>> WELCOME TO TODAY'S COVID-19
SIG SEMINAR.
I'M AT FOOD AND DRUG
ADMINISTRATION.
IT GIVES ME GREAT PLEASURE TO
INTRODUCE A PIONEER IN THE FIELD
OF CORONAVIRUS, DR. MALIK PEIRIS
FROM UNIVERSITY OF HONG KONG,
DEGREE IN MEDICINE SRI LANKA, N
2003 IN THE FIRST SARS OUTBREAK
HE IDENTIFIED AND DISCOVERED THE
NOVEL CORONAVIRUS KNOWN AS THE
FIRST SARS CORONAVIRUS, DURING
THE EPIDEMIC IN HONG KONG
FOLLOWED BY CANADA.
DURING THE COVID PANDEMIC, HE
CONTRIBUTED SEMINAL FINDINGS IN
UNDERSTANDING THE DISEASE AND
LED STUDIES IN HONG KONG.
HE HAS PUBLISHED IN TOP TIER
JOURNALS WITH NUMEROUS AWARDS
AND HONORS, HE'S VERY HUMBLE
ABOUT HIS ACHIEVEMENTS AND
SUPPORTS STUDENTS AND SCIENTISTS
AROUND THE WORLD.
TODAY HE WILL SHARE HIS
EXPERIENCE AND STUDIES TO
COMPARE DIFFERENT FORMS OF
VACCINES INCLUDING mRNA COVID
VACCINES IN HONG KONG.
DR. MALIK, WELCOME.
PLEASE TAKE IT AWAY.
>> THANK YOU FOR THE KIND
INTRODUCTION. I'LL
TALK ABOUT OUR EXPERIENCE IN
HONG KONG, OF THE RNA VACCINES
IN COMPARISON WITH THE WHOLE
VIRUS INACTIVATED VACCINES.
CONFLICTS OF INTEREST, WE HAVE
PATENTS ON USE ON SURVEILLANCE
WITH THE UNIVERSITY AND NOT MY
PERSONAL PROPERTY, SO TO SPEAK.
I MIGHT AS WELL START WITH MY
ACKNOWLEDGMENTS, FUNDING FROM
THE HONG KONG UNIVERSITY GRANTS
COMMITTEE, THE RESEARCH HEALTH
BUREAU, ALSO FROM NIH.
I'LL BE TALKING ABOUT A NUMBER
OF COHORTS, PATIENT COHORTS, ONE
GROUP OF THEM HAVE BEEN
COORDINATED BY BEN, MY
COLLEAGUE, WITH NANCY.
ANOTHER CLINICAL COHORT BY DAVID
HUI AT CHINESE UNIVERSITY OF
HONG KONG, A NEIGHBOR
UNIVERSITY.
AND WE HAVE A PEDIATRIC COHORT I
WON'T HAVE TIME TO TALK ABOUT
TODAY.
AND LABORATORY WORK BY TWO
GRADUATE STUDENTS LARGELY.
THE OUTLINE, I WILL TELL YOU
ABOUT THE HONG KONG EXPERIENCE
WITH COHORTS, RELEVANT TO WHAT
FOLLOWS, BITE MAIN PART WILL BE
COMPARISON OF -- BUT THE MAIN
PART WILL BE COMPARISON.
WHEN I TALK OF THE RNA VIRUS I'M
TALKING ABOUT THE PFIZER
BioNTech VACCINES,
EFFECTIVENESS AND END WITH
IMPLICATIONS FOR CORRELATES OF
PROTECTION.
I DON'T HAVE ANSWERS FOR THAT
CORRELATES OF PROTECTION BUT I
WILL MAYBE RAISE SOME QUESTIONS
ABOUT CURRENT DOGMA REGARDING
CORRELATES OF PROTECTION.
HONG KONG IS A SPECIAL REGION OF
CHINA, OFF THE COAST OF CHINA
HERE, 7.3 MILLION POPULATION,
AND RELEVANT TO THIS, THIS TALK,
THE HEALTH CARE PARTICULARLY FOR
NOVEL AND SEVERE INFECTIOUS
DISEASES FOR THE WHOLE
POPULATION WOULD BE PROVIDED BY
A CENTRAL HOSPITAL AUTHORITY
SYSTEM WITH CLINICAL DATA
CENTRALLY ACCESSIBLE AND
DIGITIZED, HIGHLY CONNECTED
DENSE URBAN POPULATION, GLOBAL
TRAVEL HUB.
DURING COVID OF COURSE
INTERNATIONAL TRAVEL WAS
SEVERELY CURTAILED AND HAS
EXCELLENT FOOD IF YOU WANT TO
VISIT.
THIS SUMMARIZES THE EXPERIENCE
FROM COMMENCEMENT IN JANUARY
2020.
SO FOR TWO YEARS ESSENTIALLY WE
HAD VERY LITTLE COVID, THIS
SHOWS NOTHING BUT THAT IS NOT
TRUE.
JUST THAT THE SCALE IN RELATION
TO THIS PEAK, THE SMALLER PEAKS
YOU SEE HERE ARE INVISIBLE BUT
ESSENTIALLY ALL INTRODUCTIONS
ESSENTIALLY WERE CONTAINED
THROUGH PUBLIC HEALTH MEASURES,
ALTHOUGH WE NEVER HAD A COMPLETE
LOCKDOWN.
SO, BY THE END OF 2021, THE
SEROPREVALENCE WAS WAY LESS THAN
1%, AND THEN IT WAS OMICRON THAT
HIT US AT THAT POINT IN TIME.
INITIALLY IT WAS DELTA THAT WAS
INTRODUCED THROUGH IMPORTED
HAMSTERS, B1 THROUGH RETURNING
AIR CREW, BUT THOSE WERE
CONTAINED AS WELL, BUT IT WAS
BA.2 LEAKING FROM A QUARANTINE
HOTEL THAT LED TO THIS MAJOR
OUTBREAK.
BY THE END OF THAT PARTICULAR
OUTBREAK ABOUT 45% OF THE
POPULATION HAD BEEN INFECTED,
BASED ON SEROPREVALENCE STUDIES
AS WELL.
AND RELEVANT AGAIN TO WHAT I'M
GOING TO TALK ABOUT, MOST ST
SPECIMENS FOR THE STUDIES WHY
COLLECTED PRIOR TO THIS MAJOR
PEAK, SO WHEN THERE WAS VERY
LITTLE VIRUS CIRCULATION, SO
THEREFORE THE DATA IS UNLIKELY
TO BE CONFOUNDED BY UNSUSPECTED
INFECTION.
NOW, THE TWO VACCINES WE'RE
TALKING ABOUT OF COURSE YOU'RE
FAMILIAR WITH PFIZER
BioNTech AND THE OTHER ONE
WAS WHOLE VIRUS INACTIVATED
VACCINE, SINOVAC.
THESE ARE TWO OF THE MOST WIDELY
USED VACCINES GLOBALLY.
THESE ARE THE COHORTS.
DEDICATED COHORTS WERE SET UP
FOR COVID WITH MANY OF THEM WITH
COLLECTING BLOOD SAMPLES, SOME
PBMCs FOR STUDIES, AND TODAY I
WILL BE REFERRING TO SOME OF
THESE COHORTS, AND INCLUDING
VERY BRIEFLY THE BLOOD DONOR
COHORT AS WELL.
THE METHODS WE WERE USING WAS
SPIKE RECEPTOR BINDING DOMAIN
ELISA, SURROGATE NEUTRALIZATION,
BE FC GAMMA RECEPTOR 3 BINDING
ANTIBODIES INDICATORS OF ADCC,
RECEPTOR 2 ANTIBODIES, WHICH IS
INDICATOR OF ADCP, ANTIBODY
AVIDITY AND T-CELL RESPONSES.
SO, VERY EARLY WITHIN A FEW
MONTHS OF VACCINATION WHICH
COMMENCED IN EARLY 2021 IN HONG
KONG DATA SUGGESTED THE
CORONACAV VACCINE PROVIDED
HARDLY ANY RESPONSE, TWO DOSES
HAD MARKED RESPONSE WHETHER
NEUTRALIZATION ANTIBODY RECEPTOR
BINDING DOMAIN, SPIKE ELISA OR
NEUTRALIZATION COMPARED TO RNA
BioNTech VACCINE.
THIS IS A LARGER COHORT SHOWING
THE SAME THING, BioNTech
PROVIDING MUCH HIGHER LEVELS OF
NEUTRALIZING ANTIBODY, AND ALSO
OF COURSE GIVEN THE FACT YOU
START AT LOWER LEVEL ANTIBODY
.
SOME COHORTS WERE CONVALESCENTS
PATIENTS INITIALLY, WE LOOKED AT
WANING ANTIBODY NEUTRALIZING
ANTIBODY IN THESE COHORTS.
AND INDEED PUBLISHED SOME OF THE
EARLY DATA SUGGESTING THAT
NEUTRALIZING ANTIBODY IS LONG
LASTED AND NOT SHORT LASTED, AS
WAS BEING REPORTED FROM SOME OF
THE EARLY STUDIES USING
PSEUDOTYPE NEUTRALIZATION, BUT
THEN CRUCIALLY ARE THE TWO
COHORTS, 350 EACH, NOT
RANDOMIZED BUT BASED ON WHAT
INDIVIDUALS DECIDED TO OPT FOR
OF THE TWO VACCINES.
NOW, BECAUSE THEY WERE NOT
RANDOMIZED WE HAD A SUBSET OF 49
FOR EACH VACCINE, WHICH WAS AGE
MATCHED, AND YOU CAN SEE THE
DEMOGRAPHICS OF THAT COHORT SO
I'LL BE USING BOTH THESE.
SO IF YOU TAKE THIS WHOLE COHORT
COHORT
350, YOU HAVE MARKED DIFFERENCE,
ONE MONTH AFTER THE SECOND DOSE.
AND NOW IF YOU USE THE AGE
MATCHED COHORT ESSENTIALLY YOU
HAVE THE SAME RESULTS.
AND THIS IS NEUTRALIZING PRNT 50
AND 90 LEVELS.
AGAIN YOU CAN SEE SUPERIOR
PERFORMANCE OF THE BioNTech
VACCINE.
WHAT DO THESE BLOOD PRODUCTION
NEUTRALIZATION TEACHERS MEAN?
WE USE THE DATA AND STUDIES FROM
DAVENPORT AND OTHERS PUBLISHED
IN 2021 AND SUBSEQUENTLY WHERE
ESSENTIALLY ESTIMATED CORRELATE
OF 50% PROTECTION FROM
REINFECTION OR BREAKTHROUGH
INFECTION WAS 20% OF THE
CONVALESCENTS NEUTRALIZING
ANTIBODY TITER.
WE USED CONVALESCENT SERA AND ON
THAT BASIS 50% PROTECTION THRESH
ROLLED FOR PRNT 50 WAS 1 IN 26,
AND 50% PROTECTION TITER FOR
PRNT90 WAS 1 IN 8.8 OR 1 IN 9.
I WILL USE THOSE AS THRESHOLDS
OF PROTECTION AS WE GO ALONG.
IF I APPLY THAT TO THE DATA THAT
I SHOWED YOU, YOU CAN SEE THAT
BOTH VACCINES DO BY AND LARGE
LEAD TO NEUTRALIZING ANTIBODY
TITERS ABOVE THRESHOLD OF
PROTECTION PRNT 50 LIES HERE.
THE FACT THE VACCINE IS AT LOWER
LEVEL, THIS WOULD FALL BELOW
THESE PROTECTIVE THRESHOLDS ONE
WOULD EXPECT, FALL BELOW THESE
.
THIS IS THE ELISA, THE SPIKE,
SAME DIFFERENCE AND SPIKE, A
MARKED DIFFERENCE BETWEEN THE
TWO VACCINES.
IF YOU LOOK AT THE SPIKE FC
GAMMA RECEPTOR 3A ANTIBODIES,
AGAIN WE STILL SEE THIS
DIFFERENCE, MARKED DIFFERENCE
BETWEEN THE TWO VACCINES.
BUT ON THE OTHER HAND IF YOU
LOOK AT ANTIBODIES BINDING TO
THE N PROTEIN AS ONE WOULD
EXPECT, WE DO NOT HAVE A
RESPONSE WITH THE RNA VACCINE,
WHEREAS YOU DO HAVE A RESPONSE
WITH THE INACTIVATED VACCINE,
WHICH CONTAINS THE WHOLE VIRUS
AND THEREFORE WILL CONTAIN OTHER
PROTEINS OF THE VIRUS AS WELL.
WHEN WE LOOK AT ANTIBODY AVIDITY
WE SEE ADVANTAGE OF THE RNA
VACCINE HERE, FOR THE FC GAMMA
RECEPTOR 3 ANTIBODY HERE.
THE BINDING AS WELL AS THE
AVIDITY DIFFERENCE.
IF YOU LOOK AT THE BINDING TO
THE N PROTEIN, THEN AGAIN WE
HAVE THE CORONAVAC VACCINE
HAVING SOME ANTIBODY, NOT
PRESENT IN THE RNA VACCINE.
BECAUSE THE NEUTRALIZING
ANTIBODY RESPONSES WITH THE
CORONAVAC WAS RELATIVELY POOR,
WE WERE CONCERNED ABOUT HOW WE
CAN BOOST THAT AND WE TOOK A
SUBSET OF THIS COHORT BASICALLY
THOSE THAT HAVE LOWER ANTIBODY
TITERS, AND RANDOMIZED THEM TO
RECEIVE -- 40 TO RECEIVE
CORONAVAC, 40 BioNTech, AGE
MATCHED SUBSET OF THE WEAK
RESPONDERS TO THE CORONACAV, A
BOOSTER WITH THE SAME VACCINE,
OR RNA VACCINE.
OWN THESE WHO RECEIVED
CORONAVAC, IF THEY GET BOOSTER
THIRD DOSE YOU HAVE MARKED
IMPROVEMENT, THIS IS TO THE
ANCESTRAL VIRUS.
THIS IS A DIFFERENT COHORT, NOW
WE HAVE THE THIRD DOSE OF
BioNTech, AGAIN YOU CAN SEE
ANCESTRAL VIRUS, CORONAVAC AND
BOOSTER IS PRETTY CLOSE TO THREE
DOSES OF BioNTech, BUT THREE
DOSES OF CORONAVAC IS LESS.
SAME FOLLOWS WITH OMICRON
VARIANT, THREE DOSES OF
CORONAVAC LEADS TO VERY LITTLE
NEUTRALIZING ANTIBODY.
AND THIS POINT CONCLUSION WAS
THAT BOOSTER OF BioNTech
WITH TWO DOSES OF CORONAVAC WITH
INTRODUCE HIGH NEUTRALIZING
ANTIBODY AND CROSS-REACTION TO
EMERGING VARIANTS SUCH AS
OMICRON.
LOOKING AT FURTHER VARIANTS, YOU
CAN SEE AGAIN THREE DOSES OF
BioNTech DOES PROVIDE
CROSS-NEUTRALIZATION, EVEN TO
THINGS LIKE BA.4 AND BA.5,
CORONAVAC DOES NOT, BUT TWO
DOSES OF CORONAVAC FOLLOWED BY
BioNTech VERY SIMILAR IN
PATTERN, MAYBE SLIGHTLY LOWER
BUT SIMILAR IN PATTERN TO
VARIANTS, TO THREE DOSES OF
BioNTech.
IN REGARDS TO REACTIVITY, IN
RELATION TO THE SARS CoV
VIRUS, YOU HAVE VARIANTS,
OMICRON IN RECEPTOR BINDING
DOMAIN HAS 93% SIMILARITY.
THIS IS THE BAT CORONAVIRUS,
EVEN MORE DISTANT THAN OMICRON,
AND PANGOLIN, MORE DISTANT, AND
WHEN YOU COME TO SARS 1, MORE
DISTANCE TOO COMPARED TO
ANCESTRAL SARS CORONAVIRUS.
NOW, SOMEONE IN THE DUKE
UNIVERSITY IN SINGAPORE HAD
DEVELOPED A MULTIPLEX SURROGATE
NEUTRALIZATION ASSAY, HE HAD THE
RECEPTOR BINDING DOMAIN OF
SARS-COV-2 VARIANTS AND RELATED
TO BOTH SARS 1 AND SARS 2, ALSO
SARS CORONAVIRUS 1.
WHEN WE USED THAT, IF YOU FOCUS
ON THE THREE DOSES OF
BioNTech FOR EXAMPLE HERE,
AND THAT WOULD BE THIS GROUP
HERE, THESE DARK BARS, SO YOU
CAN SEE THERE'S QUITE HIGH
LEVELS OF SURROGATE NEUTRALIZING
ANTIBODY TO THE ANCESTRAL VIRUS
TO VARIANTS, INTERESTINGLY THE
BAT RaTG13 AND PANGOLIN SARS
CoV VIRUS DOES BETTER WITH
THREE DOSES OF BioNTech IS
NOT SO FAR AWAY FROM SOME OF
THESE VARIANTS.
SO INTERESTINGLY, OMICRON IS
EVEN MORE DIVERGENT, ALTHOUGH IN
TERMS OF SIMILARITY IT IS LESS
DIVERGENT THAN THESE BAT AND
PANGOLIN VIRUSES IN TERMS OF
IMMUNE EVASION, IT IS MORE
DIVERGENT.
SUGGESTING REALLY THAT OMICRON
HAS RISEN THROUGH IMMUNE
EVASION.
YEAH, RIGHT.
AND AGAIN YOU CAN SEE THE
CORONAVIRUS, THE CORONAVAC
BOOSTED WITH BioNTech GIVES
SIMILAR RESULTS.
RIGHT.
NOW, HERE THIS IS AGAIN SIMILAR
RESULTS, NOW THIS IS WITH THREE
DOSES OF BioNTech.
TWO DOSES OF BioNTech HERE.
AND THESE ARE PEOPLE WHO HAD
RECOVERED FROM SARS WITH ONE
DOSE OF BioNTech, AND YOU
CAN SEE THAT JUST A SINGLE DOSE
OF BioNTech INCREASES THE
BREADTH OF PROTECTION ACROSS ALL
THE VARIANTS BUT ALSO THESE BAT
AND PANGOLIN PRECURSORS, SOME
CROSS-REACTIVITY WITH SARS
CORONAVIRUS 1 RELATED WITH SARS
CORONAS WELL.
WHEN WE LOOK AT THOSE WHO
RECOVERED FROM SARS 1, AS YOU
REMEMBER SARS 1 HIT HONG KONG IN
2003, WE GOT SOME OF THOSE
SURVIVORS FROM SARS 1 AND, YOU
KNOW, GOT THEIR VACCINES IN DUE
COURSE, AND YOU CAN SEE SARS 1
EXPOSURE FOLLOWED BY TWO DOSES
OF BioNTech GIVES YOU PRETTY
BROAD COVERAGE ACROSS ALL THESE
SARS VIRUSES INCLUDING BAT
PANGOLN, BUT INDEED OMICRON IS
THE ONE WITH THE WEAKEST
RESPONSE.
COMING BACK TO THE SITUATION AT
THE END OF 2021, BECAUSE WE WERE
QUITE FEARFUL WITH THE MODELS OF
OMICRON THAT THIS GOING TO BREAK
THROUGH INTO HONG KONG, ALTHOUGH
FOR TWO YEARS HAD VERY ALSO
INFECTION, THIS SUMMARIZES WHAT
I TOLD YOU IN TERMS OF DIFFERENT
DOSAGE SCHEDULES BUT IN RELATION
TO OMICRON BA.1 AT THIS POINT IN
TIME, YOU CAN SEE THAT THREE
DOSES WOULD BE REQUIRED TO
PROVIDE PROTECTIVE IMMUNITY,
THREE DOSES OF CORONAVAC WOULD
NOT DO THE JOB.
TWO DOSES CORONAVAC WITH ONE
DOSE OF BioNTech IS
ADEQUATE, AND THOSE WHO
RECOVERED FROM SARS CORONAVIRUS
2 INFECTION A SINGLE DOSE WOULD
GIVE GOOD PROTECTIVE
NEUTRALIZING ANTIBODIES, AGAIN
KEEPING IN MIND THIS IS THE
THRESHOLD OF PROTECTION THAT I
TALKED ABOUT, ARISING FROM MILES
DAVENPORT'S STUDIES.
NOW, IN THE DAVENPORT GROUP,
PROTECTIVE THRESHOLD WAS AGAINST
SYMPTOMATIC INFECTION.
THEY DID TRY TO ESTABLISH
PROTECTIVE THRESHOLD FOR SEVERE
DISEASE BUT CONFIDENCE INTERVALS
WITH LOAD, MAYBE AROUND 1 --
WERE LOW, 1 IN 3 OR 1 IN 4, YOU
CANNOT ACCURATELY MEASURE IN
NEUTRALIZING ASSAY.
AT THE END OF 2021, WE WERE
QUITE WORRIED BECAUSE A GOOD
PART OF THE POPULATION HAD BEEN
VACCINATED WITH TWO OR THREE
DOSES OF CORONAVAC, AND EVEN IN
SPITE OF THAT, PARTICULARLY THE
OVER 60 AGE GROUP WAS EXTREMELY
VACCINE HESITANT, AND COVERAGE
OF EITHER VACCINE WAS QUITE LOW,
AND INDEED FEARS WERE QUITE WELL
FOUNDS, WHEN OMICRON HIT WE HAD
HIGH LEVELS, PRIMARILY IN THOSE
WHO RECEIVED NO VACCINE AT ALL.
STUDIES WERE DONE DURING THE
OMICRON BA.2 WAVE.
YOU CAN SEE HERE IN TERMS OF
MILD OR MODERATE DISEASE, TWO
DOSES OF EITHER VACCINE
PROVIDING RELATIVELY MODEST OR
NO PROTECTION, BUT THREE DOSES
OF BioNTech AS WE EXPECTED
FROM NEUTRALIZATION STUDIES WAS
PROVIDING REASONABLE PROTECTION
AGAINST MILD INFECTION, BUT WHAT
WAS SURPRISING WAS THAT
CORONAVAC WAS NOT THAT FAR
BEHIND, ALTHOUGH IF YOU'LL JUST
LOOK AT THE NEUTRALIZING DATA
YOU WOULD EXPECT IT TO BE MILES
BEHIND.
AND MOST HAPPILY, IN TERMS OF
PEOPLE WHO HAD THREE DOSES OF
EITHER VACCINE, EITHER
BioNTech OR CORONACAV, THE
PROTECTION FROM SEVERE OR FATAL
DISEASE WAS EXCELLENT.
SO THAT WAS VERY FORTUNATE.
BUT AS I POINT OUT, THERE'S A
MARKED DISCREPANCY BETWEEN THE
VACCINE EFFECTIVENESS AND THE
NEUTRALIZING ANTIBODY TITERS
THAT WE SEE, THAT WAS ONE
VACCINE EFFECTIVENESS STUDY
WHICH IS RETROSPECTIVE STUDY
BASICALLY BUT THIS IS A
PROSPECTIVE COHORTS OF 8600
INDIVIDUALS CONDUCTING WEEKLY
RAPID ANTIGEN TESTS, A DESIGNED
STUDY FROM OUR SCHOOL OF PUBLIC
HEALTH.
WHAT YOU CAN SEE AGAIN IS THREE
DOSES OF BioNTech AND THREE
DOSES OF CORONAVAC AND THIS IS
AGAINST ANY INFECTION BECAUSE
THIS WOULD DETECT NOT JUST
SYMPTOMATIC INFECTION BUT ANY
INFECTION, BioNTech IS
BETTER THAN CORONAVAC BUT NOT BY
MUCH.
AGAIN IF YOU JUST LOOK AT THE
NEUTRALIZATION DIFFERENCE, YOU
SEE THIS HUGE DIFFERENCE BETWEEN
THE TWO.
SO YOU WOULD EXPECT A MUCH
BIGGER DIFFERENCE IN VACCINE
EFFECTIVENESS.
A THIRD STUDY BASED ON
POPULATION-BASED SEROLOGY
COHORT, AGAIN COMES TO SIMILAR
CONCLUSION.
BOTH VACCINES WERE PROVIDING
THREE DOSES OF EITHER VACCINE
WAS PROVIDING SOME PROTECTION,
AND IN THIS CASE IT IS AGAINST
ANY FORM OF INFECTION AT ALL.
NOT JUST SYMPTOMATIC OR SEVERE
INFECTION.
SO, OF COURSE WE WANTED TO LOOK
AT T CELLS BECAUSE THAT ONE
WOULD EXPECT BROADER
CROSS-REACTIVITY, AND THESE ARE
THE COHORTS THAT WE USE, AND
JUST TO QUICKLY GO THROUGH THAT,
WHAT YOU HAVE HERE IS THAT IN
TERMS OF CD4 RESPONSES, BOTH
VACCINES DO PROVIDE A RESPONSE
TO SPIKE OVERLAPPING PEPTIDES,
THERE'S A CD8 RESPONSE WITH
BioNTech BUT NOT
SIGNIFICANTLY SO WITH CORONAVAC.
AND VERY IMPORTANTLY, THERE WAS
NO MARKED DIFFERENCE BETWEEN THE
T-CELL RESPONSES TO THE WILDTYPE
SPIKE PEPTIDES OR OMICRON SPIKE
PEPTIDES.
AND IF YOU LOOK, ALTHOUGH BOTH
VACCINES WERE PROVIDING FAIRLY
CLEAR T-CELL RESPONSES, TO
OMICRON, THE RNA VACCINE WAS
SIGNIFICANTLY HIGHER.
NOW, SINCE THE INACTIVATED
VACCINE CONTAINS MULTIPLE
PEPTIDES, OR MULTIPLE PROTEINS,
NOT JUST SPIKE, WE ALSO LOOKED
AT THE POOL OF OVERLAPPING
PEPTIDES INCLUDING MMNE AND
ESSENTIALLY RESULTS WERE
ESSENTIALLY THE SAME.
SO, RESPONSES TO CD8, TO BOTH
WILDTYPE AND OMICRON AT QUITE A
SUBSTANTIAL LEVEL.
AND THEN IF YOU FOLLOW THESE
PATIENTS UP, YOU SEE THAT AFTER
TWO DOSES, AND THEN AFTER SOME
MONTHS, THERE'S SOME REDUCTION
IN THE T-CELL RESPONSES, AND A
BOOSTER WILL BRING THIS BACK TO
MORE OR LESS THE SAME LEVELS AS
WAS FOUND AFTER THE TWO DOSES.
IT DOESN'T SEEM TO GO MUCH
HIGHER BUT IT JUST REVERSES THE
WAITING THAT YOU SEE.
AND THIS WAS TRUE FOR CD4 AND
CD8 RESPONSES.
AND BOTH VACCINES INDUCE THE
PARTICULARLY T CELL EFFECTOR
MEMORY.
IF I JUST SUMMARIZE THIS PART OF
IT, IN TERMS OF INUST NEUTRALIG
ANTIBODY, COMPARED TO
INACTIVATED VACCINE, THREE DOSES
OF THE RNA VACCINE ELICITED GOOD
CROSS-NEUTRALIZING ANTIBODY TO
VARIANTS SUCH AS OMICRON, TWO
DOSES OF CORONAVAC WITH RNA
BOOSTER ELICITED A GOOD
NEUTRALIZING ANTIBODY TO
VARIANTS.
HOWEVER, MULTIPLE FIELD STUDIES
SUGGESTED THAT THREE DOSES OF
EITHER VACCINE PROTECTS WELL
FROM SEVERE DISEASE AND NOT
GREATLY -- AND LEAVING ASIDE
SEVERE DISEASE, THE VACCINE
EFFECTIVENESS WAS NOT MARKEDLY
DISSIMILAR EVEN FROM INFECTION.
ALTHOUGH, AGAIN, AT THE
NEUTRALIZING ANTIBODY LEVEL,
THERE WAS A STARK DIFFERENCE
BETWEEN THE TWO VACCINES.
NOW BOTH VACCINES ELICITED
T-CELL RESPONSES TO ANCESTRAL
VIRUS AND TO THE OMICRON BA.1.
BUT CORONAVAC ELICITS ALSO
ANTIBODIES TO N, WHICH MAY
CONTRIBUTE TO PROTECTION, SO WE
NEED TO BETTER UNDERSTAND THE
CORRELATES OF PROTECTION IS FROM
SEVERE DISEASE OR EVEN FROM
INFECTION, ASSOCIATED WITH
INACTIVATED VACCINES, AT LEAST,
BECAUSE IT APPEARS THAT THE
INACTIVATED VACCINES ARE
OPERATING THROUGH PROTECTIVE
MECHANISMS WHICH CANNOT BE
MEASURED COMPLETELY OR CAPTURED
COMPLETELY BY NEUTRALIZING
ANTIBODY.
AS I SAID IN TERMS OF THE BROAD
PROTECTION, IN PRIMED
INDIVIDUALS ELICITS BROAD
NEUTRALIZING ANTIBODY, ANOTHER
RANDOMIZED COHORT, WE HAD PEOPLE
WHO HAD BEEN VACCINATED WITH
CORONAVAC OR BioNTech, FOR
TWO DOSES, THEN RANDOMIZED TO
RECEIVE EITHER THIRD DOSE OF
CORONAVAC OR THIRD DOSE OF
BioNTech.
THOSE WHO HAD BioNTech
RANDOMIZED TO RECEIVE A THIRD
DOSE OF BioNTech OR
CORONAVAC.
BLOOD SAMPLES WERE COLLECTED.
OMICRON WAVE HIT IN BETWEEN
THESE TWO BLOOD COLLECTIONS.
IT SHOWS THE NUMBERS AND
RANDOMIZATION, THEN A SMALLER
SUBSET WHICH WE TOOK FOR MORE
DETAILS STUDY IN TERMS OF BLOOD
NEUTRALIZING ANTIBODY AND T CELL
RESPONSES.
SIDE EFFECTS WERE COMPARISON,
RNA VACCINES SLIGHTLY MORE SIDE
EFFECTS, SUCH AS FEVER, ACHES,
PAINS, CHILLS, AS ONE WOULD
EXPECT.
THIS AGAIN FROM THIS COHORT,
SAME PATTERN OF INACTIVED, THOSE
WHO HAD TWO DOSES OF
BioNTech AND A DOSE OF
CORONACAV, IT DOESN'T SEEM TO BE
THE NUMBER BECAUSE THE CORONAVAC
BOOSTER
AGAIN AS BASED ON THIS ONE WOULD
EXPECT THREE-DOSE CORONACAV AND
TWO DOSE BioNTech WITH
CORONAVAC BOOSTER TO HAVE POOR
VACCINE EFFECTIVENESS.
THIS COHORT WENT THROUGH THE BIG
FIRST REAL BIG WAVE.
IN THAT COHORT 58 SARS
CORONAVIRUS IDENTIFIED WITHIN 4
TO 6 MONTHS OF POST-BOOSTER,
BOTTOM LINE THE VACCINE
EFFECTIVENESS WAS NOT MARKEDLY
DIFFERENT.
SO AGAIN THE SAME STORY, THAT
THE NEUTRALIZING ANTIBODY
RESPONSES DID NOT REALLY PREDICT
OBSERVED VACCINE EFFECTIVENESS.
LOOKING AT THESE ANTIBODIES
MEDIATING, AND ALSO ANTIBODY
AVIDITY AND T CELL RESPONSES IN
THESE COHORTS THESE ARE THE --
THIS IS THE IgB TO ANCESTRAL
AND BA.2 SPOKE, AS EXPECTED.
WE HAVE THE BioNTech BOOSTER
DOING BETTER BUT EVEN THOSE WHO
HAD CORONAVAC DO HAVE SOME
RESPONSE TO OMICRON BA.2
ALTHOUGH AT LOWER LEVEL.
AGAIN, A MUCH MARKEDLY -- WELL,
A SMALLER DIFFERENCE THAN WITH
NEUTRALIZATION.
RIGHT, SO IF YOU LOOK AT THE
ADCC AND ADCP MEDIATING
ANTIBODIES, THESE WERE THE
RESPONSES IN THESE COHORTS TO
BA.2 WHERE BioNTech BOOSED
ONES HAD HIGHEST ANTIBODY
RESPONSES BUT CORONAVAC GROUPS
HAD SOME DETECTABLE RESPONSES
AND WE DON'T KNOW WHAT CORRELATE
OF PROTECTION, IF ANY, THESE
CARRY.
AND THIS IS THE SAME FOR THE FC
RECEPTOR 2A ANTIBODIES.
IN TERMS OF ANTIBODY AVIDITY, IF
YOU LOOK AT ANTIBODY AVIDITY,
AGAIN IT FOLLOWS THAT THE
BioNTech BOOSTER GROUP HAVE
HIGHER ANTIBODY AVIDITY THAN
CORONAVIRUS BOOSTED GROUP
CERTAINLY TO OMICRON.
SINCE ACTIVATED FOLLICULAR T
HELPER CELLS HELP B CELLS TO
FORM TERMINAL CENTERS AND
DRIVE -- BELIEVED TO DRIVE
AVIDITY ANTIBODY RESPONSES WHAT
YOU SEE HERE IS THE TFH
RESPONSES TO THE THREE VACCINES,
THIS IS NOT ANTIGEN SPECIFIC
RESPONSES BUT OVERALL RESPONSES
IN 7th DAY AFTER THE VACCINE,
CAN YOU SEE CC-B GROUP HAS A
VERY GOOD RESPONSE HERE AND BB-B
GROUP HAS ALSO A REASONABLE
RESPONSE.
OVERALL IT SEEMS THAT THE
ANTIBODY AVIDITY DOES CORRELATE
WITH THIS TFH CELL RESPONSE THAT
WE OBSERVED.
THE N ANTIBODY BINDING IS SEEN
HERE AS I SAID, IT'S ONLY THOSE
WHO HAD CORONACAV AND BOOSTED BY
CORONAVAC, INACTIVATED VACCINE
BOOSTER WHO HAVE DETECTABLE
ANTIBODY TITERS TO BINDING
ASSAYS IN AVIDITY SAYS IN ADCC
AND ADCP ANTIBODY ASSAYS AS
WELL.
NOW, IN ANTIBODIES, OF COURSE
ARE NOT -- N ANTIBODIES ARE NOT
THOUGHT ABOUT MUCH IN TERMS OF
PROTECTIVE -- CONFERRING ANY
PROTECTION, BUT THERE WAS THIS
PAPER LAST YEAR WHERE THEY DID
LOOK AT PASSIVE TRANSFER OF N
ANTIBODIES, THIS IS IN A MOUSE
STUDY, AND SHOWED THAT PASSIVE
TRANSFER IN THE MOUSE MODEL DID
LEAD TO REDUCTION IN VIRUS RNA
COPIES IN THE LUNG, AND THEN
THIS IS WITH POLYCLONAL
TRANSFER, AND IF YOU DO THE SAME
PASSIVE TRANSFER USING A
MONOCLONAL ANTIBODY TO N, AGAIN
THEY CAN DEMONSTRATE QUITE
MARKED PROTECTIVE EFFECTS, AND
THEY POSTULATE AND HAVE SHOWN
THAT N PROTEIN IS PRESENT ON THE
CELL -- INFECTED CELL SURFACE
AND CAN MEDIATE ADCC SO ONE CAN
WONDER WHETHER AT LEAST SOME OF
THIS DISCREPANCY BETWEEN THE
INACTIVATED VACCINES AND RNA
VACCINES MAY BE MEDIATED BY N.
T-CELL RESPONSES WERE COMPARABLE
ACROSS THE GROUPS.
THOSE THAT HAD THE BioNTech
BASICALLY HAD MORE T-CELL
RESPONSES TO THE SPIKE PROTEIN,
AND THOSE WHO HAD CC-C,
INACTIVATED VACCINE, HAD MORE
BIAS TOWARDS THE OTHER PEPTIDES
OF THE VIRUS AS ONE WOULD
EXPECT.
IF YOU LOOK AT T CELL QUALITY,
ASSESSED BY POLY FUNCTIONALITY,
IN TERMS OF MULTIPLE CYTOKINE 2,
SHOWN HERE IN THE PEPTIDE POOLS,
YOU CAN SEE THIS INACTIVATED
VACCINE GROUP DOES SEEM TO HAVE
A TREND TO HAVE STRONGER
POLYFUNCTIONAL T-CELL RESPONSE.
SO, JUST TO CONCLUDE THAT
PARTICULAR STUDY, ESSENTIALLY
WHAT WE SEE WAS THAT LOOKING AT
THE FOUR ARMS OF THE RESPONSE,
IN TERMS OF SPIKE IgG,
NEUTRALIZATION, AND AVIDITY,
C.C.-C AND CC-B HAVE THE
RESPONSES.
IN TERMS OF T CELLS, THEY ARE
MORE OR LESS COMPARABLE ACROSS
THE GROUPS.
IN TERMS OF THE POLYFUNCTIONAL
RESPONSES IT IS BEST IN --
CERTAINLY IN TERMS OF THE
MULTIPLE PEPTIDES, IT IS BETTER
IN THE CORONAVAC GROUP.
TO SUMMARIZE ESSENTIALLY LASTING
AND QUALITY T CELLS AGAINST THE
SPIKE AND NEM, AND ANTIBODY
RESPONSES IN CORONAVAC PRIMED
DONORS MAY BE IMPORTANT SO I
THINK WE DO NEED A BETTER
UNDERSTANDING OF THE CORRELATES
OF PROTECTION OF INACTIVATED
VACCINES BECAUSE THE
NEUTRALIZING DATA CERTAINLY DOES
NOT RECORD WITH WHAT WE OBSERVED
IN VACCINE EFFECTIVENESS
STUDIES.
AS I MENTIONED, PRIMING WITH
SARS CORONAVIRUS 1 LEADS TO
BROAD CROSS-PROTECTION, THIS MAY
BE RELEVANT TO BROADLY
CROSS-PROTECTIVE VACCINES.
I WILL END.
I'VE GIVEN MY ACKNOWLEDGMENTS.
AND I'LL BE HAPPY TO TAKE ANY
QUESTIONS.
THANK YOU.
>> THANK YOU, MALIK, FOR THIS
LOVELY TALK.
WE HAVE A FEW QUESTIONS.
HOW DOES THIS DATA WITH THE
CORONAVAC COMPARE TO ASTRAZENECA
VACCINE OR NOVAVAX?
>> RIGHT.
SO I CANNOT REALLY COMMENT ON
THAT BECAUSE WE REALLY DIDN'T
USE ANY OF THOSE VACCINES IN
HONG KONG.
WE DON'T HAVE DATA OURSELVES.
WE HAVE SOME RETURNING TRAVELERS
VACCINATED WITH THESE BUT NOT
ENOUGH FOR STUDIES, WE CAN'T
COMMENT ON ADENOVIRUS OR PROTEIN
VACCINES.
>> OKAY.
AND SO LET'S SEE.
QUITE A FEW QUESTIONS.
>> SO I THINK JUST ONE THING
REGARDING THE ADENOVIRUS VECTOR
VACCINES OR ASTRAZENECA, ONE
POINT, AT A RECENT MEETING ON
THIS, IT WAS POINTED OUT THAT IN
THE U.K. AS YOU REMEMBER THEY
GAVE SINGLE DOSE AND THEY DID
NOT GIVE THE SECOND DOSE BECAUSE
OF INITIAL SHORTAGE OF VACCINE
SUPPLY.
BUT AS SHE POINTED OUT, THAT
SINGLE DOSE DID SEEM TO CONFER
SOMETHING LIKE 70% VACCINE
EFFECTIVENESS OVER THE PERIOD OF
ABOUT FOUR OR FIVE MONTHS, AS
SHE SAYS, THIS WAS IN THE
ABSENCE IN THAT VACCINE IN THE
ABSENCE OF ANY DETECTABLE OR
SIGNIFICANT NEUTRALIZING
ANTIBODY RESPONSES.
THERE ARE SOME DISCREPANCIES IN
HOW VACCINES PROTECT.
>> SINCE AGING CAN PLAY A ROLE
IN ANTIBODY AVIDITY DO YOU SEE
DIFFERENCES IN ANTIBODY AVIDITY
BETWEEN DIFFERENT AGE GROUPS,
BETWEEN THE INACTIVATED
CORONAVAC VAC AND mRNA
VACCINE?
>> YEAH, SO I MEAN WE DON'T HAVE
ENOUGH NUMBERS THAT WE'VE DONE
AVIDITY STUDIES ON, TO
CONFIDENTLY SHOW AGE-RELATED
EFFECTS, BUT I DO TAKE YOUR
POINT ABOUT THE ROLE OF AGING IN
THESE ANTIBODY RESPONSES.
YEAH, UH-HUH.
>> SURRENDER HAS A QUESTION.
ANY AGE DIFFERENCES ALSO FOR
ADCC OR ADCP ACTIVITY BETWEEN
mRNA VERSUS INACTIVATED
VACCINES?
>> YEAH, SO WE HAVE THE SAME
PROBLEM IN THE NUMBERS THAT WE
USE.
WE USED AGE-MATCHED GROUPS BUT
THE NUMBERS WERE NOT SUFFICIENT
FOR US TO LOOK AT THE IMPACT OF
AGE ON THE RESPONSES PER SE.
>> GENERAL QUESTION, SO GIVEN
WHAT YOU'VE SHOWN US TODAY, IT
SOUNDS LIKE T-CELL RESPONSES ARE
A BETTER GAUGE OF LONG-TERM
PROTECTION THAN NEUTRALIZING
TITERS.
IS THAT HOW YOU WOULD SORT OF
FRAME IT BASED ON WHAT YOU'VE
LEARNED?
>> WELL, I WOULD SAY THAT AT
LEAST FOR THE INACTIVATED
VACCINES, I DON'T THINK
NEUTRALIZING ANTIBODY IS TELLING
US THE WHOLE STORY.
NOW, THAT MAY ALSO BE TRUE FOR
THE OTHER VACCINES, BUT TO A
LESSER EXTENT.
I MEAN, IN OTHER STUDIES DONE BY
A NUMBER OF STUDIES, I MEAN,
ONES DONE BY THE AUSTRALIAN
GROUP, MILES DAVENPORT AND
OTHERS, THEY FOUND CLEAR
CORRELATION IN PUBLISHED
CLINICAL TRIALS, CLEAR
CORRELATION BETWEEN NEUTRALIZING
TITERS AND PROTECTION.
THAT SEEMED TO BE A GOOD
CORRELATE OF PROTECTION AND
THAT'S HOW THEY CAME UP WITH
THESE THRESHOLDS.
AND THIS WAS ALSO TRUE FOR
VARIANTS, WHICH THEY DID LATER.
BUT LIKE I SAY, I MEAN, I
WOULDN'T COMPLETELY DISMISS IS
NEUTRALIZING ANTIBODY FOR RNA
VACCINES, FOR THE ADENOVIRUS
VECTORED VACCINE, CORRELATIVE
EVIDENCE THERE, BUT WHAT I'M
BEGINNING TO THINK AND WHAT MY
COLLEAGUES ARE BEGINNING TO
THINK IS THAT CERTAINLY FOR
INACTIVATED VACCINES THAT IS NOT
THE ONLY PART OF THE STORY.
SO I THINK, YEAH, WE HAVE TO
LOOK WIDER THAN THAT.
>> WHAT IS YOUR VIEW ON
PERSISTENT RESERVOIRS OF THE
VIRUS BEING PRESENT IN THESE
INDIVIDUALS THAT HAVE BEEN --
THAT COULD BE BOOSTING THE
IMMUNE RESPONSE OVER TIME?
>> WE DON'T REALLY SEE A BOOST
OF IMMUNE RESPONSE OVER TIME, IN
THE ABSENCE OF REPEATED
INFECTION, BECAUSE IN THOSE THAT
WE HAVE FOLLOWED, YOU KNOW, WHAT
WE DO SEE IS WANING ANTIBODY.
OF COURSE THERE MAY BE SOME
INDIVIDUALS WHERE THERE'S VIRUS
PERSISTENCE AND BOOSTING, AFTER
BREAK THROUGH INFECTIONS?
>> AFTER BREAKTHROUGH
INFECTION, YEAH.
>> I KNOW THE DATA ON
PERSISTENCE IN THE
GASTROINTESTINAL TRACT AND
THINGS LIKE THAT, OF COURSE THE
WHOLE STORY ABOUT LONG COVID AND
PROLONGED COMPLICATIONS OF
COVID.
AND BUT I MEAN ESSENTIALLY, WHAT
WE DO SEE IS WANING ANTIBODY,
BUT LIKE I SAY, I CAN'T EXPLORE
THE POSSIBILITY THAT SOME MINOR
SUBPOPULATION DOES HAVE, YOU
KNOW, A BOOST FROM PERSISTENT
VIRUS ACTIVITY.
>> RIGHT.
THERE'S A QUESTION REGARDING
THE -- BASED ON EMERGENTS OF NEW
VARIANTS, WHAT IS THE STRAIN
COMPOSITION FOR VACCINES IN
CONGRESS -- HONG KONG, FOR FAL,
DO YOU HAVE THOUGHTS?
>> PFIZER/BIONTECH, WE SWITCHED
TO BIVALENT WITH ANCESTRAL AND
BA.5, USED CURRENTLY, BUT IF
THERE IS AN UPDATED VACCINE THAT
BECOMES AVAILABLE, CLEARLY HONG
KONG WOULD CONSIDER USING THAT
AS WELL.
NOW, THE INACTIVATED VACCINES
ALSO HAVE -- ARE COMING UP WITH
OMICRON-BASED INACTIVATED
VACCINE BUT I HAVEN'T REALLY
SEEN ANY CLINICAL DATA ON THAT,
SO THAT'S SOMETHING THAT WE
MIGHT ALSO NEED TO CONSIDER.
AND THEN THE OTHER THING ON THE
HORIZON OF COURSE AT LEAST IN
THIS PART OF THE WORLD IS THIS
INTRANASAL VACCINE COMING FROM
MAINLAND CHINA, WHICH IS ADENO5
VECTORED VACCINE GIVEN
INTRANASALLY, ON THE BASIS OF
EARLY CLINICAL TRIALS RESULTS
THAT THEY ARE SHOWING SEEMS
QUITE PROMISING, SEARCH IN TERMS
OF IMMUNOGENICITY, I DON'T THINK
THERE IS GOOD VACCINE
EFFECTIVENESS DATA YET SO THAT'S
ANOTHER THING THAT CERTAINLY WE
WOULD CONSIDER.
>> ANY THOUGHTS ON TRANSMISSION
BLOCKING?
>> CLEARLY THERE'S NO EVIDENCE
OF IT.
IT'S VERY CHALLENGING TO LOOK AT
TRANSMISSION BLOCKING, BUT,
YEAH, CLEARLY THAT WOULD BE --
YEAH, THAT WOULD BE THE MAJOR
INTEREST IN SUCH A VACCINE
BECAUSE ON THE IMMUNOGENICITY
STUDIES INDUCING GOOD INTRANASAL
IMMUNITY BUT ALSO QUITE
SURPRISINGLY QUITE GOOD SYSTEMIC
ANTIBODY RESPONSES AS WELL,
WHICH IS SURPRISING FOR ME
ANYWAY.
>> THANK YOU SO MUCH FOR YOUR
TALK.
AND THIS ENDS TODAY'S SEMINAR.
>> THANK YOU.