARE STATISTICALLY
DIFFERENT THAN PLACEBO.
WE'RE EXCITED NOW TO MOVE THIS
PROGRAM TO A PHASE 2 ALLERGEN
CHAMBER STUDY, REALLY TO CONFIRM
2004 SAFETY, TO DEMONSTRATE
EFFICACY WITH RESPECT TO
ALLERGEN CHALLENGE IN CONTROLLED
SETTING WITH AIRWAY ALLERGY
EXPOSURE IN DEFINED DOSE, NUMBER
OF GRAINS OF RAGWEED AND
INCREASE COHORT SIZE A LITTLE
BIT TO UNDERSTAND MORE OF THE
KINETICS HOW THE RESPONSE WORDS
AND IF WE CAN SEE RESPONSE WITH
THE DRUG AND HOW WE SCORE THEM.
SO, EVEN MORE EXCITING THESE
PHASE 1 ARE THE INDICATION AND
FOLLOW-ON WITH THE 2004
INTRANASAL VACCINE TRIAL, NOW WE
HAVE MUCOSAL ADJUVANT THAT
DE-RISKS, NOT ONLY WE'LL USE IN
ALLERGEN POTENTIALLY EXPAND TO
INDICATION WITH FOOD ALLERGIES
BUT WE NOW HAVE EFFECT OF
MUCOSAL ADJUVANT, 2004, MUCOSAL
ADJUVANT.
[AUDIO DISTORTION]
FOR FLU, COVID, RSV, NOW WE CAN
POTENTIALLY MOVE INTO OTHER
INDICATIONS, NOW THAT WE'VE BEEN
DE-RISKED.
[AUDIO DISTORTION]
AS WELL AS POTENTIAL MUTATIONS,
NASOPHARYNGEAL CANCERS, WE NOW
2004 HAS IMPACTS AS FAR AS
CHECKPOINT, THERE MIGHT BE
CAUSALLY DELIVERED --
[AUDIO DISTORTION]
WITH THAT I'D BE HAPPY TO TAKE
ANY QUESTIONS.
AND AGAIN I WILL THERE BE AT NIH
HERE ON WEDNESDAY AND THURSDAY
THIS WEEK.
>> ANY QUESTIONS FOR DR. EVANS?
I HAVE A COUPLE QUESTIONS.
JAY, REALLY GOOD TALK.
THE QUESTIONS ARE IN YOUR MOUTH,
YOU'RE DOSING RAGWEED TWO DAYS,
48 HOURS AFTER THE LAST -- YOUR
ADJUVANT, RIGHT?
SO, YOU'RE GOING TO HAVE
INFLAMMATION WITH ADJUVANT.
THEN YOU'RE EXPOSING RAGWEED
DURING THAT INFLAMMATION RELATED
TO THE ADJUVANT.
WHAT IF YOU GO, YOU KNOW, TWO OR
THREE OR FOUR WEEKS AFTER THE
ADJUVANT BEFORE YOU GIVE THE
RAGWEED, DO YOU SEE SAME AFFECT?
MY FEAR, YOU'RE HAVING ANTIGEN
SPECIFIC EFFECT BECAUSE YOU'RE
EXPOSING TO RAGWEED, ALMOST
IMMEDIATELY THEREAFTER, WITHIN
TWO DAYS, SO THEREFORE YOU'RE
GOING TO HAVE RESIDUAL
INFLAMMATION FROM THAT.
I WONDER IF THAT'S ALSO WHAT
YOU'RE SEEING IN YOUR HUMAN
STUDIES TOO WITH RAGWEED
CHALLENGES BECAUSE YOU'RE DOSING
WITH ADJUVANT, YET THE RAGWEED
COMING CLOSE THEREAFTER, AND
INDUCING ANTIGEN-SPECIFIC
RESPONSE IN HUMANS, INTERESTED
IN YOUR THOUGHTS, WHETHER YOU
DELAYED PERIOD OF TIME FROM
RAGWEED EXPOSURE IN MICE, YOU
KNOW, THREE OR FOUR WEEKS AFTER
THE ADJUVANT.
>> THAT'S A GREAT QUESTION.
UNFORTUNATELY, THE MOUSE ALLERGY
MODEL IS ACUTE MODEL.
IF YOU LEAVE OVER TIME WITHOUT
REEXPOSING THEY DESENSITIZE.
WE HAVE A WEEK WINDOW WHERE WE
CAN CHALLENGE WITH ALLERGEN
BEFORE THE MICE START LOSING
THEIR SENSITIVITY.
THEY LOSE SENSITIVITY, THAT
COMPLICATED EFFECT, THOSE ARE
SOME QUESTIONS WE WANT TO ANSWER
IN HUMANS.
WE DO KNOW IN MICE, GIVE
INTRANASALLY, COME BACK WITH
LIKE INFLUENZA CHALLENGE, YOU
GET A WINDOW OF NON-SPECIFIC
PROTECTION WHERE MICE HAVE SOME
PROTECTION, INDUCED BY SIMILAR
MECHANISM, STIMULATING NATURE
IMMUNE RESPONSE, IN THAT MODEL
WE'VE SEEN UP TO 14 DAYS
[AUDIO DISTORTION]
WE THINK THAT WINDOW WILL BE
SIMILAR.
OF COURSE WE WON'T KNOW UNTIL WE
GET INTO PEOPLE, IF YOU GIVE A
DOSE OF 2004, INTRANASALLY,
DIFFERENT TIME SLOT TO 7 DAYS IN
MOUSE MODEL, IN VIVO CHALLENGE
AS WELL, TWO OR THREE DAYS, YOU
SEE THAT PROTECTION.
BUT UNFORTUNATELY THE MOUSE
MODEL HAS LIMITATIONS.
>> JAY, WONDERFUL TALK.
AND ALONG THOSE SAME LINES IN
YOUR HUMAN STUDY WITH INI 2004
ARE YOU COLLECTING NASAL WASH
SAMPLES TO MONITOR IMMUNE
RESPONSE, HOW LONG THEY LAST
FOR?
>> WE DID DO SOME ON NASAL SWAB,
TO LOOK AT CYTOKINES.
THOSE ANALYSES, IT LOOKS LIKE WE
MIGHT HAVE INCREASE IN TNF,
IL-10, PLACEBO MODEL, ONLY NINE
SUBJECTS, IT'S HARD.
IT'S TOUGH BECAUSE ANYTHING TO
DO WITH A PATIENT, NASAL MUCOSA,
CAN IMPACT ANYTHING YOU DO THAT
CAUSES INFLAMMATION.
WE SAW IN PLACEBO GROUP SOME
PROTECTION WITH RAGWEED, DOING
SALINE RINSE CAN HELP ALLEVIATE
SYMPTOMS.
WE TALKED ABOUT DOING OTHER
TYPES OF COLLECTION INTRANASALLY
TO GET MORE INTRACELLULAR
RESPONSES BUT HAD TO BOUNCE BACK
WITH SAFETY AND EFFICACY.
WE'D LOVE TO HEAR THOUGHTS ON
OTHER WAYS TO USE MULTI- OMICS
TO ASSESS.
>> I HAVE THE SAME SORTS OF
THOUGHTS.
THIS IS JIM GURN FROM WISCONSIN.
THE NASAL SWABS THESE DAYS, IT'S
THE SAME TECHNIQUE AS THE COVID
TESTS, CAN GIVE A REALLY NICE
CELLULAR SAMPLE YOU CAN ANALYZE
FOR RNA AND DNA, AND AS WE MOVE
FORWARD, HOPEFULLY YOU'LL
CONTINUE TO SEE POSITIVE RESULTS
BUT IT WOULD BE REALLY HELPFUL
TO KNOW WHAT'S GOING ON AT THE
MUCOSA, AT THE GENE LEVEL.
AND, YOU KNOW, THAT I THINK THE
POINT'S BEEN MADE IN THE LAST
TWO LECTURES KNOWING MECHANISMS
WILL HELP IN TERMS OF APPLYING
ADJUVANTS IN THE BEST POSSIBLE
WAY, BUT THAT JUST SOMETHING TO
CONSIDER BECAUSE IT'S PRETTY
NON-TRAUMATIC, WE KNOW IF KIDS,
EVERY KID HAS HAD 20 OF THESE
THINGS, GOING TO SCHOOL, MAY NOT
LIKE THEM THAT MUCH BUT IT'S NOT
VERY TRAUMATIC AND THINGS
RESOLVE QUICKLY AFTER A LITTLE
BRUSHING.
>> I NEED TO CUT THE DISCUSSION
SHORT.
WE'RE RUNNING SIGNIFICANTLY
BEHIND SCHEDULE ALREADY.
THANK YOU SO MUCH.
>> THANK YOU.
>> NEXT SPEAKER, DR. CHEVRIE.
WE HEARD ABOUT ADVANCED STAGE
ADJUVANTS FROM DR. PULENDRAN,
NOW WE'LL HEAR ABOUT EVEN MORE
COMPLEX ADJUVANTS.
>> CAN YOU HEAR ME?
>> YES, WE CAN.
PLEASE PROCEED.
>> I'LL TRY TO KEEP IT IN THE
FIVE MINUTES I HAVE.
JUST KIDDING.
I'LL TRY TO BE AS SHORT AS
POSSIBLE.
I'LL TELL YOU BRIEFLY IN THE LAB
WE'RE INTERESTED IN ASKING AND
HOPEFULLY ANSWERING FUNDAMENTAL
QUESTIONS ABOUT THE IMMUNE
SYSTEM ACROSS MULTIPLE SCALES
RANGING FROM CELLS AND PATHWAYS
TO ORGANS AND HOW CELLS
COMMUNICATE WITH TISSUES.
AND TODAY THE PROJECT I'D LIKE
TO DISCUSS STARTED FROM A VERY
BASIC QUESTION, HOW DO IMMUNE
CELLS SENSE COMBINATIONS.
WHEN WE ASKED THROUGH THE LENS
OF INNATE IMMUNE PATHWAYS, AS
WE'VE HEARD, CHARLIE JANEWAY AND
BEFORE HIM FOLKS FOUND TOLL
PATHWAYS, FAST FORWARD THREE
DECADES THERE'S DOZENS OF SUCH
PATHWAYS THAT CAN SENSE
MOLECULES, CONSERVED IN
MICROBES.
THE POINT I'M TRYING TO MAKE
THERE'S DOZENS OF PATHWAYS
INCLUDING TOLL LIKE RECEPTORS,
AND A BUNCH OF OTHERS THAT ALL
CONVERGE WITHIN CELLS, SHARED
AMONG FAMILIES OF SUCH PATHWAYS.
AND TARGET PROTEINS AND IMPACT
ADAPTATION RESPONSE.
ANOTHER STUDY ABOUT THE PATHWAYS
IN ISOLATION, WHEN WE STARTED
STUDIES THE QUESTION WAS DRIVING
US HOW DO CELLS SENSE MULTIPLE,
BECAUSE THERE'S PAUCITY OF
KNOWLEDGE ABOUT HOW THESE
PATHWAYS WORK TOGETHER, RIGHT?
WE HAD TO DISCOVER WHAT ARE THE
RECEPTORS, MOLECULES DOWNSTREAM,
NOW HOW DO THEY WORK TOGETHER,
RIGHT?
AS BALI SHOWED, IN THE YELLOW
FEVER VACCINE MULTIPLE MOLECULES
THAT ACT TOGETHER, VERY
DIFFICULT TO STUDY THESE.
AND SO ONE OF THE PROBLEMS, I'LL
SKIP THROUGH THIS, ONE POINT IS
THAT TWO SIGNALS AT A TIME
STUDIES AND MANY EXAMPLES OF
SYNERGY, INDEPENDENCE AND
ANTAGONISM.
IT'S DIFFICULT TO PREDICT FROM
EFFECTING OF SINGLES.
IF YOU GO HIGHER, THERE'S MUCH
LESS STUDIES.
SO HERE WHAT WE SET OUT TO DO IS
TRY TO STUDY HOW CELLS RESPONSE
TO HIGHER EFFECTS OF
COMBINATION.
ONE OF THE PROBLEMS IS THAT
BECOMES QUICKLY INTRACTABLE
EXPERIMENTALLY, NUMBER OF
EXPERIMENTS WITH COMBINATIONS
EXPLODES EXPONENTIALLY, RIGHT?
A WAY OF EXAMPLE I LIKE TO USE
IMAGINE YOU HAVE A THOUSAND
MOLECULES IN THE LIBRARY,
INTERESTED IN MINING ALL
POSSIBLE COMBINATIONS OF
RECOMMENDATIONS, THAT'S ABOUT 40
BILLION ASSAYS, THAT WOULD TAKE
A VERY LONG TIME, A LOT OF GRAD
STUDENTS AND POSTDOCS, EVEN ME
JOINING IN WOULD NOT DO
ANYTHING, RIGHT?
THE QUESTION WE'RE INTERESTED
IN, COULD WE DO AWAY, AND JUST
PREDICT WITHOUT TESTING
EVERYTHING?
TO TEST THIS, THAT WOULD
HOPEFULLY UNCOVER SOME RULES
ABOUT THE RELATIONSHIP BETWEEN
THE SIGNAL IN THE SYSTEM.
TO TEST THIS ON A SMALL SCALE
INITIALLY BASICALLY HYPOTHESIS
SELECTED HALF A DOZEN LIGANDS
THAT TARGET DIFFERENT PATHWAYS,
TRLs, C TYPE LECTIN RECEPTORS,
DNA SENSORS, USING SETS OF SEVEN
SIGNALS PERFORMED THE SCREEN,
WHAT IS IT SHOWING?
ESSENTIALLY EFFECTS OF SEVEN
SIGNALS, EITHER USED ALONE OR
PAIRWISE COMBINATIONS IN GREEN,
21 PAIRS.
IF YOU COMBINE, UP TO 35
TRIPLETS IN ORANGE.
COLORS SHOW YOU ESSENTIALLY
NUMBER OF T CELLS DIFFERENTIATED
IN THE PRESENCE OF DENDRITIC
CELLS STIMULATED WITH DIFFERENT
ADJUVANTS.
I'LL SKIP THROUGH THE DETAILS
BUT THE KEY THING WE'RE ABLE TO
EXTRACT FROM THE DATASET WAS
THAT ESSENTIALLY THE EFFECTS OF
THE TRIPLET, HIGHER ORDER
EFFECT, CAN BE PREDICTED WITH
KNOWLEDGE FROM ONLY THE BLUE AND
GREEN, SIGNALS AND PAIRS, IN
OTHER WORDS MEASURING SINGLES
AND PAIRS.
ON THIS PLOT THE X-AXIS SHOWS
YOU -- EACH DO T -- EACH DOT ISA
TRIPLET
WHAT IS THE T-CELL RESPONSE WHEN
EXPOSED TO CELLS TREATED WITH
ANY OF THE 35 TRIPLETS?
AND Y-AXIS SHOWS THE CALCULATED
PROLIFERATION INDEX.
IN OTHER WORDS THE VALUE
PREDICTED BY USING ONLY DATA
FROM SINGLES AND PAIRS.
YOU SEE TRACKING CORRELATION
THAT SUGGESTS INDEED PAIRWISE
AND SINGLING ARE SUFFICIENT TO
MEASURE THIS SUGGESTING
EXPERIMENTS ARE PERHAPS
TRACTABLE BY UNCOVERING RULES IN
THE SYSTEM.
DOES THIS PROPERTY APPLY IN VIVO
OR ANOTHER WAY TO FRAME THIS
DOES IT I HAVE APPLICATION, IS
IT USEFUL TO BUILD SOME
VACCINES, FOR EXAMPLE?
SO TO GET TO THAT QUESTION AND
TEST OUR HYPOTHESIS REGARDING
THE RULE IN VIVO WHAT WE DID
FIRST IS TO USE A CELL BASED
VACCINE, WHEREBY THE CELLS ARE
STIMULATED IN A DISH WITH THIS
COMBINATION OF ADJUVANTS, WHAT
NOT, INJECT IN A MOUSE, FOCUSED
ON SIMPLIFIED MAMMALIAN MODEL
THAT CARRIES MODEL ANTIGEN AND
MEASURED TUMOR VOLUME OVER TIME.
THE REASON WE TURN TO DISEASE
JUST SO I RELATE TO PREVIOUS
COMMENTS MADE IS THAT OF COURSE
SOME MOLECULES CAN ACTIVATE
CELLS, HERE BY DOING THIS TYPE
OF IN VITRO SYSTEMS YOU CAN
ISOLATE WHICH CELLS ARE
STIMULATED AND NOT OTHERS.
AND RESULTS WERE STRIKING, HERE,
FOR EXAMPLE, I'M SHOWING EFFECTS
OF 12 OUT OF THE 35 TRIPLETS.
AND YOU CAN SEE TOP ROW AGAIN
THIS IS TUMOR VOLUME, AS A
FUNCTION OF TIME.
TOP ROW YOU SEE FOUR TRIPLETS
THAT HAVE QUITE A STRONG EFFECT
ON DECREASING TUMOR GROWTH.
HERE YOU SEE ORANGE LINE IS MICE
THAT WERE IMMUNIZED WITH THE
CELL-BASED VACCINES.
WHILE CONTROLS WERE GROWING
RAPIDLY, THAT WAS STRONGLY
DECREASED BY THE FOUR TRIPLETS.
THE EIGHT OTHER TRIPLETS WE
TESTED AT TIME WERE NOT ABLE TO
DO THIS.
AND IMPORTANTLY THE KEY THING TO
HIGHLIGHT IS THAT IF WE GO BACK
AND MEASURE ONLY SINGLES AND
PAIRS AND TEST OUR HYPOTHESIS
SHOW INDEED WE HAVE HAVE
PREDICTED WHICH TRIPLETS WOULD
HAVE BEEN USEFUL TO TEST.
SO THIS TO ME LED TO A
CONCLUSION THAT I LIKE TO THINK
OF THE PATHOGEN SENSING NETWORK
MORE THAN THE SUM OF PARTS, NOT
MORE THAN THE SUM OF PAIRS.
AGAIN, HIGHER ORDER EFFECTS, AND
THIS SUGGESTS A SIMPLIFYING RULE
NOW INNATE SENSING OPERATES.
THIS HAS IMPLICATION THAT I
WON'T DISCUSS TODAY.
THE MAIN THING TO FOCUS IS THAT
THIS STUDY WAS FOUNDATIONAL IN
TERMS OF BUILDING OUR ADJUVANT
EFFORTS.
AND THANKS TO SUPPORT FROM THE
MMCA PROGRAM, MOLECULAR
MECHANISM, WERE ABLE TO LAUNCH
MECHANISTIC STUDIES THAT AIM TO
TRY TO UNDERSTAND WHY SOME OF
THE TRIPLETS WORKED, WHAT IS THE
SECRET MECHANISTIC EFFECTS.
AND THIS IS A BIT OF BUSY SLIDE.
I'LL GIVE A BRIEF OVERVIEW,
SYSTEMATICALLY WITH THE IDEA
ACROSS SCALE, TRYING TO TEASE
APART WHAT HAPPENS IN
INTRACELLULAR CROSS-TALK, AS
WELL AS ORGANISM WIDE.
I'LL TELL YOU ABOUT A COUPLE
SNAPSHOT RESULTS.
FIRST THE PROTEIN LIFE CYCLE,
WHAT HAPPENS IN THE
TRANSLATIONAL MACHINERY WHEN
CELLS ARE EXPOSED TO TRIPLETS
THAT SEEM TO HAVE VERY STRONG
ANTITUMOR EFFECT.
WHEN WE LOOK AT ONE OF THE
TRIPLETS, LPS THAT TARGET THREE
FAMILIES OF PATHOGEN SENSORS, WE
MEASURED PROTEOME EXCHANGES,
WHAT IS THE EXCHANGES OF ALL
PROTEINS IN THE CELL, ASKED WHAT
ARE THE CODONS THAT MIGHT BE
PREFERENTIALLY USED, WE FOUND
THERE'S A VERY STRONG BIAS IN
BOTH UP AND DOWNREGULATED GENES,
OR PROTEINS, RATHER, IN THE
GLUTAMINE CODONS.
WHEN WE COLLABORATED WITH LOCAL
EXPERT IN TRANSLATION, TAU PAN,
WE MEASURED ALL TRANSFERASE RNA
IN THE CELL TO SHOW THIS WAS
CORRELATED WITH THIS SHIFT IN
TRANSFER RNA, SO tRNAs THAT
ENCODE FOR THIS GLUTAMINE, SO
YOU HAVE CTC AND TTC BASICALLY
DECODER SITES.
ONE OF THE OTHER THINGS WE
OBSERVED WAS INTERESTING AS
WELL, THESE tRNAs SHOWN ON
THE RIGHT SIDE, THIS IS THE
TERTIARY STRUCTURE OF A TRANSFER
RNA, YOU CAN SEE WHEN YOU LOOK
AT THE TRIPLET, LSG, THERE'S
DECREASES IN EPITRANSCRIPTOMIC
MODIFICATION, THOSE ARE CHEMICAL
MODIFICATIONS INSTALLED ON SOME
OF THE BASES THAT COMPOSE THIS
RNA.
AND SPECIFICALLY AT THIS U34
SITE, GOING DOWN BUT BEING
HYPO-MODIFIED AT THIS
TRANSCRIPTOMIC SITE.
THERE MIGHT BE SOMETHING IN
TERMS OF HOW IMMUNE CELLS CAN
REGULATE TRANSITIONAL EFFECT.
I'LL SKIP THIS.
I WAS GOING TO TELL YOU THE
ENZYME THAT MODIFIED IS ALSO
REGULATED ONLY BY TRIPLET AND
NOT SINGLES AND PAIRS, BACK TO
THE FACT PERHAPS THERE'S
SOMETHING SPECIAL THAT HAPPENS.
NOW ONE OF THE THINGS ASKED
GOING FROM THIS TENSION BETWEEN
THEORY OR FUNDAMENTAL QUESTIONS
IN APPLICATIONS, COULD THIS BE
HELPFUL IN TERMS OF MANIPULATING
IMMUNE SYSTEM, IN OTHER WORDS IF
WE TWEAK RESPONSES COULD WE
IMPACT THINGS?
HERE KATE OVEREXPRESSED
tRNAs, FROM GLUTAMINE.
IF YOU FOCUS ON LEFT PLOT AT
IL-12, CTC AND NOT TTC, YOU SEE
HOW BOOST IN SOME OF THESE
CYTOKINES, RIGHT?
SUGGESTING AGAIN THIS IS SORT OF
A PROOF OF PRINCIPLE MODIFYING
tRNAs MIGHT HELP MODULATE
ADJUVANT RESPONSES WHICH IS AN
AREA THAT HASN'T BEEN MUCH
EXPLORED TO MY KNOWLEDGE.
THIS IS JUST TO GIVE SNAPSHOTS
ABOUT HOW THESE DETAILED
MOLECULAR STUDIES CAN YIELD
VALUABLE INFORMATION ON HOW YOU
MIGHT WANT TO MODULATE ADJUVANT
RESPONSES.
AND A COUPLE MINUTES TO TELL YOU
HOW THESE THINGS -- WHAT DID WE
DISCOVER IN TERMS OF MECHANISM
IN IN VIVO.
WE TURNED TO A MODEL, A POX
VIRUS, WE'VE HEARD ABOUT
MONKEYPOX IN THE PAST YEARS.
WE TURNED TO POX VIRUSES BECAUSE
OF LIKE INSPIRED BY SOME OF THE
WORK WITH THE YELLOW FEVER
VACCINE, PERHAPS THE OLDEST
VACCINE EVER, POX VIRUS VACCINE
AGAINST SMALLPOX, RIGHT?
THAT LED TO ERADICATION OF THE
DISEASE IN THE LATE '70s, SAME
WITH ADJUVANTS, VACCINES CHANGE,
WE DON'T KNOW HOW IT WORKS TO
DATE, WE HAVE CLUES BUT DON'T
KNOW SPECIFIC DETAILS.
WE CAN USE THIS VACCINE THAT CAN
AGAIN IMMUNIZE AGAINST SMALLPOX
IN HUMAN, IN MICE WHAT WE DO, WE
USE THIS WESTERN RESERVE STRAIN
OF VIRUS THAT IS LETHAL, AND IT
IS LETHAL BECAUSE IT CARRIES --
YOU SEE WHITE PARTS, THE TWO
CIRCLES, TWO SIDES OF THE
CIRCLES ARE THE GENOMIC DNA OF
EACH VIRUS STRAIN.
YOU CAN SEE THAT THE VACCINE
STRAIN WHICH WAS OBTAINED
THROUGH EMPIRICAL, LOST THE
WHITE PARTS IN THE PATHOGENIC
GENOME, THE RED STRAIN WESTERN
RESEARCH IS LETHAL, THE BLUE
STRAIN CAN INNOCUOUS.
WE TESTED A PROTECTIVE TRIPLET,
BENCHMARKED IT, I'M SHOWING MICE
THAT WERE VACCINATED AND THREE
TO FOUR WEEKS LATER CHALLENGED
THROUGH RESPIRATORY ROUTE WITH
LETHAL DOSE OF THE WESTERN
RESERVE STRAIN.
EACH LINE IS INDIVIDUAL MOUSE,
WEIGHT OVER TIME, MICE NOT
VACCINATED IN LIGHT GRAY DO NOT
DO VERY WELL.
THE ONES VACCINATED WITH MVA ARE
FULLY PROTECTED AS EXPECTED.
WHEN YOU DO VERY SIMPLE VACCINE
WITH POLY ICs, THE
COMBINATION, YOU HAVE VERY
STRONG PROTECTION, NOT AS GOOD
AS MVA, YOU'RE JUST USING A
SINGLE PEPTIDE AS ANTIGEN SO
QUITE REMARKABLE YOU CAN EVEN DO
THIS.
TO GO FURTHER WE CHECKED WHETHER
THERE WAS TRUE SYNERGY IN THE
TRIPLETS, HERE I'M SHOWING THE
WEIGHT CHANGES IN MICE
IMMUNIZED, CHANNELED WITH
SINGLES IN BLUE, PAIRS IN GREEN.
THERE'S SUPPOSED TO BE DATA
THERE.
THE ORANGE ONE IS PROTECTED.
WHEN WE COMPARED AND ASKED WHAT
IF WE JUST TOOK OFF THE SHELF
ADJUVANTS, WOULD THEY DO THEIR
JOB?
YOU HAVE TO BELIEVE ME ALL THE
GUYS IN BLACK BASICALLY DO WORSE
OR SIMILAR TO ASO1, NOT
PROTECTING MUCH, HZG, YOU'RE
SUPPOSED TO SEE THIS, THIS
TRIPLET IS POTENT IN PROTECTION,
MORE SO THAN EXISTING ADJUVANTS.
IF WE LOOK AT SOME JUST VERY
BRIEF MECHANISTIC INSIGHTS, ABLE
TO GATHER, SEEMS TO DEPENDENT ON
IL-18.
NOT IL--1B OR TNF.
WE ASKED WHETHER THIS MIGHT BE
CORRELATED WITH T-CELL RESPONSES
BECAUSE AS MOST OF YOU PROBABLY
KNOW IT'S DIFFICULT TO MAKE
VACCINES GOOD AT INDUCING T-CELL
RESPONSES.
HERE WHAT I DIDN'T TELL YOU IS
THAT THIS ADJUVANT TRIPLET WAS
DOING ITS JOB THROUGH INDUCING
T-CELL RESPONSES.
AND WHEN YOU COMPARE INDUCTION
OF T CELLS IN DRAINING LYMPH
NODE IN TRIPLET IN ORANGE
COMPARED TO SINGLES IN BLUE OR
PAIRS IN GREEN YOU SEE YOU HAVE
THIS CORRELATION IN TERMS OF
PROTECTION EFFECT, SO THE
TRIPLET WITH THE HIGH NUMBER OF
T CELLS IS BETTER AT PROTECTING.
AND PERHAPS ALSO TO RESONATE
WITH COMMENTS MADE EARLIER ABOUT
THE FACT THAT IT IS DIFFICULT TO
INDUCE MEMORY T CELLS IN MUCOSAL
SITES, DIFFICULT TO DELIVER
ADJUVANTS THROUGH THIS ROUTE,
HERE WHAT WE DISCOVERED BOTH IN
MVA CASE BACK IN THE DAY, ALSO
IN ADJUVANT TRIPLET, IF YOU
ADMINISTER TRIPLET AT SKIN
YOU'RE ABLE TO REMOTELY OR
DISTANTLY SEE RESIDENT MEMORY T
CELLS IN THE LUNG, BROAD
IMPLICATIONS, IMPORTANT TO SEE
THE T CELLS.
I'LL SKIP THE DATA.
IF YOU LOOK AT MVA THIS PLOT
SHOWS NUMBER OF CELLS PER TOTAL
LIVE CELLS IN THE LUNGS AT 3 TO
4 WEEKS, YOU CAN SEE THEY INDUCE
SIMILAR NUMBER OF MEMORY T CELLS
SPECIFIC FOR THAT ANTIGEN.
LOOKING FORWARD I'LL JUST --
LAST TID-BIT OF INFORMATION,
INTERESTED IN TRYING TO MAP OUT
WHAT HAPPENS BEYOND INNATE AND
ADAPTIVE CELLS, WHAT HAPPENS
ACROSS TISSUES, YOU MENTIONED
IT'S IMPORTANT TO FIGURE OUT
WHAT DO THESE VACCINES AND
ADJUVANTS DO ACROSS THE BODY.
FOR THAT IN OTHER EFFORTS
DEVELOPED TOOLS TO ESSENTIALLY
MAP OUT EFFECTS OF ANYTHING YOU
INJECT INTO A MOUSE ON ALL CELLS
OF THE BODY AT ONCE.
WHAT WE DO, WHOLE MOUSE
SECTIONS, FOLLOWED BY SPATIAL
TRANSCRIPTOMICS, FOR EXAMPLE
TYPE OF DATA YOU CAN LOOK AT
LOOKS LIKE THIS.
WE HAVE A SECTION OF A MOUSE,
SAGITTAL SECTION OF A MOUSE, THE
BRAIN HERE, THYMUS, HEART, THE
LUNGS, THE LIVER, THE STOMACH,
THE SPLEEN, KIDNEY AND SO ON.
THIS IS ESSENTIALLY mRNA
LEVELS ACROSS THE TRANSCRIPTOME,
EVERY 30-MICRON SPOT, YOU CAN
RECAPITULATE ALL THE TISSUES YOU
EXPECT IN A MOUSE.
INJECT WITH LPS YOU CAN SEE THE
CONTROL SETTING LOOKING AT
INFLAMMATORY MEDIATORS WHICH IS
SAA FAMILY SERUM, AMYLOID
FACTORS.
SAA 1, 2, 3 SHOWN HERE.
1 IS INDUCED IN LIVER AND COLON,
2 IN LIVER AND KIDNEY, SAA 3
INDUCED IN EVERY CELL TYPE.
A SIMPLE EXAMPLE YOU CAN MAP OUT
WHAT HAPPENS ACROSS THE BODY, WE
HOPE TO APPLY TO TRY TO BETTER
UNDERSTAND WHAT HAPPENS WHEN YOU
INJECT INTO ANIMAL.
WE COULDN'T DO THIS IN ANY OTHER
SYSTEM AT THE MOMENT.
WITH THAT I'LL CONCLUDE AND
THANK YOU VERY MUCH FOR YOUR
ATTENTION.
>> ANY QUESTIONS?
>> JUST A COMMENT.
WHAT YOU'RE SAYING IS WE ALREADY
HAVE THE TOOLS TO RESCUE
VACCINES THAT HAVE FAILED BEFORE
BECAUSE WE HAVEN'T LOOKED AT THE
COMBINATIONS.
THANK YOU.
>> THANK YOU FOR HELPING CATCH
US UP ON TIME A BIT.
WE'RE ABOUT HALF AN HOUR BEHIND
WHERE WE EXPECTED TO BE.
SO, I'M GOING ASK STAFF TO BE
VERY BRIEF IN THE CONCEPT
CLEARANCE PRESENTATIONS, I THINK
EACH HAVE BETWEEN FOUR AND SEVEN
SLIDES, SO I'M SURE WE'LL CATCH
UP.
I DON'T WANT TO GO BEYOND 3:45
OR SO BECAUSE I WANT TO BE
RESPECTFUL OF COUNCIL MEMBERS,
MAY HAVE TRAINS OR PLANES TO
WATCH, AND OTHER MEET, ON THEIR
AGENDA THIS AFTERNOON.
CARMEN, YOU'RE UP FIRST.
FOR THE NEW COUNCIL MEMBERS,
BRIEF PRESENTATIONS BY OUR STAFF
ON INITIATIVES THAT ARE EITHER
NEW OR UP FOR RENEWAL
RECOMPETITION AND PROGRAMS THAT
WILL BE DEVELOPED INTO RESEARCH
SOLICITATIONS, AND WE LOOK
FORWARD TO YOUR INPUT ON THESE
AND IN THE INTEREST OF TIME
WE'LL ASK FOR AN EN BLOC
APPROVAL FOR THESE AFTER THE
THREE ARE PRESENTED.
IF IT TURNS OUT DISCUSSION ABOUT
ANY ONE GETS PROBLEMATIC, WE MAY
GO ONE BY ONE.
BUT THAT'S A RARE OCCURRENCE.
CARMEN, THANK YOU
>> THANK YOU, DAN.
I'M TALKING ABOUT A NEW
INITIATIVE TO STUDY RADIATION
INJURY.
FOR THE NEW COLLEAGUES IN THE
ROOM, HIGHLIGHTS ABOUT A
PROGRAM, RADIATION NUCLEAR
COUNTERMEASURES PROGRAM, THE
GOAL TO DEVELOP PRODUCTS FOR
TREATMENT AND DIAGNOSIS OF
RADIATION INJURY.
WE DEVELOP ANIMAL MODELS,
ESTABLISH RADIATION FACILITIES,
FUND RESEARCH ACROSS THE
SPECTRUM FROM BASIC TO ADVANCED,
WORKING WITH OUR GOVERNMENT
PARTNERS, WE WORK WITH PRIVATE
INDUSTRY, ACADEMIA, THIS
PARTICULAR INITIATIVE WILL BE
FOCUSED ON THE BASIC RESEARCH
END OF THE SPECTRUM,
ANTICIPATING THAT APPLICANTS
WILL COME IN WITH MODELS THAT
ARE EARLY IN DEVELOPMENT,
EXPLORING MECHANISMS, TARGETS OF
INJURY, AND DOING VERY EARLY
EFFICACY STUDIES FOR MEDICAL
COUNTERMEASURES.
SO WE WORK CLOSELY WITH THE FDA,
WE'LL CONTINUE TO DO THAT.
THEY ACTUALLY HAVE A LOT OF
INTEREST IN ALTERNATIVE MODELS,
IN DECEMBER 2022 THE FDA
MODERNIZATION ACT WAS PASSED,
AUTHORIZING USE OF THESE
ALTERNATIVE PLATFORMS IN LIEU OF
ANIMAL STUDIES FOR CERTAIN DRUGS
BEFORE ENTERING A SAFETY TRIAL.
THAT'S OF INTEREST TO US TOO
BECAUSE WE HAVE ALREADY BEEN
FUNDING SOME PROGRAMS IN OUR
PORTFOLIO, TO GIVE A FEW
HIGHLIGHTS OF EXAMPLES OF
STUDIES, THIS PARTICULAR STUDY
OUT OF STANFORD UNIVERSITY, DR.
WU'S WORK, PLURIPOTENT STEM
CELLS, CREATING HEART AND
VASCULAR TISSUES, CELL-TO-CELL
INTERACTIONS CAN BE STUDIED IN
MATURE TISSUES.
A VISUAL OF THE CARDIAC ORGANIE
UNDER EXPOSURE.
TOP ROW, FOCUS ON ROW 1, OVERLAY
OF GFP, RED STAIN FOR VASCULAR,
GREEN IS CARDIAC TISSUE.
YOU MAY APPRECIATE COMPARING TO
ROW 3, DIMINISHING ARE
CARDIOMYOCYTES, GREEN
DIMINISHING, THIS IS A VISUAL
REPRESENTATION OF DATA HE HAS
QUANTIFIED.
SO THIS IS OF INTEREST TO US,
IMPACT OF RADIATION ON CARDIAC
TISSUE.
AND FOR OUR AGENCY PARTNERS FROM
NASA, WHO ARE PART OF THIS
INITIATIVE WITH US, THEY ARE
INTERESTED IN PROLONGED EFFECTS
OF SPACE FLIGHT RADIATION.
ANOTHER PROJECT WITHIN OUR
PORTFOLIO IS FROM CORNELL
UNIVERSITY, DR. RAPHI CREATED
ENDOTHELIAL CELLS THAT ARE ABLE
TO BE MATURED TO REGENERATE WITH
ETV-2, MASTER REGULATOR IN FETAL
JESS RATION -- GESTATION, ABLE
TO SHOW STABLE STRUCTURE IS
CREATED WITH POSSIBILITY OF --
HE'S SHOWN IT'S ABLE TO SHUTTLE
HUMAN BLOOD ADEQUATELY SO THE
IDEA HERE IS THAT THESE RESET
ENDOTHELIAL CELLS COULD BE USED
AS A MEDICAL COUNTERMEASURE FOR
INJURY TO VASCULAR TISSUE, TO
FREEZE CELLS, BANK, TRANSPORT TO
TREATMENT SITES AFTER PUBLIC
HEALTH ENERGY INVOLVING
RADIATION.
ONE MORE EXAMPLE, OUT OF
UNIVERSITY OF PITTSBURGH, HE HAS
PERFUSABLE BIOREACTOR, HAS BEEN
ABLE TO TAKE A FULL THICKNESS
HUMAN SKIN FLAP FROM PLASTIC
SURGERY DISCARD, RESOURCE --
REPURPOSED MATERIAL, HE'S ABLE
TO KEEP THE SKIN FLAP VIABLE FOR
UP TO A MONTH.
THIS IS REALLY INTERESTING
BECAUSE BIOREACTOR IS PORTABLE,
SMALL ENOUGH TO FIT INTO AN
IRRADIATOR, ABLE TO SEE IN REAL
TIME THE EFFECTS OF RADIATION ON
THE SKIN.
THAT'S REALLY IMPORTANT BECAUSE
THE SKIN IS THE FIRST ORGAN TO
FEEL THE IMPACT OF IONIZING
RADIATION, AND THERE ARE LIMITED
COUNTER-MEASURES AVAILABLE TO
TREAT SKIN RADIATION INJURY.
AFTER THAT HE'S ABLE TO EXTRACT
VARIOUS CELLS, CONDUCT
ASSESSMENTS TO GET AT THE
MECHANISM.
AND SO WE'RE VERY INTERESTED IN
THE U01 MECHANISM, WE HAVE
EXPERIENCE WITH U01 GRANTS.
THIS GRAPH SHOWS SINCE 2012 THE
MANY SPECIFIC TOPIC AREAS WE'VE
COVERED, FROM VASCULAR INJURY TO
CELLULAR THERAPIES, CAME IN WITH
THIS COHORT WITH CELLULAR
THERAPIES.
WE HAVE A MICROBIOME COHORT
FINISHING THE FIRST YEAR, MAKING
GREAT STRIDES IN UNDERSTANDING
EFFECTS OF RADIATION ON THE
MICROBIOME AND HOW THE
MICROBIOME COULD BE HARNESSED TO
REJUVENATE INJURED TISSUE.
WE HAVE ANNUAL MEETINGS, INVITE
GOVERNMENT PARTNERS, ENCOURAGE
COLLABORATION ACROSS THE
CONSORTIUM TO LEVERAGE THE
PROJECT.
AND THEN FINALLY MY LAST SLIDE,
THIS INITIATIVE HAS THE GOALS OF
DEVELOPING THESE ALTERNATIVE
HUMAN MODELS TO SIMULATE
RADIATION INJURIES, TO DEVELOP
MEDICAL COUNTERMEASURES, TEST
EFFICACY, WE'RE HOPING THESE
WILL ADDRESS THE GAPS THAT ARE
INNATELY SEEN BETWEEN
PRE-CLINICAL AND HUMAN STUDIES
AND UNDERSTAND ORGAN-SPECIFIC
INJURIES AND FINALLY REDUCE
ANIMAL USE, THESE ARE FIVE-YEAR
AWARDS, PLENTY OF TIME TO MAKE A
LOT OF PROGRESS.
AND WE'RE HOPING TO AWARD ABOUT
SEVEN TO EIGHT APPLICATIONS.
AND THAT'S IT.
I'M HAPPY TO TAKE QUESTIONS.
>> ANY QUESTIONS OR DISCUSSION?
FOR NEW COUNCIL MEMBERS, OVER
THE NEXT FEW YEARS YOU'LL HEAR
QUITE A FEW OF THESE RADIATION
COUNTERMEASURE PROPOSALS BECAUSE
WE HAVE A LOT OF FLEXIBILITY
WITH THE FUNDING THAT GOES INTO
THIS PROGRAM.
AND WE HAVE HISTORICALLY
DEVELOPED QUITE A FEW LONGER AND
SHORT-TERM INITIATIVES TO TAKE
ADVANTAGE OF THAT FLEXIBILITY.
THIS IS A PROGRAM THAT HHS ASKED
NIAID TO BE RESPONSIBLE FOR, IN
CASE YOU'RE WONDERING WHY IS
THIS RADIATION COUNTERMEASURES
PROGRAM HOUSED IN DAIDS.
IT'S BECAUSE AT THE TIME IN 2005
WHEN THEY STARTED, NCI WAS NOT
PARTICULARLY INTERESTED IN THIS
AND WE HAD EXPERIENCE WITH
CONGRESS AND HHS HAVING A LOT OF
CONFIDENCE IN OUR INSTITUTE'S
ABILITY TO TAKE ON THINGS LIKE
THIS BASED ON -- AT THAT POINT
IT WAS ANTHRAX PRECEDED
BIODEFENSE FUNDING.
IT LANDED HERE AND OUR STAFF
HAVE DONE A GREAT JOB
SUCCESSFULLY MANAGING THIS
PROGRAM.
YOU'LL HEAR MORE ABOUT THESE
INITIATIVES.
AND THE NEXT ONE IS GOING TO BE
PRESENTED BY TOM WINTERS, WHO IS
ON THE SCREEN RIGHT THERE.
GO AHEAD, TOM.
>> THANK YOU.
LET ME SHARE MY SCREEN.
AND HOPEFULLY I'M GOING TO THE
CORRECT ONE.
CAN YOU SEE MY SCREEN OKAY?
>> WE CAN SEE YOUR SCREEN BUT
WE'RE SEEING ME, NOT YOU.
>> OKAY.
>> I'D RATHER SEE YOU.
>> I WOULD MUCH RATHER HAVE ME
UP THERE.
NOT SURE WHY IT'S SHOWING YOU,
DAN.
I'M SORRY.
LET ME TRY RESTARTING THIS.
MY APOLOGIES.
>> MAY NOT BE ANYTHING YOU CAN
CONTROL, SO I'LL LIP SYNC WHILE
YOU TALK.
[LAUGHTER]
>> OKAY.
WELL, LET ME GET THE SHARE UP SO
YOU CAN AT LEAST SEE MY SLIDES.
I'M HOPEFUL THAT THIS WILL WORK
FOR YOU.
OKAY.
CAN YOU SEE MY SLIDES OKAY?
>> YEAH, WE SEE YOUR SLIDES.
>> OKAY, GREAT.
ALL RIGHT.
SO I'M GOING TO BE PRESENTING A
2026 INITIATIVE CONCEPT FOR A
CONTRACT MECHANISM, FOR THE
DEVELOPMENT OF RADIATION/NUCLEAR
COUNTERMEASURES OR FOR
BIODOSEMETRY DEVICES.
CARMEN SHOWED YOU THIS
DEVELOPMENT PROCESS, RADIATION
NUCLEAR COUNTERMEASURES PROGRAM
USES.
FOR BASIC RESEARCH END OF THE
SCALE, WHICH SHE WAS TALKING
ABOUT, WE TYPICALLY USE GRANTS
AND COOPERATIVE AGREEMENTS, WHAT
THE U01 MECHANISMS AND
INTERAGENCY AGREEMENTS WITH
OTHER GOVERNMENT PARTNERS.
WE ALSO HAVE ADVANCED
DEVELOPMENT THAT WE DO PIVOTAL
STUDIES AND HELP PEOPLE MOVE
TOWARDS IND SUBMISSIONS TO THE
FDA, PHASE 1 SAFETY STUDIES, BUT
WHAT I'M GOING TO TALK ABOUT
TODAY IS EARLY PRE-CLINICAL
DEVELOPMENT WORK, TALKING ABOUT
DOING THINGS LIKE LEAD
OPTIMIZATION, LARGE ANIMAL
EFFICACY STUDIES, SAFETY AND
TOXICOLOGY.
THIS IN OUR PROGRAM USES THE
BROAD AGENCY ANNOUNCEMENT
CONTRACT MECHANISM, WE ISSUE
SOLICITATIONS ABOUT ONE TO TWO
YEARS, THREE-YEAR AWARDS, AND
ONE OF THE THINGS THAT'S
INSTRUMENTAL ABOUT THIS, ALLOWS
AUTHORS TO PROPOSED STATEMENT OF
WORK, TAILORED TO THE PRODUCT
THEY INTEND TO SUBMIT PROPOSALS
FOR AND ALLOWS CONTRACT OFFICERS
REPRESENTATIVE TO WORK WITH THEM
AND HELP THEM STAY ON THE
CRITICAL PATH TO LICENSURE WITH
THE FDA.
CURRENTLY FDA APPROVED SIX
HEMATOPOIETIC ACUTE RADIATION
SYNDROME COUNTER MEASURES, FIRST
TWO APPROVED IN 2015 WITH GREAT
DEAL OF SUPPORT FROM RNCP AND
NIAID, IN 2018 WITH OTHER
SUPPORT, LUKIN WAS APPROVED BY
FDA.
IN 2021 WITH RNCP AND NIAID
SUPPORT END PLATE WAS APPROVED,
IN 2022 AND 2023 THESE
APPROVALS, THESE DRUGS LIKE LAST
STIMULATE BONE MARROW TO
INCREASE NEUTROPHILS.
THESE ARE DRUGS THAT HELP WITH
REGENERATION OF THE
HEMATOPOIETIC SYSTEM, BUT THERE
IS A NEED FOR DRUGS TO TREAT
OTHER ORGAN INJURIES, FOLLOWING
RADIATION EXPOSURE, NO SUCH
DRUGS CURRENTLY EXIST.
WE NEED TO SUPPORT APPROVAL OF
PRODUCTS TO TREAT OTHER
RADIATION-INDUCED ORGAN
INJURIES.
THE HISTORY OF THIS PROGRAM
BETWEEN 2020 AND THE PRESENT IS
30 CONTRACTS HAVE BEEN AWARDED,
THROUGH 11 SOLICITATIONS, THESE
CONTRACTS HAVE STUDIED AGENTS TO
TREAT INJURY IN THE GI TRACT AND
VARIOUS ORGANS AS WELL AS LOOK
AT RADIONUCLIDE DECORPORATION.
WITH FOUR PRODUCT TRANSITIONS TO
BARDA.
WE'VE AWARDED TWO ADDITIONAL
BAAs.
JUST AS AN EXAMPLE OF SOME OF
THESE PRODUCTS THAT HAVE BEEN
LOOKED AT THROUGH THESE TYPES OF
CONTRACTS, THIS IS A
BIODOSEMETRY PRODUCT DEVELOPED
BY PERMALOGIC LOOKING FOR RISK
OF NEUTROPENIA IN HUMANS
FOLLOWING EXPOSURE THAT COULD
INDICATE NEED FOR INTERVENTION.
THIS IS A PRODUCT BEING
DEVELOPED WHICH IMPROVES WOUND
HEALING FOLLOWING RADIATION --
CUTANEOUS RADIATION INJURY, THIS
IS A MODEL, WOUNDS FORMED ON THE
SKIN OF PIG USING 45 GRAY DOSE
OF RADIATION, AND THIS AGENT
SHOWN TO SPEED WOUND CLOSURE AND
AS A RESULT OF THESE STUDIES
PRIMARY ENDPOINT HAS BEEN
ESTABLISHED FOR PIVOTAL STUDIES
OF WOUND CLOSURE.
THIS IS INNOVATIVE FOR TREATING
GI INJURIES FOLLOWING EXPOSURE
TO RADIATION, CYTOKINES TO THE
GI TRACT, A PROBIOTIC PRODUCT
WHICH LACTOBACILLUS REUTERI, AND
UPON DELIVERY THE BACTERIA
EXPOSED, THAT INDUCE EXPRESSION
OF ENDOGENOUS PHAGES THAT LYSE
THE BACTERIA, BEING DEVELOPED BY
CHROMOLOGIC.
PROPOSED BAA TO PROMOTE
ACCELERATION OF PRE-CLINICAL
MCMS OR ASSAYS, SUPPORTS
EFFICACY STUDIES OF LARGE
ANIMALS AND SUPPORTS IND
SUBMISSIONS AND INVESTIGATIONAL
USE ONLY SUBMISSIONS FOR
LICENSURE.
BIOMECHANISM ALLOWS AUTHORS TO
PROPOSE THEIR OWN STATEMENT OF
WORK APPROPRIATE TO THE PRODUCT
THEY ARE PROPOSING TO WORK WITH
WE EXPECT 8 TO 10 PROPOSAL,
INTEND TO FUND 2 TO 3, THESE ARE
3-YEAR CONTRACTS.
IF ANYONE HAS SLIDES ALL BE
HAPPY TO ANSWER THEM.
IF THERE'S NO QUESTIONS I'LL
STOP SHARING AND TURN THE FLOOR
BACK OVER TO YOU.
>> OKAY, SEEMS LIKE THERE'S NO
DISCUSSION ON THAT.
JOE, YOU'RE UP NOW.
THANKS, TOM.
>> HERE WE GO.
GOOD AFTERNOON, I'M JOE BREEN,
SECTION CHIEF IN BASIC
IMMUNOLOGY BRANCH, WOLFGANG'S
PARTNER IN CRIME.
HE'S INNATE IMMUNE, I'M THE
OTHER.
I'M GOING TO TELL BUT AN
INITIATIVE CONCEPT, RENEWAL,
IMMUNE EPITOPE DATABASE AND
ANALYSIS RESOURCE, IT'S BEEN IN
EXISTENCE FOR SOME TIME.
SO, THIS SLIDE SHOWS THE
ENTRYWAY INTO THIS ANALYSIS
RESOURCE AND DATABASE.
THE OBJECTIVE IS TO PROVIDE
UNIQUE PUBLIC REPOSITORY OF
IMMUNE EPITOPE DATA AS WELL AS
ANALYSIS TOOLS TO SUPPORT
ACCELERATED OF THERAPEUTICS,
DIAGNOSTICS, VACCINES FOR
INFECTIOUS, ALLERGIC, IMMUNE
MEDIATED DISEASES COVERING ALL
OF NIAID WITH THE EXCEPTION OF
HIV BECAUSE THERE'S A COMPARABLE
DATABASE FUNDED SEPARATELY FOR
THAT PURPOSE.
AND IT REALLY IS A UNIQUE PUBLIC
DATABASE.
TO DATE THERE'S NOTHING LIKE IT
AVAILABLE TO THE PUBLIC.
THERE ARE COMMERCIAL VENTURES
AND IN FACT THE WHOLE DATABASE
HAS BEEN DOWNLOADED AND LICENSED
BY COMMERCIAL PARTNERS BUT WE
DON'T KNOW WHAT THEY DO WITH
THAT DATA.
ON THE RIGHT IS A SNAPSHOT HOW
FOLKS GET ACCESS TO IMMUNE
EPITOPES IN THE IMMUNE EPITOPE
DATABASE THROUGH A NUMBER OF
MEANS THAT ARE PRE-FILTERED OR
OPEN TEXT.
A LITTLE BIT OF THE NUMBERS OF
WHAT'S AVAILABLE IN THE
DATABASE, I'LL GO THROUGH THAT
IN THE NEXT SLIDE.
SO THE WEBSITE THAT REPRESENTS
THE WAY TO GET INTO THE DATABASE
PROPER HAS BEEN PUBLICLY
AVAILABLE SINCE 2005.
INITIALLY THIS CONTRACT WAS
ANNOTATING EPITOPES THAT WERE
GENERATED THROUGH B AND T CELL
EPITOPE DISCOVERY PROGRAMS BUT
THAT DATA -- AND THAT CONTINUES
TODAY BUT THAT REPRESENTS ABOUT
A QUARTER OF WHAT'S AVAILABLE IN
THE IDB.
MOST IS GENERATED BY CURATING
THE LITERATURE, SO THEY HAVE
CURATED 25 HOW REFERENCES,
PubMed CITATIONS THAT
CONTAIN EPITOPE DATA,
2.2 MILLION EPITOPES.
THE STRENGTH OF THAT, THOSE ARE
AVAILABLE TO COMPARE ACROSS MANY
DIFFERENT SPECIES, DATA TYPES,
ET CETERA.
AND FOR BOTH ANTIBODIES AND T
CELL EPITOPES.
SONG THAT HAS DEVELOPED OVER THE
LAST FIVE YEARS OF THE CONTRACT
IS CONNECTING EPITOPE DATA IN A
PAPER WITH B AND T-CELL RECEPTOR
REPERTOIRE DATA, INCREASINGLY
REPORTED.
WE DON'T STORE THAT DATA IN IDB
BUT DO REFERENCE IT SO YOU CAN
MAKE COMPARISONS.
IT REALLY CONNECTS TO OTHER NCBI
RESOURCES WHAT THAT DATA IS
COLLECTED.
AND THERE'S VERY BROAD IN TERMS
OF NUMBER OF ORGANISMS, MHC
ALLELES, AND THE GROUP
THEMSELVES HAVE PUBLISHED 130
PUBLICATIONS SINCE 2012,
PRIMARILY IN TOOL MAKING.
THIS IS REALLY A DATABASE WHICH
IS CURATION OF THE LITERATURE
AND THEN TOOLS WHICH ARE
GENERATED BY THE TEAM THAT HOLD
THE CONTRACT, OR IN FACT THEY
CAN TAKE IN TOOLS THAT ARE MADE
IN THE COMMUNITY, SO THAT MAKING
A SINGLE PLACE WHERE PEOPLE CAN
USE THOSE TOOLS WITH ALL OF THE
RICH DATA THAT'S IN THE IDB.
ANOTHER NEW DEVELOPMENT,
ACCOMPLISHMENT IS DEVELOPMENT OF
APPLICATION PROGRAMMING
INTERFACE, API, SO THAT THE
OTHER PROGRAMS AND NIAID THAT
CONTAIN VARIOUS DATA TYPES CAN
BASICALLY TALK TO EACH OTHER,
AND CAN BE ACCESSED TOGETHER,
INCREASE POWER OF EACH OF THEM
ACTUALLY, LIKE IMPORT,
BIOINFORMATICS RESOURCE CENTERS,
FUNDED FROM DMID AND THE IMMUNE
SPACE WHERE DATA CAN BE
VISUALIZED, INCREASING POWER OF
ANY SINGLE DATABASE, NIAID IS
GENERATING WHAT REQUIRES THIS
INTERFACE, API, AND NIH-WIDE
STRATEGY EVENTUALLY THAT'S HOW
THESE WILL BE CONNECTED.
AND THE LAST BULLET, SO THERE'S
THE DATABASE, THEN THE ANALYSIS
RESOURCE, TOOLS FOR ANTIBODY AND
T CELL EPITOPES, HOW TO GET
PEOPLE TO UTILIZE THIS, WE'VE
ALWAYS HAD AN ANNUAL WORKSHOP
FUNDED BY THE CONTRACT TO BRING
PEOPLE IN TO SHOW THEM HOW TO
USE THE TOOLS, AND TO REALLY
PROVIDE A USER WORKSHOP.
AND WE WERE SURPRISED AND
HAPPILY SO WITH THE PANDEMIC WE
COULDN'T DO THAT RESPONSIBLY SO
WE CONVERTED IT TO VIRTUAL AND
IT REALLY INCREASED -- INSTEAD
OF 50 PEOPLE IN A ROOM, NOW WE
HAVE 700 PEOPLE WORLDWIDE ACROSS
60 COUNTRIES, MANY LOW RESOURCE
COUNTRIES.
SO IT'S REALLY BEEN A VERY
STRONG OUTCOME.
I'M NOT CONVINCED WE SHOULDN'T
STILL BRING PEOPLE TOGETHER IN A
ROOM BECAUSE AS WE KNOW
DIFFERENT THINGS HAPPEN THERE.
BUT THE REACH HAS CERTAINLY BEEN
INCREASED.
SO, WHAT CAN DATA DO FOR THE
PUBLIC?
AND THE RESEARCH COMMUNITY?
THESE ARE THREE EXAMPLES.
I'M NOT GOING THROUGH IN DETAIL
BUT EVEN TODAY WE HEARD
DISCUSSIONS OF H1N1, HOW SIMILAR
IS THIS TO WHAT'S BEEN
CIRCULATING IN THE ANIMAL
COMMUNITY, HUMAN COMMUNITY,
COULD THERE BE UNIQUE EPITOPES
THAT ARE BETWEEN H 5 ON THE
ANTIBODY SIDE OR T CELL SIDE IN
FACT, AND WHAT SHOULD WE EXPECT
IN TERMS OF CROSS-PRESENTATION.
IEDB FOLKS DID A META-ANALYSIS,
THIS TIME AVIAN FLU SOME YEARS
AGO, THEY ARE DOING THIS NOW FOR
H 5 TO HELP US UNDERSTAND HOW
CLOSELY RELATED THE NEWER H 5s
ARE WITH WHAT'S CURRENTLY
CIRCULATING BASED ON WHAT'S
AVAILABLE IN THE DATABASE AND
SEQUENCES THAT THEY CAN GET
THEIR HANDS ON.
WHICH MANY ARE PUBLIC.
IDB TEAM HAS DONE WHICH THAT IDB
TO LOOK FOR UNIQUE T CELL
EPITOPES.
MOST RECENTLY FOR SARS AND
PANDEMIC EARLY ON THIS GROUP WAS
ABLE TO COMPUTATIONALLY
DETERMINE AREAS THAT MIGHT BE
UNIQUE TO SARS-COV-2, THOSE
AREAS, FOR EXAMPLE, FOR T CELL
EPITOPES WHICH MIGHT BE
CROSS-PRESENTED WITH SEASONAL
CORONAVIRUSES, AND INTERESTINGLY
THIS, THE T CELL MILIEU, SEEMED
TO BE MUCH MORE CONSTANTLY
SO-CALLED PAINTED WITH EPITOPES
THAN THE ANTIBODY SIDE WHERE WE
KNEW THERE WERE CHANGES WITH
VARIANTS.
SO LEADING US TO WHEN WE
UNDERSTOOD A LITTLE BIT MORE
ABOUT T CELL MEMORY, IMPORTANT
ISSUES WITH TRYING TO ADDRESS
WHOSE'S BEEN INFECTED, WHO HAS
NOT.
TURNS OUT THE T CELL MEMORY WAS
SUPER IMPORTANT IN HELPING TO
UNDERSTAND THAT BECAUSE OF THE
ISSUES WITH DURABLE ANTIBODIES
AND MEMORY IN FACT.
AND MY LAST SLIDE IS REALLY THE
SCOPE OF WHAT WE'RE PROPOSING
FOR THE RENEWAL REMAINS THE SAME
WITH CONTINUED EMPHASIS ON
INTEGRATION OF DATA TYPES
INCLUDING STRUCTURES PROPOSED
WITH HIGHER DEGREE OF CERTAINTY
USING ALPHA FOLD AND RECEPTOR
REPERTOIRE, A CONTRACT FOR FIVE
YEARS AND WE ANTICIPATE A SINGLE
AWARD.
BOTTOM SHOWS SOME REACH, EVEN
TODAY THERE ARE ABOUT 37,000
MONTHLY SITE VISITS TO THE
WEBSITE, ABOUT EQUALLY SPLIT
BETWEEN ANALYSIS RESOURCE AND
DATABASE, AND ACTUALLY KEEPS
GOING UP.
SO EVEN AFTER COVID OF COURSE
THERE WAS A HUGE BUMP BUT THE
USER BASE IS STILL CONTINUING TO
GROW SO WE HAVEN'T QUITE MET
SATURATION YET IN TERMS OF
NUMBER OF SCIENTISTS ACROSS THE
WORLD USING THE DATABASE.
AND I'LL STOP THERE AND BE HAPPY
TO TAKE ANY QUESTIONS.
THANK YOU.
>> OKAY.
IN THAT CASE, WE CAN REQUEST AN
EN BLOC RECOMMENDATION TO
PROCEED AND THEN I'LL ASK FOR A
SECOND.
>> SO MOVED.
>> GREAT.
OKAY.
THEN THAT WRAPS US UP, RIGHT
BEFORE 3:30.
>> IF I COULD ASK COUNCIL
MEMBERS INTO THE ELECTRONIC
COUNCIL BOOK FOR CONCEPT
CLEARANCES.
>> THEY HAVE TO DO THAT IN THE
ECB.
YOU NEED TO GO INTO THE
ELECTRONIC COUNCIL BOOK AND MAKE
YOUR APPROVALS EVIDENT THERE.
ONCE YOU DO THAT, WE ARE WRAPPED
UP AND WISH EVERYBODY SAFE
TRAVELS HOME AND THANK YOU FOR
PARTICIPATING TODAY.
[END OF PROGRAM]