>> GOOD MORNING, NIH.
GOOD MORNING.
I AM NINA SHORE IESM THE DEPUTY
DIRECTOR FOR INTRAMURAL RESEARCH
AND TODAY IT IS MY DISTINCT
PLEASURE TO INTRODUCE THE 2024
PHILLIP S. CHEN JR. Ph.D.
DISTINGUISHED LECTURER
DR. STEPHEN WHITEHEAD AND TO
WELCOME TO TO NIH DR. DR. PH P
CHEN.
>> FIRST A NOTE, THE LECTURE ON
INNOVATION AND TECHNOLOGY
TRANSFER WAS ESTABLISHED IN 2006
BY THE NIH DEPUTY DIRECTOR FOR
INTRAMURAL RESEARCH AND THE NIH
OFFICE FOR TECHNOLOGY TRANSFER.
ON THE OCCASION OF DR. CHEN'S
RETIREMENT, AFTER OVER 41 YEARS
OF SERVICE TO THE NIH, THE
LECTURESHIP HONORED DR. CHEN'S
REMARKABLE DIVERSE AND CREATIVE
CONTRIBUTIONS TO THE NIH AND
ESPECIALLY TO ITS INTRAMURAL
RESEARCH PROGRAM AND TO THE
FIELD OF TECHNOLOGY TRANSFER.
DR. CHEN RECEIVED HIS Ph.D. IN
PHARMAICOLOGY FROM THE
UNIVERSITY OF ROCHESTER.
DURING HIS DISTINGUISHED CAREER
AT NIH, HE SERVED UNDER 8 NIH
DIRECTORS AND HELD SCIENTIFIC
AND LEADERSHIP POSITIONS IN 2
INSTITUTES, 1 DIVISION AND THE
OFFICE OF THE DIRECTOR.
IN 1986 DR. CHEN ESTABLISHED THE
NIH OFFICE OF TECHNOLOGY
TRANSFER TO IMPLEMENT THE
PROVISION OF THE FEDERAL
TECHNOLOGY TRANSFER ACT.
HE FORMULATED THE GUIDING
PRINCIPLES UPON WHICH TECHNOLOGY
TRANSFER FUNCTIONS TODAY
INCLUDING AS MANY OF THE
AUDIENCE WILL REALIZE THE
SIGNIFICANCE OF THIS, INCLUDING
CREATING THE COOPERATIVE
RESEARCH AND DEVELOPMENT
AGREEMENT FONDLY KNOWN AS THE
CREDA.
ABOVE ALL, DR. CHEN OFFERED
NIHERS WISE, TRUSTED AND
COMPASSIONATE COUNCIL AND THIS
EARNED HIM THE RESPECT,
ADMIRATION AND GRADDITUDE OF
BOTH OF THE SCIENTIFIC AND THE
ADMINISTRATIVE COMMUNITIES AT
NIH.
TODAY'S SPEAKER AND THE 2024
RECIPIENT OF THE CHEN
LECTURESHIP IS DR. TEFEN
W--STEPHEN WHITEHEAD, HE VEEFED
HIS MASTERS FROM BRIGHAM YOUNG
YESTERDAY AND HIS Ph.D. FROM
OREGONITATE UNIVERSITY.
HE JOINED NIAID 29 YEARS AGO AS
A POST DOCTORAL FELLOW HE IS
CURRENTLY A SENIOR INVESTIGATOR
IN THE LABORATORY OF VIRAL DECS
AT NIAID.
HIS RESEARCH IS FOCUSED ON THE
DEVELOPMENT AND EVALUATION OF
VACCINE CANDIDATES FOR DENG UE
AND OTHER VECTOR BORN DISEASES.
OVER THE COURSE OF THESE
PROJECTS HE HAS DEVELOPED
VARIOUS LIFE ATTENUATE VACCINE
CANDIDATES WITH A LEAD
TETRAVALENTINEDDENT DENG UE
CANDIDATE CURRENTLY COMPLETING
PHASE 3 CLINICAL EVALUATION IN
BRAZIL.
IN 2018 HE WAS HONORED WITH THE
AMERICAN SOCIETY FOR
MICROBIOLOGIES MORRIS HILLAMAN
AWARD AND HE IS THE INVENTOR IN
OVER 10 PATENT GROUPS AND THE
DENG UE VIRUS TECHNOLOGY HAS
BEEN LICENSED AROUND THE WORLD
TO 8 PHARMACEUTICAL COMPANIES IN
AN EFFORT TO CONTROL DENGUE
DISEASE.
>> PLEASE JOIN US IN WELCOMING
WITH OUR SPEAKER AND THEN PLEASE
JOIN US FOR A RECEPTION IN THE
LIBRARY FOLLOWING THE LECTURE.
THANK YOU.
[ APPLAUSE ]
>> THANK YOU, I AM VERY PLEASED
TO BE HERE TO GIVE THIS LECTURE
TO HONOR DR. CHEN AND ALL OF THE
CHAMPIONSHIP HE HAS FOR TECH
TRANSFER BECAUSE AS WE WILL
DISCUSS TECH TRANSFER MATTERS
AND THIS WOULD NOT BE POSSIBLE
WITHOUT THE HELP OF THOSE
OFFICES.
LET ME BEIMIN BRIEFLY BY SAYING,
WE WILL TALK ABOUT AN ARTHROPOD
BORN VIRUS, SPECIFICALLY DENGUE
VIRUS, ARGT O VIRUSES, THE ARGT
O POD SIDE IS MOSQUITOES TICKS
AND FLIES, VIRUS SIDE IS
DIFFERENT FLAVI VIRUSES, ALPHA
VIRUSES, BUNUA VIRUSES AND
HERE'S A LIST OF THE MEDICALLY
IMPORTANT VIRUSES.
IT IS REGRETTABLE THAT YOU
MECHANIZE MANY OF THEM BECAUSE
THEY'RE ALL STILL AROUND, OKAY
IN YOU WILL--YOU KNOW DENGUE
VIRUS, ZIKA VIRUS, YOU ARE
HEARING ABOUT MYO VIRUS,
UNFORTUNATELY YOU'RE LEARNING
ABOUT VENEZUELANS EQUINE VIRUS,
IF YOU HAVEN'T ALREADY, YOU WILL
HEAR ABOUT ORAPUSH VIRUS, A
BUNYA VIRUS THAT IS REEMERGING.
A RESPONSE TO THOSE INFECTIONS
INCLUDES PRIMARY TREATMENT AND
CARE CENTERS, THAT IS THE TOP OF
THE LIST THEN WE HAVE SACK
SEENS, WE HAVE VECTOR CONTROL
AND REPELLANTS.
WE HAVE A FEW THAT ARE IN
DEVELOPMENT, THERAPEUTICS
ANTIVIRALS, SOME OF THESE
VIRUSES WE'VE LEARNED ON
SEXUALLY TRANSMITTED SO WE CAN
CONTROL THE DAMAGE FROM THOSE
VIRUSES USING CONDOMS AND BIRTH
CONTROL.
AS WE LEARNED FROM ZIKA VIRUS,
THERE ARE TRAVEL RESTRICTIONS
AND SCREENINGS THAT GO ON, WE
ARE CHECKING THE BLOOD SUPPLY
FOR MANY OF THESE AND THERE MAY
BE OTHERS THAT NEED TO COME
FORWARD.
SOME OF THE CHALLENGES FOR
DEVELOPING VACCINES TO THESE ARE
THAT MOST OF THE ARBOVIRUS
INFECTIONS MOST LOW OCCUR IN
THESE SHORT LIVED EPIDEMICS, THE
EXCEPTION OF COURSE BEING DENGUE
VIRUS WHICH IS ALWAYS WITH US.
THIS LOW DISEASE INCIDENCE MAKE
ITS VERY DIFFICULT TO DO
EFFICACY TRIALS FOR VACCINES AND
YOU KNOW, THESE ARE SHORT
SPORADIC OUTBREAKS, BY THE TIME
YOU HAVE A VACCINE CANDIDATE
READY AND YOU'RE READY TO TEST
IT, THE VIRUS HAS MOVED ON, IT'S
NO LONGER CIRCULATING.
IT'S HARD TO PREDICT WHAT THE
NEXT OUTBREAK WILL BE AND YOU
KNOW MANY OF THESE ARE WHAT WE
CALL ORPHAN VACCINES, THEY'RE
NOT PROFITABLE INVESTMENTS FOR
PHARMACEUTICAL COMPANIES.
SO THAT'S A DIFFICULT AND THEN
THERE'S ALWAYS THIS WIDE GAP
BETWEEN CLINICAL DISCOVERY AND
EVALUATION WHICH IS ILLUSTRATED
HERE AS YOU MOVE FROM BENCH TO
BEDSIDE, THE VALLEY OF DEATH FOR
MANY VACCINES IS AS WE GET INTO
THESE CLINICAL TRIALS.
BUT EVEN ONCE YOU'VE INITIATED A
CLINICAL TRIAL, AND THIS IS
WHERE TECH TRANSFER COMES IN,
YOU NEED AN IMPLEMENTATION
SCHEME OR PROGRAM.
THIS NEEDS TO MOVE FORWARD INTO
A PHARMACEUTICAL COMPANIES THAT
CAN PRODUCE A VACCINE.
NOW THIS BENCH TO BODY SIDE TO
IMPLEMENTATION CAN TAKE A
CONSIDERABLE AMOUNT OF TIME AND
SO YOU CAN SEE THESE VARIOUS
VACCINES ON THE LEFT, GENERALLY
7, 8, 9, YEARS FROM BEGINNING TO
APPROVAL.
THE EXCEPTION IS ON THE BOTTOM,
SANOFI PASTOR AND SEVERAL OTHER
COMPANIES BEGAN WORKING ON WHAT
THEN BECAME THE DENG VAXIA, IN
1971 WITH DIFFERENT VERSION OF
THE PLATFORM, IT TOOK THEM 44
YEARS.
NOW TONGUE IN CHECK, AND I SAID
BECAUSE IT'S OF COURSE IT'S 44
YEARS, BECAUSE IT'S FOR A ZACH
SEEN AND 10 YEARS FOR EACH
VACCINE.
THE DENGUE VIRUS WE'RE TALKING
ABOUT TODAY IMPORTANTLY COMES IN
4 DISTINCT SEROTYPES.
IT'S A SINGLE STRAPPEDDED
POSITIVE SENSE RNA VIRUS, 4
DISTINCT SEROTYPES, REALLY MEAN
4 DISTINCT VIRUSES, THEY REALLY
ARE VERY DIFFERENT.
THEY ACT VERY DIFFERENTLY IN
MOST ASSAYS AND MOST
INVESTIGATIONS.
IMPORTANT IN THIS SLIDE IS THE
ENVELOPE PROTEIN ON THE OUTSIDE
OF THE VIRUS PARTICLE, THAT IS
THE TARGET FOR NEUTRALIZING
ANTIBODY.
ALL OF THESE NONSTRUCTURAL
PROTEINS, THE MAIORITY OF THE
GENOME ARE--HAVE DIFFERENT
REPLICATION FUNCTIONS BUT THEY
ARE THE PROTEINS THAT CONTAIN
MOST OF THE T-CELL EPITOPES THAT
ARE RECOGNIZED.
THIS IS WHERE YOU FIND DENGUE.
THREE BILLION PEOPLE LIVE IN
THIS ZONE WHERE YOU HAVE
FREQUENT OR SPORADIC OUTBREAKS
OF DENGUE.
IT'S FAIRLY OLD DATA FROM 2013,
ESTIMATED 390 MILLION ANNUAL
INFECTIONS, ABOUT A HUNDRED
MILLION OF THEM ARE CLINICALLY
APPARENT.
BUT IT'S IMPORTANT TO NOTE THAT
DENGUE IS BOTH AN ESTABLISHED
DEC, AND AN EMERGING AND
REEMERGING DISEASE.
THIS IS WHAT DENGUE DISEASE
LOOKS LIKE, THE DENGUE
CLASSIFICATION YOU ARE GOING TO
HAVE THE MAJORITY OF INFECTIONS
LEAD TO A SYMPTOM ADIC
INFECTIONS, SOME OF THEM ARE
DENGUE WITHOUT WARNING SIGNS
ISSUES THOSE ARE GBL LYE
UNREPORTED.
AS YOU MOVE UP THE PYRAMID, HAVE
YOU A SMALL PERCENTAGE THAT HAVE
THESE WARNING SIGNS LISTED AND
THEN SOME WITH SEVERE DENGUE.
OKAY?
FORTUNATELY WITH PROPER
MANAGEMENT, THE CASE FATALITY
RATE IS PROBABLY LESS THAN HALF
A PERCENT.
BUT THAT IS WITH PROPER CASE
MANAGEMENT SO IF I WERE TO COME
DOWN WITH SERIOUS DENGUE, I
WOULD WANT TO BE TREATED BY
BRIDGET WILSON IN VIETNAM OR
MAKE DR. LAKAMARA IN SRI LANKA.
THEY ARE VERY GOOD.
THEY DON'T HAVE FATAL CASES.
MOST OF THE PEOPLE YOU ENCOUNTER
ON THE STREET OF SOUTHEAST ASIA,
BANGKOK FOR EXAMPLE ARE IMMUNE
TO ALL 4 DENGUE SEROTYPES, THE
QUESTION IS HOW DID THEY GET
THAT WAY?
AND THE WAY THEY GET THAT WAY IS
BY SEQUENTIAL EXPOSURE TO
DIFFERENT DENGUE SEROTYPES,
REMEMBER, THERE'S 4 SEROTYPES,
THEY ENCOUNTER THESE AT
DIFFERENT TIMES IN THEIR LIFE
BEGINNING IN CHILDHOOD, SO HERE
IS ADULT A FROM A STUDY WE DID,
PREVACCINATION, YOU CAN SEE THEY
HAVE--THIS PERSON HAS REALLY
GOOD NEUTRALIZING ANTIBODIES TO
ALL 4 SEROTYPES.
THIS IMPORTANT DOESN'T NEED
VACCINATION.
ON THE OTHER SIDE, HERE'S A
CHILD BEFORE VACCINATION HAD NO
DENGUE ANTIBODIES, WE CALL THEM
DENGUE NAIVE, PULSE VACCINATION,
VERY GOOD IMMUNE RESPONSE.
SO THIS IS WHAT NATURAL IMMUNITY
LOOKS LIKE.
CAN WE SAFELY INDUCE THIS
IMMUNITY IN CHILDREN IS THIS AND
THE WAY YOU WOULD DO THAT IS
EITHER THROUGH SIMULTANEOUS
TETRAVALENTINEDDENT VACCINATION,
GIVING ALL 4 SEROTYPES AT ONCE
OR POSSIBLY SEQUENTIAL
VACCINATION.
THIS IS HOW SEQUENTIAL
VACCINATION WORKS.
WE TESTED THIS IN THE CLINIC,
2-7 YEARS LATER WE RECALLED THE
VOLUNTEERS WHO GOT THE VACCINE
AND GAVE THEM DENGUE 1.
WE WANTED ON TO SEE WHAT THE
NEUTRALIZING ANTIBODIES LOOK
LIKE EMPLOY SO HERE ON DAY 0,
WHEN WE HAD RECALLED THESE
INDIVIDUALS READY TO GIVE THEM
DENGUE 1, THESE FOLKS STILL HAD
SOME ANTIBODY TO DENGUE 4.
NO ANTIBODY FOR 2 AND 3.
AFTER WE ADMINISTERED DENGUE 1,
WE SEE THIS NICE BOOST IN DENGUE
4 NEUTRALIZING ANTIBODY TITERS,
PRIMARY IMMUNIZATION TO DENGUE
1.
THIS IS WHAT YOU WOULD EXPECT
EMPLOY BUT WE ALSO SEE THESE
NICE ANTIBODY TITERS TO DENGUE 2
AND 3.
THESE INDIVIDUALS HAVE NEVER
SEEN DENGUE 2 AND 3 BUT THEY
HAVE THIS CROSS PROTECTIVE WHAT
WE CALL HETEROTYPIC ANTIBODY TO
THE SEROTYPES.
SEQUENTIAL EXPOSURE TO DENGUE
ILLICITS CROSS REACTIVE
ANTIBODIES BUT YOU HAVE TO CAN
ISSUES WHAT IS THE QUALITY OF
THESE CROSS PROTECTIVE
ANTIBODIES?
ARE THEY PROTECTIVE?
YOU ALSO HAVE TO ASK, YOU KNOW
ONCE I'VE BEEN EXPOSED TO 1
SEROTYPE, WHAT IS THE
CONSEQUENCE OF HAVING THIS
ANTIBODY PROFILE AND THE
CONSEQUENCE IS FAIRLY SEVERE.
YOU CAN HAVE A ANTIBODY
DEPENDENT ENHANCEMENT OF YOUR
DENGUE INFECTION.
PREEXISTING IMMUNITY TO 1 DENGUE
SEROTYPE REALLY IS THE GREATEST
RISK FACTOR FOR A MORE SEVERE
INFECTION, MORE SEVERE DISEASE
WHEN YOU GET YOUR SECOND
INFECTION.
THE WAY THIS WORKS IS, YOU HAVE
IT HETEROGENEOUS OR O TYPIC
ANTIBODY FROM YOUR PREVIOUS
INFECTION, THE NEW INCOMING
VIRUS, BINDS TO THESE
ANTIBODIES, BUT THEY'RE NOT
NEUTRALIZED SO THESE ARE BINDING
NONNEUTRALLIZING ANTIBODIES,
THIS ANTIBODY VIRUS COMPLEX,
THEN HAS ACCESS TO FC GAMMA
RECEPTOR CELLS SUCH AS
MONOCYTES, MORE INTERACTION
MEANS MORE INFECTION, MORE
INFECTION MEANS AN INCREASED
VIRUS LOAD, IT'S HYPOTHESIZED
THIS LEADS TO AN INCREASE IN NS
1 PRODUCTION, INCREASED VASEIO
PERM ANLT MORE DISEASE.
THIS IS ASPECT DEPENDENT AND HAS
BEEN.
THIS IS WHY PARTIAL IMMUNITY TO
DENGUE IS DANGEROUS.
WHAT WE MEDE IS A VACCINE THAT
CAN PROVIDE VACCINE
TETRAIMMUNITY.
IN THE EARLY DAYS OF LABORATORY
INFECT YOWZ DISEASE, WE DECIDED
TO DEVELOP A LIVE ATTENUATE
DENGUE VACCINE.
WHY?
ROBERT CHANIC THOUGHT IT WAS A
GOOD IDEA.
BRIAN MURPHY THOUGHT IT WAS A
GOOD IDEA.
THE WHOLE LAB THOUGHT IT WAS A
GOOD IDEA.
I JUST WANT TO PONT OUT SOME OF
THE INDIVIDUALS IN THIS, JOE
[INDISCERNIBLE], CHRIS HANSEN
STILL WITH THE OFFICE OF THE
DIRECTOR IN DIR AND BRIAN MURPHY
THERE IN THE CENTER GIVING A
VERY STERN LOOK.
THIS IS HOW WE STARTED AND THE
REASON DEVELOPING A LIVE
ATTENUATE VACCINE MADE SOME
SENSE WAS BECAUSE IT HAD BEEN
SUCCESSFUL FOR OTHER FLAVI
VIRUSES, FOR YELLOW FEVER VIRUS,
FOR JAPANESE ENSEVILLE O VIRUS,
THE ANTIGENS AND EPITOPES YOU
DON'T HAVE TO WORRY IF THEY ARE
DESTROYED IN ACTIVATION, THEY
ARE PRESENTED IN THEIR NATIVE
CONFIRMATION, YOU ARE GENERALLY
EXPECTED TO HAVE LIFE LONG
IMMUNITY ESPECIALLY IF YOU'RE
LIVING IN AN ENDEMIC AREA WHERE
YOU CAN BE BOOSTED WHEN YOU'RE
SUSCEPTIBLE.
THEY CAN BE VERY INEXPENSIVE TO
PRODUCE, I WILL TELL YOU WE
PRODUCE OUR VIRUSES A TENTH OF
THE 7 PFU IN TISSUE CULTURE WE
ADMINISTER THEM AT 10 TO THE 3.
SO EVERY ML IS THEY--THE
KRETICALLY 10,000 DOSES, A FLASK
OF CELLS WITH DENGUE CAN BE
ABOUT A MILLION DOSES.
THEY'RE HIGHLY IMMUNOGENIC, AS
YOU WOULD EXPECT FOR A LIVE
ATTENUATE VACCINE, THEY ONLY
REQUIRE 1 DOSE.
THIS IS WHAT I BELIEVE MOST
PEOPLE DON'T APPRECIATE ABOUT
LIVE VACCINES.
FOR LIVE VACCINES, INFECTION IS
REQUIRED FOR IMMUNE STIMULATION.
YOU HAVE TO BE INFECTED.
THE VIRUS NEEDS TO REPLICATE.
THERE'S NOT ENOUGH ANDROGEN
ROUGH ATOM IMENNIC LOAD IN THAT
VACCINE TO DO ANYTHING IF THAT
VIRUS ISN'T GOING TO REPLICATE.
AND YOU CAN LOOK AT THIS
REPLICATION BY LOOKING IN THE
BLOOD FOR THE VIRUS LOAD, FROM
THE VACCINE EITHER BY DIRECT
CULTURE OR RTPC R, CAN YOU LOOK
AT IMMUNITY WHETHER IT'S
ANTIBODY OR T-CELL IMMUNITY, YOU
CAN LOOK AT EVEN SOME OF THE
CLINICAL SIDE EFFECTS OF THAT
VACCINATION.
BUT TO BE AN EFFECTIVE, LIVE,
TETRAVALENT VACCINE ALL FOR
SEROTYPE COMPONENTS NEED TO
REPALATELICATE.
THAT IS THE FOUNDATION FOR
DEVELOPING THE NIH VACCINE.
NOW I ASK THED QUESTION, IS IT
REALLY THIS SIMPLE?
WOULD VIRUS REPLICATION--VACCINE
REPLICATION BE A CORLATTIVE
PROTECTION?
I BELIEVE IT IS.
AGAIN, TO BE A
TETRAVALENTINEDDENT VACCINE, ALL
4 NEED TO REPLICATE.
HERE ARE THE LIVE ATTENUATE
VACCINES THAT HAVE BEEN
DEVELOPED OVER THE LAST 20
YEARS.
THERE'S A SANOFI PASTOR AT
CANNED WHAT AND TB003 WHICH WE
CALL THE NIH VACCINE OR NOW WE
CALL IT THE BOTONDV, YOU CAN SEE
THESE ARE IN DIFFERENT NUMBER OF
DOSES, THIS IS THE PLATFORM FOR
THESE VACCINES.
FOR THE SANOFI VACCINE, DENG
VAXAI, ALL VIRUS BACKBONE AND
THEY SUBSIDIARY CONSTITUTE IN
THE SUBITUTE PROTEINS FROM
DENGUE 1, 2, 3, 4.
SO THIS IS A VACCINE BACKBONE
EXPRESSING THE ANTIGENS FOR
DENGUE 1, 2, 3, 4.
FOR TAKEDA, IT WAS ATTENUATE
DENGUE 2 BACKBONE AND THEN AGAIN
THEY MADE THESE CHIMERIC VIRUSES
IN WHICH DENGUE 1, 3, 4 ARE
EXPRESSED AND HERE'S THE NIH
VACCINE, KIND OF A COMBINATION
OF THESE DIFFERENT EFFORTS AND
WE WILL TALK MORE ABOUT THAT.
SO, WHAT ABOUT THE EFFICACY AND
THE LONG-TERM SAFETY OF THE
SANOFI DENG VAXIA, RACKINATION
OCCURRED DURING THE YEAR,
VACCINATION EVERY 6 MONTHS, A
YEAR OF EFFICACY ANALYSIS AND
THEN YEAR 3 SAFETY.
AND THIS IS WHERE THEY RECOGNIZE
THE FIRST PROBLEM WITH THIS
VACCINE.
SO IN INDIVIDUALS WHO ARE
VACCINATED WHO ARE
SERO-NEGATIVE, YOU HAD A
REGGATIVE RISK OF
HOSPITALIZATION GREATER THAN 1.
WHEN YOU BROKE THIS DOWN BY
DIFFERENT ANAL GROUPS, THESE
KIDS THAT WERE 2-5 IN THEIR
STUDY HAD A 7 FOLD HIGHER RISK
OF HOSPITALIZATION ON THEIR NEXT
EXPOSURE TO DENGUE.
SO THIS WAS A BIT OF A RED FLAG.
WAS THIS A SURPRISE?
IT WAS.
TO MANY OF US WE ALREADY KNEW
THIS WAS A RATHER IMBALANCED
VACCINE.
HERE'S DATA IN NAIVE SUBJECTS
VACCINATED WITH 3 DOSES.
AFTER THE VERY FIRST DOSE, THIS
IS WHAT THE NEUTRALIZING
ANTIBODY TITERS LOOK LIKE.
AND YOU CAN SEE IT'S CLEARLY
DOMINATED BY DENGUE 4.
THERE'S A 70 FOLD DIFFERENCE
BETWEEN THE ANTIBODY RESPONSE
BETWEEN DENGUE 1 AND DENGUE 4.
THEY GIVE A SECOND DOSE, DENGUE
4 ANTIBODIES CONTINUE TO WANE AS
EXPECTED, SO YOU DON'T SEE A
BOOST, I SUPPOSE ALL OF THIS
DENGUE 4 IN THE SECOND DOSE WAS
COMPLETELY NEUTRALIZED FROM THE
FIRST DOSE, MAYBE A LITTLE BIT
OF ANTIBODY FOR DENGUE 1, 2, 3.
BUT REALLY IT'S PRINCIPALLY A
DENGUE 4 VACCINE, IT'S NOT
BOOSTED.
DENGUE 1, 2, 3, RESPONSES
IN
INCREASE A LITTLE BIT BUT DOES
THIS IMBALANCED IMMUNE RESPONSE
LEAD TO VARIABLE EFFICACY AND
INDEED IT DID.
SO WHEN THEY LOOK AT EFFICACY IN
LATIN AMERICA, SO HERE'S ANOTHER
NUMBER OF DENGUE CASES CAUSED BY
DENGUE 1, 2, 3, 4.
HERE'S DENGUE 4.
HERE IN BRAZIL, MOST OF THE
CASES AT THAT TIME, SO NICE
EFFICACY TO DENGUE 4, BECAUSE
IT'S A DENGUE 4 VACCINE.
THAT MAKES SENSE.
IN MEXICO MOSTLY DENGUE 1 AND 2
ARE CIRCULATING DURING THE
TRIAL, VERY LOW EFFICACY, OKAY
IN IRONICALLY, THE FIRST COUNTRY
TO AUTHORIZE THIS VACCINE WAS
MEXICO.
DENG VAXIA WORKS REALLY WELL AS
A FILL IN VACCINE, I DON'T WANT
TO LEAD YOU ASTRAY AND SAY THE
VACCINE IS NOT USEFUL BECAUSE
THE EFFICACY AGAINST SERIOUS
DENGUE DEC CAN BE AS HIGH AS 93%
BUT THAT VACCINE NEEDS TO BE
GIVEN TO SOMEBODY WHO ALREADY
HAD DENGUE.
IF YOU'VE HAD DENGUE THEN YOU
CAN BE VACCINATED BECAUSE, AGAIN
THIS IS--THIS WOULD BE WHAT WE
WOULD CALL A SEQUENTIAL
VACCINATION STRATEGY.
YOU HAVE A PRIMING FROM A
PREVIOUS EXPOSURE FROM MOTHER
NATURE.
MOTHER NATURE GIVES YOU THE
FIRST DOSE, SANOFI GIVES YOU
DOSE 2, 3, AND 4.
OKAY IN THE BOTTOM LINE IS
INCOMPLOAT OR PARTIAL IMMUNITY
TO DENGUE REMAINS PROBLEMATIC.
TAKEDA, DEVELOPED THEIR VACCINE
DURING THEIR TRIAL THEY CALL IT
TAK003.
REALLY GOOD EFFICACY AGAINST
HOSPITALIZATION, THAT'S BECAUSE
HOSPITALIZED INDIVIDUALS ARE
HAVING PRIMARILY A SECOND OR
THIRD INFECTION OKAY, IF YOU
VACCINATE THESE PEOPLE, YOU CAN
PROTECT AGAINST A SERIOUS SECOND
AND THIRD VACCINATION.
BUT AGAIN THEIR IMMUNO
GENERATEDISSITY APPEARS
IMBALANCED, SO THEIR PUBLISHED
DATA IN SERONAIVE INDIVIDUALS
YOU CAN SEE THIS HUGE DOMINANCE
FOR DENGUE 2.
THE TAKEDA VACCINE IS
PREDOMINANTLY A DENGUE 2
VACCINE.
WHEN YOU LOOK AT EFFICACY
WHETHER IT'S 18 MONTH OR 36
MONTH GOOD EFFICACY FOR DENGUE 1
AND 2, THEY COULD NOT
DEMONSTRATE EFFICACY FOR DENGUE
4 BECAUSE THERE WERE NO CASES
BUT THEY REPORTED NO EFFICACY TO
DENGUE 3.
BY 36 MONTHS THEY HAD
ACCUMULATED A ENOUGH CASES THAT
YOU SAW A NEGATIVE EFFICACY FOR
DENGUE 3, A NEGATIVE EFFICACY
FOR DENGUE 4.
THIS WAS RECENTLY APPROVE INDEED
SEVERAL COUNTRIES WITHOUT A
REQUIREMENT FOR SEROPOSITIVITY
OR REVACCINATION TESTING.
YOU JUST WANT TO IMIF IT TO AGE
GROUPS WHERE YOU THOUGHT MOST OF
THE PEOPLE HAD ALREADY HAD THEIR
FIRST INFECTION.
THEIR APPLICATION AT THE USFDA
HAS SUBSEQUENTLY BEEN WITHDRAWN.
I DO NOT KNOW THE REASON FOR
THAT.
THERE'S LOTS OF SPECULATION
EMPLOY OKAY, THOSE ARE THE OTHER
VACCINES.
NOW WHAT ABOUT THE NIH
TETRAVALENT DENGUE VANNING SEEN.
WE MOVED FOR HUNDREDS OF
DIFFERENT CONSTRUCTS, VIRUS
CONSTRUCTS, MOST OF THESE MADE
IN THE LABORATORY BY CHRIS AND
CATHY HANLY AND JOE BLANEY,
HUNDREDS OF DIFFERENT
CONSTRUCTS, SOME OF THEM
PRECEDED THROUGH PRECLINICAL
EVALUATION IN A LOT OF DIFFERENT
MONKEYS, AND THEN WE CHOSE TO GO
FORWARD.
I PUT A GOLD STAR HERE, THIS IS
WHAT MADE THE DIFFERENCE FOR US.
WHY OUR VACCINE WORKS.
BECAUSE WE WENT AND TESTED EACH
OF THESE INDIVIDUALLY IN HUMAN
PHASE 1 TRIALS TO MAKE SURE THEY
WERE COMPLETELY INFECT YOWZ
COMPLETELY REPLICATIVE, BUT THAT
TOOK US HONESTLY ABOUT A DECADE
AND PEOPLE KEPT ASKING JUST PUT
THE TETRAVALENT TOGETHER BUT WE
WEREN'T SURE WHAT TO PUT
TOGETHER, WE WANTED TO MAKE SURE
THIS WAS GOING TO WORK SO WE
COULD MAKE SURE OF THIS FINAL
FORMULATION.
THIS FORMULATION IS A FULL
LENGTH DENGUE 1 WITH THIS DELTA
30 MUTATION, THIS KELTA 30
MUTATION IS IN THE THIRD PRIME
UTR, WE TALK OUT THIS LITTLE BIT
OF STEM LOOP AND WHAT WE SEE IS
INCREASED SUSCEPTIBILITY TO TYPE
1 INTERFERONSON THAT'S HOW THE
VIRUSES ARE ATTENUATE.
WE DID THE SAME THING FOR DENGUE
4, THE DELTA THIRD, WHAT WE DID
FOR DINGHY 3 WAS CREATE A DELTA
30, IT DIDN'T WORK SO WE NEEDED
A DELTA 31 MUTATION SHOWN UP
HERE AND FOR DENGUE 2, DENGUE 2
DELTA THIRD DID NOT WORK SO WE
MADE A CHIMERIC USING THE DENGUE
4 AND THE PREM AND E FROM
KENNINGY 2.
WE CONDUCTED 31 DIFFERENT TRIALS
FOR THIS VACCINE.
FINALLY COMING TO A CANDIDATE
FORMATION, WE TEST INDEED
THAILAND AND BANGLADESH, WE
DEMONSTRATE THAD YES IT IS A
SINGLE DOSE VACCINE, MINIMAL
BOOST AFTER THE SECOND DOSE IT'S
UNIFORMLY INFECTIOUS AND
IMMUNOGENIC IN DENGUE NAIVE
SUBJEKS, YOU CAN FILL IT IN WITH
THOSE USING SEROTYPES, IT'S SAFE
IN OALTDER ADULTS, IT'S SAFE IN
INFANTS CAN CHILDREN AS YOUNG AS
1 YEAR, YOU GET A STRONG T-CELL
RESPONSE, YOU CAN HAVE
PROTECTION AFTER 30 DAYS WHICH
IS IMPORTANT FOR THE TRAVELER,
INDICATION, AND YOU GET--WE
DEMONSTRATED SOLID AGAINST
DENGUE VIRUS CHALLENGE, 2 AND 3.
VERY QUICKLY HERE'S THE DESIGN
OF THE STUDY WE DID IN BANGKOK,
HD ESCALATION STUDY, LOOKING AT
SAFETY, IMMUNO GENERATEDISSITY,
VIREMIA, AND DETERMINING THE
EFFECT OF PREEXISTING ANTIBODY.
VERY QUICKLY, I THINK I SKIP
DOWN HERE REALLY QUICK BECAUSE I
WANT TO SHOW YOU.
THIS IS WHAT INDIVIDUALS IN
BANGKOK LOOK LIKE THAT WERE
ENROLLED IN THE STUDY.
BEFORE VACCINATION, SO PREVAXIA,
73% OF THE ADULTS HAD A
NEUTRALIZING ANTIBODY TITER
AGAINST ALL 4 SERO TYPES, MOST
OF THEM, ALMOST ALL OF THEM HAD
ANTIBODY AGAINST AT LEAST 1 OR 2
SEROTYPES OF DENGUE.
THIS IS WHAT ADULTS LOOK LIKE IN
BANGKOK.
YOUNG KIDS, YOU KNOW ONLY 4% OF
THEM HAD A REALLY COMPLETE
IMMUNE RESPONSE TO DENGUE.
SO THIS IS--THIS IS NATURAL
SEQUENTIAL IMMUNITY AT WORK HERE
IN THE ADULTS.
THIS IS WHAT WE SAW AFTER
VACCINATION.
EVERYBODY MOVES CLOSER TO THAT
END POINT INCLUDING THE YOUNG
CHILDREN, OKAY, REMEMBER, I
ASKED YOU AT THE VERY BEGINNING,
CAN THIS TYPE OF NATURAL
IMMUNITY BE INDUCED IN YOUNG
CHILDREN?
CAN WE SAFELY INDUCE THIS IPT
GREATERUNITY IN CHILDREN?
AND MY ANSWER WOULD BE YES.
THESE CHILDREN'S IMMUNE PROFILE,
THAT LOOKS VERY SIMILAR TO WHAT
YOU SEE AFTER NATURAL INFECTION
IN ADULTS.
WE HAVE DEVELOPED A HUMAN
CONTROLLED INFECTION MODEL
DURING THIS PROCESS, SO A MODEL
FOR DENGUE 2 AND 3.
WE ADMINISTERED THIS VIRUS, NOT
A VACCINE, IT'S A VIRUS, TO
ADULTS HERE IN THE U.S., A
HUNDRED% OF THEM HAVE A VIREMIA,
WITH A PEAK TITER SOMEWHERE
ABOVE 2 LOGS FOR DENGUE 2, LOWER
FOR DENGUE 3.
MOST OF THESE INDIVIDUALS HAVE A
RASH, THIS IS WHAT THE TYPICAL
RASH LOOKS LIKE, SO THIS IS THE
RASH FROM OUR DENGUE 2 CONTROL
INFECTION MODEL, OUR DENGUE 3,
THIS IS THE CROSSED LEGS OF A
NATURAL INFECTED PERSON AND THIS
IS ON THE CHEST OF THIS
VOLUNTEER, THESE LITTLE MACULES,
HA'S WHAT WE SEE WITH THE DENGUE
VACCINE.
SO THE DENGUE VACCINE IS VERY
DIFFERENT RASH FROM WHAT WE SEE
IN NATURAL INFECTION OR HUMAN
CONTROL MODEL.
SO WE WILL SET UP A STUDY WHERE
WE VACCINATE OR GIVE PLACEBOS TO
2 GROUPS OF INDIVIDUALS, WE WILL
COME BACK WITH A THOUSAND FFU OF
DENGUE VIRUS, WE WILL LOOK AT
THIS FOR PROTECTION AGAINST RASH
AND THE VIRUS.
THIS IS WHAT WE SEE.
IN OUR PLACEBOS A HUNDRED
PERCENT INFECTION, A HUNDRED%
RASH.
IN SACK SINEES, NO VIREMIA AND
NO RASH, SAME FOR DENGUE 3, NO
VIREMIA, NO RASH, WE ARE A
HUNDRED% PROTECTION IMON
STRAIGHTED IN OUR CONTROLLED
HUMAN INFECTION MODEL.
OKAY, WE HAVE A VACCINE, WE
THINK IT'S GOING TO WORK.
WHAT ARE WE GOING TO DO WITH
THIS IN WE TURN TO TECHNOLOGY
TRANSFER AND WE HAVE LICENSED
THIS TECHNOLOGY WHICH INCLUES
THE PATENT RISE, BIOLOGICAL
MATERIALS, METHODS AND
PROCEDURES, ALL OF OUR PHASE 1
AND 2 DATA TO SUPPORT THE
REGULATORY FILINGS, AND IT ALSO
INVOLVES A LOT OF HAND HOLDING
FROM OUR END.
YOU CAN'T JUST LICENSE AND WALK
AWAY.
THAT GENERALLY DOESN'T WORK.
WE LICENSE THIS COMPANY FOR USE
IN THE U.S., EUROPE AND CHINA,
TO THE BUTANTAN IN BRAZIL, WE
ARE NOW WITH 4 IN INDIA, AND
WE'RE WITH DR. REDDY'S
PHARMACEUTICALS, AND WE'VE ALSO
WORKED HERE ON THE GOVERNMENT'S
REQUEST TO WORK ON THE
DEVASTATING DENGUE SEASON
THEY'VE HAD WITH MEDIgE N, AND
VABIO TECH, AND HERE'S THE FIRST
PHASE 3 STUDY PERFORMED BY THE
FIRST INSTIEWS BUTAN TAN, THIS
IS THE NIH VACCINE PRODUCED IN
THEIR HANDS PRODUCED IN THEIR
FACILITIES, IT'S BEEN PUBLISHED
IN 2 DIFFERENT JOURNALS.
THIS STUDY WAS 16,000
INDIVIDUALS IN 16 CLINICAL SITES
ACROSS BRAZIL.
THE STUDY WAS CONDUCTED WITH
IMPECCABLE PRECISION.
IF YOU LOOK AT THIS, 10,259
RECEIVED VACCINATION.
AT THE END OF THIS ANALYSIS AT
3.7 YEARS, 10,215 OF THEM WERE
STILL IN THE PERPROTOCOL
EFFICACY POPULATION, THIS IS
REMARKABLE RETENTION FOR A PHASE
3 STUDY.
SO KUDOS TO THEM.
HD ESCALATION, THIS WAS THE
FIRST VACCINATION ON
FEBRUARY 2016--WHAT WE DID, WHAT
THEY THEN DID IS A 2 YEAR
ANALYSIS THAT WAS CARRIED OUT ON
JULY 13th 2021, EVERYBODY IN
THAT STUDY HAD COMPLETED 2 YEARS
OF A VACCINATION ON THAT CUT OFF
DATE.
THEY ALSO DID AN ANALYSIS WHERE
AT THAT CUT OFF DATE THEY LOOKED
ADDED ALL THE EFFICACY
REGARDLESS OF TIME SINCE
VACCINATION, A MEAN OF 3.7
YEARS.
SOME OF THESE INDIVIDUALS HAD
ALREADY REACHED OUR 5 YEAR
POINT.
AND THEN THERE WILL BE A 5 YEAR
ANALYSIS WHICH IS ONGOING
BECAUSE THE STUDY COMPLETED ON
JULY 13th OF THIS YEAR, 0 TO 6
MONTHS POST VACCINATION FOR
EVERYBODY.
AND IN BRAZIL, THE INCIDENCE OF
DENGUE SHOWN IN THE BLUE LINE
VARIES FROM YEAR TO YEAR, BUT
DURING THIS TRIAL, WHAT DIDN'T
VARY WAS THE LACK OF CIRCULATION
OF DENGUE 3 AND 4 AND YOU CAN
SEE DOWN HERE WHAT% OF THE CASES
WERE CAUSED BY DENGUE 3 AND 4.
THEY DID HAVE AN OUTBREAK OF
DENGUE 3 BEGINNING IN 2023 INTO
2024.
WE WERE HOPING TO HAVE SOME OF
THOSE CASES IN THE TRIAL BY THE
CUT OFF POINT, JULY OF THIS
YEAR.
THEY HAD CAPTURED 0 CASES, STILL
0 CASES OF DENGUE 3, MOSTLY
BECAUSE IT WAS IN AREAS THAT
WERE NO LONGER HAD VACCINEES
BEING MONITORS AND ALSO THERE
WAS REALLY ONLY ABOUT A THOUSAND
INDIVIDUALS LEFT IN THE TRIAL AT
THAT POINT.
LOOKING AT THE 2 YEAR EFFICACY
DATA, OVERALL 80% EFFICACY AFTER
2 YEARS, SPHEVENT% FOR DENGUE 2,
90% FOR DENGUE 1, AGAIN NO
CIRCULATION OF DENGUE 3 AND 4 SO
WE CAN'T COMMENT ON THE EFFICACY
AT THAT POINT.
AT THE CUT OFF WHICH WAS A MEAN
OF ALMOST 4 YEARS, WE'RE STILL
67% OVERALL EFFICACY.
YOU CAN SEE THE EFFICACY FOR
DENGUE 1 AND 2.
HERE'S THE INCIDENCE CURVES
AFTER 3.7 YEARS.
HERE'S PLACEBOS, HERE ARE
VACCINEES, AGAIN 67% EFFICACY.
YOU CAN SEE THIS LITTLE INCREASE
THAT OCCURRED IN 2023, STILL IN
PLACEBOS IT'S A RATHER FLAT
INCIDENCE LINE.
HERE'S THE--ALL OF THE EFFICACY
STRATIFIED BY AGE AND WHETHER OR
NOT YOU'RE EXPOSED TO DENGUE OR
NOT EXPOSED TO DENGUE.
YOU CAN SEE IN RED ARE THE
VALUES FOR THE DIFFERENT AGE
GROUPS, FOR THE GROUP REGARDLESS
OF SEROTYPE, YOU CAN SEE MY
FAVORITE HERE IS THIS 80% VALUE.
THIS IS 2-6 YEAR-OLDS,
REGARDLESS OF WHETHER THEY'RE
POSITIVE OR NEGATIVE, WE HAVE
EFFICACY OF 80% IN THIS YOUNGEST
GROUP.
WHAT ABOUT SEVERE DENGUE.
EIGHTY-NINE% EFFICACY AFTER 3.7
YEARS.
IF WE LOOK AT THE 2 YEAR DATA,
IT WAS 88%, OKAY.
TWO YEARS, ALMOST 4 YEARS, WE
HAVE THE SAME EFFICACY FOR
SERIOUS DENGUE.
IF YOU COMPARE THIS TO TAKEDA'S
PUBLISHED 3 YEARS, 84%, IF WE
STRATIFY IT BY DENGUE WOKNOW AND
2, 93%, 85%, THIS VACCINE CAN
HAVE A GREAT EFFECT ON
HOSPITALIZATION AND SEVERE
DISEASE.
THIS IS THE ADVERSE EVENTS FROM
THE TRIAL.
AS I MENTIONED AND SHOWED YOU
THE PICTURE, THE MOST
PREDOMINANT ADVERSE EVENT IS THE
SKIN RASH, IT'S GENERALLY NOT
RECOGNIZED BY THE VACCINEE, IN
FACT IN CLINICAL TRIALS WE WOULD
ASK DO YOU HAVE A RASH?
AND THEY WOULD SAY NO.
THEN THEY HAD A PHYSICAL EXAM
WHERE THEIR SHIRT WAS REMOVED
AND DR. ANADURB AN, EAGILAE DURB
AN YOU WOULD POINT OUT YOU
ACTUALLY DO HAVE A RASH, IT
USUALLY OCCURRED ON THE CHEST OR
INSIDE OF THE ARMS.
SOMETIMES IT IS A LITTLE BIT
ITCHY BUT IT'S VERY SHORT LIVED.
FOURTH APPEARANCE WE CAN LOOK AT
BENCHMARKING AGAINST OTHER
DENGUE VACCINES SO I'M ONLY
SHOWING YOU PUBLISHED DATA FROM
THESE OTHER 2 VACCINES AND FROM
THE BUTANTAN VACCINE.
SO HERE'S THE 2 YEAR FOLLOW UP
FOR SANOFI, TAKEDA, OR BUTANTAN.
AFTER THE INJECTIONS EMPLOY IF
YOU LOOK AT THE 3 YEAR FOLLOW UP
DATA THERE'S NOTHING REALLY IN
THE LITERATURE FOR SANOFI, 62%
FOR TAKEDA, THE BUTANTANAFTER A
SINGLE DOSE IS STILL AT 67%.
IF YOU LOOK AT WHAT STRATIFY IT
BY SEROEXPOSED, 74% OF
SERONAIVES WITH THE
BUTANTAN VACCINE ARE PROTECTED.
THAT IS PRETTY MUCH EQUIVALENT
TO WHAT YOU SEE IN SEROEXPOSED
OR SERONAIVE OR SANOFI OR
TAKEDA.
WHEN YOU LOOK AT AGE, AGAIN,
THIS IS 80% NUMBER.
80 PERCENT PROTECTION FOR AGE
2-6 YEAR-OLDS.
THIS GROUP HAD 84% SERONIGH
EVITY.
EIGHTY% IS BET ARE GROUP THE
GROUP OF TAKEDA, OR SANOFI, AND
IF YOU LOOK AT 6-7 YEARS IT'S
75%.
WHAT ABOUT THE DIFFERENT
SEROTYPES IN WE DON'T KNOW WHAT
THE EFFICACY WILL BE FOR DENGUE
3 AND 4, BUT WE HAVE SOME
INDICATIONS AND THIS GOES BACK
TO MY ORIGINAL IDEA THAT MAYBE
YOU CAN LOOK FOR A CORLATTIVE
PROTECTION BY HOW MUCH VACCINE
VIREMIA YOU'RE SEEING.
SEE HERE'S THE VACCINE VIREMIA
PUBLISHED DAILY BASIS THEA AFTER
A SINGLE DOSE IN FLAVI-NAIVE
SUBJECTS.
SO THIS A VERY RELEVANT
COMPARISON.
ALL SERONAIVES, ALL SINGLE DOSE.
SANOFI VACCINE IS PRINCIPALLY A
DENGUE 4 VACCINE.
THIS IS WHERE YOU SEE MOST OF
THE RTPC R VIREMIA FOR THAT
VACCINE.
FOR TAKEDA, MOST OF IT IS FOUND
AS DENGUE 2, ALL OF IT IS FOUND
IN DENGUE 2.
I WILL GIVE YOU A CAVEAT, THIS
IS A SLIGHTLY DEFINITE
FORMULATION THAN THEY USE IN THE
PHASE 3 TRIAL, THEY HAVEN'T
PUBLISHED WITH THE PHASE 3
TRIAL, BUT THEY MADE ADJUSTMENTS
WITH THE SEROTYPES BUT
PRINCIPALLY IT'S DENGUE 2, THIS
IS WHAT YOU SEE FOR DENGUE 4.
WE HAVE REPLICATION OF ALL 4
SEROTYPES.
IF YOU LOOK AT THIS LEVEL OF
REPLICATION, I WOULD PREDICT
THAT THE DENGUE 3 AND 4 EFFICACY
IS GOING TO BE COMPARABLE OR
EVEN BETTER THAN WHAT WE OBSERVE
FOR DENGUE 1 AND 2.
IS IT REALLY A 1 DOSE VACCINE?
MERK WAS SKEPTICAL, THEY DIDN'T
BELIEVE US, THEY RAN THEIR OWN
TRIAL.
HERE'S THE DATA WHEN YOU LOOK AT
PERCENT OF SUBSCRECTS WITH
VIREMIA AFTER 1 DOSE, WE SEE
VIREMIA ACROSS ALL 4 SEROTYPES,
ANY SEROTYPE IT WAS 97% AFTER
DOSE 2 NO DETECTABLE VIREMIA.
OKAY?
SO IF YOU ARE LOOKING AT DOSE 2
AS SOME KIND OF CHALLENGE YOU
ARE STERILELY IMMUNE TO A BOOST
FROM FROM THAT SECOND DOSE AND
OF COURSE IN THE PLACEBOS WE SAW
NOTHING.
NOW THAT'S LOOKING AT VACCINE
VIREMIA, WHAT ABOUT LOOKING AT
NEUTRALIZING ANTIBODIES.
I HAVE TO TELL YOU THAT WHEN WE
LOOK AT NEUTRALIZING ANTIBODIES,
WE NEED TO DISCRIMINATE BETWEEN
THOSE THAT ARE HOMOTYPIC, TO THE
VIRUS THAT WAS INFECTING AND
THOSE THAT ARE HETEROTYPIC OR
CROSS REACTIVE SO AARON
[INDISCERNIBLE] AT UNC HAS THIS
RATHER COMPLICATED ASSAY WHERE
WE CAN DEPLETE OUT CROSS
REACTIVE NEUTRALIZING
ANTIBODIES.
SO YOU'RE LEFT WITH JUST
HOMOTYPIC ANTIBODIES, IF YOU DO
THAT, MOST OF THE HOMOTYPIC
ANTIBODIES FOR SANOFI ARE DENGUE
4 AS YOU WOULD PREDICT, MOST OF
THEM FOR TAKEDA ARE DENGUE 2,
YOU SEE HOMOTYPIC NONCROSS
REACTIVE NEUTRALIZING ANTIBODIES
TO ALL 4 SEROTYPES FOR THE NIH
VACCINE.
SO WE HYPOTHESIZE THAT TYPE
SPECIFIC HOMOTYPIC NEUTRALIZING
ANTIBODIES MAY BE A CORRELATIVE
PROTECTION.
WE WILL NEVER BE ABLE TO USE
THIS ASSAY GOING FORWARD BECAUSE
OF THE COMPLEXITY BUT WE'RE
REALLY TRYING TO WORK ON
DIFFERENT ASSAYS THAT WE COULD
USE TO LOOK AT THESE HOMOTYPIC
NEUTRALIZING ANTIBODY RESPONSES.
A PHASE 33 TRIAL FOR DENGUE ALL,
THAT'S THE NAME OF THE VACCINE
PRODUCED BY BIOTECH IN INDIA, IT
BEGAN JUST EARLIER THIS MONTH.
IT'S A MULTICENTER RANDOMIZED
DOUBLE BLIND PLACEBO CONTROL
STUDY TO LOOK AT EFFICACY IN
10,000 ADULTS IN INDIA.
IT'S BEING CONDUCTED BY THE
INDIAN COUNCIL OF MEDICAL
RESEARCH, THE ICMR, AND THE
NATIONAL INSTITUTE OF VIROLOGY
USING THE P A NACEA PRODUCT, 19
SITES, 7 OF THOSE SITES HAVE
BEEN INITIATED.
THE FIRST DOSE SHOWN HERE WAS
GIVEN IN THE ROTOX SITE IN THE
NORTHERN STATE.
ENROLLMENT CONTINUES AT THE 7
SITES, ALL 19 SITES SHOULD BE
ONBOARD BY NOVEMBER AGAIN THEN
THOUSAND ADULTS AGE 18-60.
IN THIS TRIAL THEY EXPECT OHM
ABOUT 10% DENGUE NAIVE EMPLOY SO
THIS IS A TRIAL THAT IS GOING TO
TEST AGAIN THE VACCINE EFFICACY
IN MOSTLY DENGUE EXPOSED
INDIVIDUALS.
I'M SURE IT IS GOING TO BE A
HOME RUN.
THERE ARE OTHERS WHO ARE
PLANNING A STUDY IN PEDIATRIC
POPULATION AND THOSE ARE
UNDERWAY.
HOW DID WE GET HERE?
IT'S ALL ON THE SLIDE, HOW DID
WE GET HERE IS BY TECHNOLOGY
TRANSFER.
WHAT STARTS ON THE BENCH, MOVES
TO THE BEDSIDE, AND THEN WE MOVE
INTO IMPLEMENTATION AND I'M
SHOWING YOU A PHOTO THAT WE
DISCOVERED FROM 1992 IN THE NIH
RECORD, THERE'S OUR FRIEND,
DR. CHEN, BRIAN MURPHY, DONEY
FAUCI, BOB CHANIC RECEIVING AN
AWARD, I DON'T KNOW WHAT IT WAS
FOR BUT I SUSPECT IT WAS WITH
COLD ADAPTED FLEW.
THIS IS PETER [INDISCERNIBLE]
THAT HANDLES MY PORTFOLIO, I AM
ETERNALLY GRATEFUL FOR ALL THE
HELP HE PROVIDES IN THIS
JOURNEY.
WITHOUT HIM THERE IS NO WAY THIS
WOULD HAVE BEEN TRANSFERRED TO
THE DIFFERENT COMPANIES.
HERE'S A LIST OF THE MOST RECENT
VACCINE DISCOVERY TEAMS HERE AT
NIH, WALTER REID, WE HAVE OUR
CONTRACTORS AT JOHNS HOPKINS
UNIVERSITY UNIVERSITY OF
VERMONT, COLLABORATIONS AT UNC,
LAHOYA ARE FOR TR CELLS MOWBT
SINAI AND ICCRDBFOR THE
BANGLADESH STUDY AND AGAIN A
SHOUT OUT TO THOSE ON THE
VACCINATION IMPLEMENTATION TEAMS
INCLUDING [INDISCERNIBLE] HERE
AT NIH THAT SPONSORS MOST OF OUR
TRIALS THROUGH CONTRACTS,
THROUGH OUR VACCINE
MANUFACTURING AT CRL AND THROUGH
TTIPO, PETER AND MARRIAN AND OUR
VACCINE LICENSEES.
THANK YOU VERY MUCH FOR YOUR
ATTENTION.
HAPPY TO ANSWER QUESTIONS.
[ APPLAUSE ]
>> OF COURSE MICs FOR
QUESTIONS, BUT I DO HAVE 1
ONLINE TO GET THE QUESTIONS
GOING, DO SKIN PUOF THULES
CONTAIN LIVE VIRUS?
>> THEY DO NOT.
SO WE HAVE DONE PUNCH BIOPSIES
TO ANSWER THAT QUESTION.
WE THINK IT'S IMMUNE RESPONSE
BUT WE HAVE PUNCHED A LOT OF
VOLUNTEERS AND HAVE TO THE BEEN
ABLE TO DETECT VIRUS IN THE
APPLIED P A PULES.
>> BEAUTIFUL TALK STEPHEN, AND
IT REALLY SHOWS IT'S IMPORTANT
TO SWEAT THE DETAILS THAT IT IS
TO TEST ALL THESE THINGS YOU
KNOW HUNDREDS OF CONSTRUCTS TO
FIND THE OPTIMAL THING.
WITH LIVE VACCINES, THERE'S
ALWAYS CONCERNS ABOUT STABILITY
WHEN IT GOES THROUGH INDIVIDUAL
OR MOSQUITO, WONDER IF YOU COULD
COMMENT ON THAT AND THE OTHER
QUESTION IS ABOUT IMMUNO
COMPROMISED HOSTS GETTING LIVE
VACCINES.
>> TWO EXCELLENT QUESTIONS, I'M
SORRY I DIDN'T HAVE TIME TO TALK
ABOUT WHAT WE LOOKED AT FOR
MOSQUITO TRANSMISSIBILITY OF THE
VIRUS.
SO THE PRINCIPLE ATTENUATING
MUTATION IS THAT DELTA 3
MUTATION IN A 3 PRIME UTR.
WE HAVE MANY, MANY ISOLATES FROM
VOLUNTEERS AT LATE DATES.
THEIR LAST DAY OF VIREMIA, WE
HAVE LOOKED AT THOSE VIRUS
SEQUENCES, 3 PRIME UTR, WE DON'T
SEE ENLARGE.
OR CONSTRICTURE OF THAT MUTATION
SO WE CONSIDER THAT STABLE.
THAT DELTA 30 MUTATION DOES
BLOCK INFECTION FELT VIRUSES IN
MOSQUITOES.
SO FOR MOSQUITOES THAT WERE
BLOOD FED BLOOD MEAL CONTAINING
VACCINES WE SEE RESTRICTED
REPLICATION AND THERE ARE
SEVERAL BLOCKS IN MOSQUITOES AND
IT'S DIFFERENT FOR THE DIFFERENT
SEROTYPES OR VIRUSES, SO SOME OF
THEM ARE BLOCKED IN THEIR
ABILITY TO AFFECT MIDGUT, SOME
AFFECT THE MIDGUT BUT DO NOT
ESCAPE FROM THE MIDGUT INTO THE
HEMOLIMP, SOME OF THEM YOU CAN
FIND IN THE HEESM O LIMP BUT
THEY DO NOT AFFECT THE SALIVARY
GLANDS SO INTRINSICALLY THEY'RE
NOT TRANSMISSIBLE BY MOSQUITO.
GIVEN THAT WE VACCINATED
INDIVIDUALS ON DAY, 6, 7, AND 8,
PEAK DAYS OF VIREMIA, AND WE FED
MODEL CITIZEN QUEET OS ON THEIR
ARM, TOOK THEM BACK TO THE LAB,
GREW THEM UP AND IN NO CASE DID
WE HAVE AN INFECTED MOSQUITO
THAT IS BECAUSE I SHOWED THE
LEVEL OF VIREMIA IS VERY LOW,
LESS THAN 10 PFU, WHICH IS NOT
ENOUGH EVEN IF IT WAS VIRULENT
TO TRANSMIT TO A MOSQUITO.
AND THE OTHER QUESTION WAS
IMMUNO COMPROMISE.
DENGUE IS NOT A SPECIFIC
ENHANCED DANGER IN IMMUNO
COMPROMISED INDIVIDUALS.
IN MANY OF THESE COUNTRIES WHERE
IT'S TRANSMITTED NATURALLY, YOU
DON'T SEE AN UPTICK IN IMMUNO
IMMUNO
COMPROMISED PATIENTS WITH DENGUE
DISEASE.
WE WOULD LOVE TO TEST THIS IN A
STUDY.
IF WE HAD THE MONEY TO DO IT, WE
WOULD BE DOING THAT STUDY AT
JOHNS HOPKINS BUT IT'S A
QUESTION THAT NEEDS TO BE
ANSWERED, SURE.
NDR. WHITEHEAD YOUR AGGREGATE
DATA IS INCREDIBLE.
SIGN ME UP.
BUT WHEN I'M THINKING ABOUT
ESSENTIALLY ASKING FOR VIRUSES
TO INFECT AT THE SAME TIME, WHEN
YOU TEASE OUT ARE YOU SEEING
BOTTLENECK EFFECTS?
AND HAVE YOU ADJUSTED THE RATIOS
AND THE VACCINE OR ANYTHING TO
ADAPT TO THOSE NEEDS?
>> THAT IS ALSO AN EXCELLENT
QUESTION.
SO AS I TOLD YOU EARLIER, EACH
OF THOSE VIRUSES IS DELIVERED AT
A THOUSAND PFUs, SO YOU'RE
GIVING 4000 PFU, THAT
DOESN'T--THE MOI IF YOU WILL,
AND THE INJECTION SITE IS STILL
VERY, VERY LOW.
SO WE DON'T SUSPECT THAT WE'RE
EVEN GETTING DOUBLY INFECTED
CELLS.
SO WE DON'T--WE DON'T THINK IT'S
A PROBLEM WITH INTERFERENCE, AND
IF YOU GO BACK TO THE OLD
LITERATURE YOU HEAR A LOT ABOUT
VIRAL INTERFERENCE AND THIS IS
MOSTLY FROM EARLY TRIALS WHICH
THEY ATTRIBUTED THE FACT THAT
THEY WEREN'T SEEING GOOD
IMMUNITY TO SOME SEROTYPES AS
VIRAL INTERFERENCE, I BELIEVE IT
WAS JUST THESE VIRUSES WERE NOT
INFECTING, SO I'M NOT A BIG
BELIEVER IN THIS VIRAL IRPT FER
ENSEL, WE HAD A DENGUE 3
CANDIDATE WHICH IS CHIMERIC THAT
WHEN WE TESTED IT, IN HUMANS, WE
GOT VERY LOW LEVELS OF
INFECTIVITY, VERY LOW IMMUNO
GENERATEDISSITY, IF WE HAD PUT
THAT IN A TETRAVALENTINEDDENT
FORMULATION WITH THIS RATHER
POORLY INFECTIOUS DENGUE 3 AND
GIVEN THAT EARLY AT THE TURN OF
THE CENTURY, THAT'S WHAT WHY
KIDS CALL IT, YOU KNOW THE EARLY
2000S, WE WOULD HAVE SAID
SOMETHING'S WRONG WITH DENGUE 3.
IT MUST BE INTERFERENCE BUT I
REALLY DON'T THINK THAT'S
PLAYING A ROLE IN THIS.
I DON'T THINK THERE'S A
BOTTLENECK.
NOW, WE INITIALLY THOUGHT THAT
MAYBE DENGUE FOCUSED ON IS A
LITTLE LESS INFECTIOUS AND WE
GAVE THAT AT A HIGHER DOSE, SO,
WE HAD A FORMULATION CALLED
TB005 WHICH WAS 3-4 LOGS FOR
DENGUE 2, 3 AND FOR DENGUE 32
EXPE 4.
WE SAW A BIT OF AN IMPROVEMENT
BUT AS WE EXPANDED THOSE STUDIES
IT REALLY DID NOT MAKE A BIG
DIFFERENCE AND WHEN YOU ARE
GOING TO INCREASE THE POTENCY 10
FOLD THAT HAS A HUGE IMPACT ON
MANUFACTURING CAPABILITIES.
SO TB0 WHERE ARE 3 IS WHAT
EVERYBODY IS MOVING FORWARD WITH
AT THIS TIME.
>> THANK YOU.
>> HI, STEVE WHAT AN INSPIRING
TALK.
GREAT TO SEE IT ALL LAID OUT.
MY QUESTION WAS ABOUT EFFICACY
OVER TIME AND THE DECREASE THAT
YOU SEE WITH ALL 3 VACCINES
ESPECIALLY JUST AGAINST
INFECTION THE CEIVERRITY
MAINTAINS THE PROTECTION, SO I
WAS WONDERING IF THAT'S THE
PLACEBO GROUP GETTING MORE
INFEBTED OR IF THEY'RE PROTECTED
RELATIVE TO THE VACCINE GROUP OR
IF YOU THINK THERE'S SOMETHING
BIOLOGICAL AND A 5 YEAR BOOST
MIGHT BE RECOMMENDED AT SOME
POINT?
>> THAT'S A GOOD QUESTION.
THE MOST COMMON QUESTION WE ARE
ASKED IS WHEN WILL YOU NEED TO
BE BOOSTED?
NOW A YELLOW FEVER VACCINE, THEY
KEEP CHANGING, YOU YOU NEED A
BOOST AT 10 YEARS, YOU DON'T
NEED A BOOST AT 10 YEARS, IT'S
LIFE LONG IMMUNITY.
WE BELIEVE IF WE ARE LOOKING FOR
EFFICACY AGAINST SERIOUS DENGUE
AND I SHOWED YOU THAT, WE REALLY
DEPARTMENT SEE A DECREASE IN
SERIOUS DENGUE, BUT IN THE
CLINICAL TRIALS WHERE YOU ARE
CAPTURING ALL THE CASES,
ACCORDING TO YOUR CASE
DEFINITION, YOU DO SEE A
DECREASE OVER TIME.
WHEN WILL THEY NEED TO BE
BOOSTED?
WELL, EVENTUALLY WE BELIEVE IF
YOU ARE LIVING IN AN ENDEMIC
AREA, YOUR CIRCULATING IMMUNITY,
YOUR CIRCULATING ANTIBODIES WILL
PROBABLY WANE TO A LEVEL WHICH
WILL ALLOW A NATURAL INFECTION,
AND YOU WILL PROBABLY BOOST, YOU
WON'T EVEN RECOGNIZE NAAS AN
INFECTION BECAUSE IT WILL BE
ASYMPTOMATIC.
THAT'S WHAT HAPPENS IN ENDEMIC
AREA.
PEOPLE LIKE ME WHO LIVE IN THE
U.S. AND GET VACCINATED BECAUSE
I WANT TO GO ON A TRIP, WE MAY
NEED A BOOSTER BECAUSE WE'RE NOT
NATURALLY EXPOSED.
GOOD QUESTION.
THAT IS SOMETHING THANKFULLY
THAT OUR PHARMACEUTICAL PARTNERS
WILL HAVE TO LOOK AT IN THEIR
PHASE 4 POST MARKETING PROJECTS.
NI HAVE ANOTHER QUESTION ONLINE,
SOMEWHAT PHILOSOPHICAL.
HAS ANYONE COMPARED THEEC
NATIONAL LIBRARY OF
MEDICINICICAL IMPLICATION OF
GENERATING THESE VACCINES VERSUS
ERADICATE MOSQUITOES?
[LAUGHTER]
>> ERADICATING MOSQUITOES, WOULD
BE MY PREFERENCE.
HONESTLY.
>> ON THE RECORD OF COURSE.
>> IS THAT POSSIBLE?
I DON'T KNOW.
I THINK VACCINATION IS MORE
POSSIBLE THAN ERADICATING
MOSQUITOES.
HAS THERE BEEN AN ECONOMIC
COMPARISON?
I'M NOT SURE.
I WILL TELL YOU A LITTLE
ANECDOTE, WE DID A VERY STUDY
EARLY IN WITH WALTER REID WHERE
SOME OF THE SCHOOLS IN THEIR
CLINICAL SITE HAD A LOT OF
DENGUE.
THEY WENT IN AND THEY SPRAYED
THESE SCHOOLS AND THEY PUT
SCREENS ON THE WINDOWS, DENGUE
INCIDENT WENT DOWN THE VERY
FIRST YEAR.
THE SECOND YEAR IT WENT DOWN.
THEN, MM, WE'RE NOT HAVING
DENGUE, WE'RE NOT GOING TO
SPRAY.
AND WE HATE THE SCREENS, IT
DOESN'T LET THE AIR FLOW
THROUGH, SO NO SPRAYING, THE
KREENS CAME DOWN, DENGUE CAM
BACK THE FOLLOWING YEAR.
SO FOR MOSQUITO ERADICATION, IT
WORKS BUT SUSTAINABILITY IS
ALWAYS THE ISSUE, UNFORTUNATELY.
>> THERE ALREADY WAS AN EFFORT
IN LATIN AMERICA TO ERADICATE
THE AEDES EJIPTI MOSQUITO.
>> FRED DID A GREAT JOB
ERADICATING MOSQUITOES UNTIL DDT
WAS TAKEN AWAY FROM HIM, BUT
THAT'S ANOTHER STORY.
GOOD COMMENT.
THANK YOU.
>> [INDISCERNIBLE]
>> WE WILL HAVE A RECEPTION AT
THE LIBRARY AFTER.
IF YOU HAVE ADDITIONAL
QUESTIONS, VERY, VERY HAPPY TO
SPEAK WITH YOU AT THAT.
NINA?
>> GREAT, WELL, THANK YOU SO
MUCH DR. WHITEHEAD AND
CONGRATULATIONS REALLY, REALLY
FANTASTIC FROM THE LABORATORY TO
THE INDIVIDUAL CLINICAL STUDY
AND HOPEFULLY OUT TO COMMUNITIES
AROUND THE WORLD AND DR. CHEN, I
THINK YOU SEE THAT YOUR LEGACY
IS NOT JUST TO NIH, IT IS TO THE
WORLD THROUGH ALL OF THOSE
YOU'VE EMPOWERED AND REALLY WE
ARE SO GRATEFUL FOR EVERYTHING
YOU'VE DONE.
SO THANK YOU ALL FOR BEING HERE
WITH US.
[ APPLAUSE ]
>> THANK YOU.