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00:00:05,320 --> 00:00:08,760
WE'LL BEGIN WITH GENERAL
ANNOUNCEMENTS

2
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WE USUALLY MAKE, AND WHEN THE

3
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COUNCIL MEMBERS ARE ABLE TO JOIN

4
00:00:12,680 --> 00:00:14,880
WE'LL GO AHEAD WITH THE

5
00:00:14,880 --> 00:00:17,160
PRESENTATION FROM TIM.

6
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WE'RE VERY FORTUNATE TODAY TO

7
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HAVE AN OPEN SESSION COUNCIL ON

8
00:00:24,120 --> 00:00:28,000
SOME OF THE T CELL EPITOPE WORK

9
00:00:28,000 --> 00:00:32,280
GOING ON AND B CELL WORK AS

10
00:00:32,280 --> 00:00:32,480
WELL.

11
00:00:32,480 --> 00:00:34,000
TIM GANDRAY LEWIS IS GOING TO

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INTRODUCE OUR SPEAKERS FOR THAT

13
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PART OF THE OPEN SESSION AGENDA.

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WE'RE ON A TIGHT TIME SCHEDULE

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BECAUSE ONE OF THE SPEAKERS IN

16
00:00:46,080 --> 00:00:47,840
THE SESSION THIS AFTERNOON HAS A

17
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COMMITMENT AT 1:30 THAT WE WILL

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ADJUST OUR SCHEDULE TO

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00:00:57,240 --> 00:00:58,440
ACCOMMODATE HIM.

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THE MAIN THINGS I NEED TO

21
00:01:01,760 --> 00:01:05,720
ANNOUNCE RIGHT NOW ARE THAT

22
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COUNCIL MEMBERS SHOULD REMAIN ON

23
00:01:06,880 --> 00:01:12,240
SCREEN WITH YOUR CAMERA ON, IF

24
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YOU SPEAK, AND ANYBODY WHO USES

25
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THE CHAT SHOULD ONLY BE FOR KIND

26
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OF INCIDENTAL COMMENTS.

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WE REALLY DO NEED ALL THE

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COMMENTS YOU MAKE TO BE ON

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SCREEN AND VERBAL.

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AND WE HAVE A FEW SBIR CONTRACT

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INITIATIVES THAT WE WILL NOT BE

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PRESENTING THIS AFTERNOON, AS

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IT'S OUR CUSTOM NOT TO PRESENT

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THOSE SBIR TOPICS BUT I NEED TO

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MENTION THEM.

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ONE IS A PROGRAM FOR REAGENTS OF

37
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NON-MA'AM MALLIAN AND

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UNDERREPRESENTED MAMMALIAN

39
00:02:08,480 --> 00:02:10,040
MODELS, AND DISEASES AGAINST

40
00:02:10,040 --> 00:02:11,720
INFECTIOUS AND IMMUNE IMMEDIATE

41
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INDICATED DISEASES, THIRD FOR

42
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ADJUVANT DEVELOPMENT FOR THE

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SAME TOPICS.

44
00:02:15,080 --> 00:02:17,400
SO THAT SHOULD COVER IT UNLESS

45
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THERE ARE SPECIFIC QUESTIONS

46
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LATER ON IN THE SESSION WHEN WE

47
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HAVE MORE TIME.

48
00:02:24,040 --> 00:02:26,240
WE CAN PERHAPS COVER THOSE.

49
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WE'LL ALSO BE PUTTING IN THAT

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PART OF THE REVIEW FOR COUNCIL

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MEMBERS, TWO TOPICS FROM OUR POD

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SET OFFICE, OFFICE FOR

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BIOINFORMATICS AND TECHNOLOGY

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DEVELOPMENT.

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ONE OF THOSE IS SOFTWARE FOR WEB

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SERVICES, TO AUTOMATE METADATA

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ENRICHMENT, AND STANDARDIZATION

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FOR DATA ON INFECTIOUS DISEASES

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AND IMMUNITY TO DISEASES.

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AND THE SECOND TOPIC IS SOFTWARE

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OR WEB SERVICES TO REREPRESENT

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EXISTING SCIENTIFIC KNOWLEDGE

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INTO A KNOWLEDGE CRAFT FORMAT.

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WITH THOSE ANNOUNCEMENTS, I'M

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GOING TO ASK TIM GANDRAY LEWIS

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TO GO AHEAD WITH A BRIEF

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AFTERNOON FOR THE AFTERNOON

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SESSION AND OUR SPEAKERS.

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TIM?

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00:03:26,240 --> 00:03:27,280
>>THANKS, DAN.

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00:03:27,280 --> 00:03:28,680
GOOD AFTERNOON, EVERYONE.

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I'M GOING TO INTRODUCE THE

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SESSION, AGAIN AS DAN SAID, I'LL

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TRY TO KEEP IT VERY BRIEF.

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MOST OF YOU KNOW THE STRUCTURE

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OF OUR EPITOPE DISCOVERY

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00:03:39,000 --> 00:03:42,320
PROMISE, B CELL EPITOPE DISCOVER

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AND MECHANISMS, OF ANTIBODY

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PROTECTION PROGRAM, LARGE SCALE

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00:03:45,120 --> 00:03:50,360
T CELL IMMUNE UP HOPE DISCOVERY

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00:03:50,360 --> 00:03:52,480
PROGRAM, BOTH FEED IN TO OUR

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00:03:52,480 --> 00:03:53,800
DATABASE AND ANALYSIS RESOURCE,

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00:03:53,800 --> 00:03:59,040
DO AN EXPERT JOB OF CURATION OF

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00:03:59,040 --> 00:04:01,040
EPITOPES FROM THE LITERATURE.

85
00:04:01,040 --> 00:04:04,640
PROGRAM OBJECTIVES ARE TO

86
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CHARACTERIZE IMMUNITY TO

87
00:04:05,640 --> 00:04:08,160
INFECTIOUS AGENTS AND VACCINES,

88
00:04:08,160 --> 00:04:11,560
AND IMMUNE MEDIATED DISEASES,

89
00:04:11,560 --> 00:04:12,080
PRODUCTS FROM DISCOVERS,

90
00:04:12,080 --> 00:04:14,400
PEPTIDES, CAN BE USED TO MAKE

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00:04:14,400 --> 00:04:16,800
REAGENTS SUCH AS TETRIMERS TO

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00:04:16,800 --> 00:04:17,800
MONITOR PROTECTIVE IMMUNITY.

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00:04:17,800 --> 00:04:19,960
WE'VE BEEN VERY FORTUNATE WITH

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00:04:19,960 --> 00:04:24,040
THIS PROGRAM THAT WE'VE BEEN

95
00:04:24,040 --> 00:04:26,440
ABLE TO ADAPT TO EMERGING

96
00:04:26,440 --> 00:04:29,720
INFECTIOUS DISEASES SUCH AS

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00:04:29,720 --> 00:04:33,880
SARS-COV-2, AND UTILIZE THIS

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00:04:33,880 --> 00:04:37,720
PROGRAM TO IDENTIFY PEPTIDES AND

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PROTECTIVE IMMUNE MECHANISMS FOR

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00:04:39,880 --> 00:04:40,480
SARS-COV-2.

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00:04:40,480 --> 00:04:50,920
AND ALSO DEVELOPMENT OF

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00:04:52,040 --> 00:04:52,840
THERAPEUTIC MONOCLONALS FOR

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00:04:52,840 --> 00:04:53,120
THERAPIES.

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00:04:53,120 --> 00:04:55,000
OVER HISTORY THE PROGRAM HAS

105
00:04:55,000 --> 00:04:58,400
BEEN VERY ADAPTABLE IN

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00:04:58,400 --> 00:05:01,600
ADDRESSING EMERGING PATHOGENS

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SUCH AS MULTIDRUG-RESISTANT

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TUBERCULOSIS, WEST NILE, ZIKA

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VIRUS, AND MOST RECENTLY

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SARS-COV-2.

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IT'S AN INCREDIBLY PRODUCTIVE

112
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PROGRAM.

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WE'VE HAD, YOU KNOW, OVER 140

114
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PUBLICATIONS FROM THE TWO T CELL

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AND B CELL PROGRAMS OVER THE

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PAST -- REALLY THIS IS JUST

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THREE YEARS THAT IT'S BEEN GOING

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ON IN THIS RENEWAL SO THIS IS

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JUST FOR THE LAST THREE YEARS,

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AND CLOSE TO 3300 EPITOPE

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RECORDS HAVE BEEN DEPOSITED. 

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ONE OF OUR CONTRACTORS YOU'LL

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HEAR FROM LATER TODAY DR.

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SETTAY, MADE MEGA POOLS OF

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PEPTIDES FROM SARS-COV-2

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AVAILABLE TO RESEARCH COMMUNITY

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AND OVER 200 INDEPENDENT

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INVESTIGATIVE TEAMS, 32

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COUNTRIES, HAVE ACTUALLY

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UTILIZED THOSE.

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ANOTHER PROJECT IS A LICENSED

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MONOCLONAL TO ASTRAZENECA, UNDER

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EXTENDED USE AUTHORIZATION FOR

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SARS-COV-2, AND IMMUNE EPITOPE

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DATABASE HAS BEEN DOING

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TREMENDOUS WORK INCLUDING

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META-ANALYSES AND SARS-COV-2 TO

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REALLY UNDERSTAND THE ROLE IN

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PEDIATRIC MYOCARDITIS.

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AND SO WITH THAT, I AM GOING TO

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BRING IN OUR SPEAKERS, OUR FIRST

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SPEAKER TODAY IS DR. JAMES CLOW

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JR., DIRECTOR OF VANDERBILT

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VACCINE CENTER.

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HE'S PROFESSOR OF PEDIATRICS AND

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PATHOLOGY, MICROBIOLOGY AND

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IMMUNOLOGY AT VANDERBILT, HOLDS

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THE ANN SCOTT HAROLD CHAIR AT

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VANDERBILT.

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I WILL TURN IT OVER TO DR.

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CROWE.

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JIM?

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>>OKAY.

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THANK YOU FOR HAVING ME.

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IT'S GREAT TO BE WITH YOU.

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I'M FLYING TO D.C. TODAY, I'M

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GOING TO BE AT THE ZIKA MEETING

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IN THE MORNING.

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I'M ALL ABOUT NIH THIS WEEK.

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IF I CAN SHARE MY SCREEN.

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YOU'VE GOT MY SLIDES AND I'M ON

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AUDIO I GUESS.

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>>LOOKS GREAT.

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>>THANK YOU.

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YOU KNOW, AS TIM SAID, I'VE BEEN

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INVOLVED IN THIS PROGRAM SINCE I

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THINK I WAS ON THE ADVISORY

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THING BEFORE IT HAPPENED AND

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THROUGH EVERY, ITERATION.

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WE WENT INTO IT, EVERYONE

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THOUGHT, OKAY, WE'RE GOING TO

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GET LIST, DATABASES OF EPITOPES,

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THAT COULD BE SLIGHTLY BORING,

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BUT I WANT TO CHANGE YOUR MIND

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ABOUT WHAT EPITOPE MAPPING IS OR

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EPITOPE DISCOVERY IS AND THINK

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MORE ABOUT THE DISCOVERY OF

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MECHANISMS AND SITES OF

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VULNERABILITY, CORRELATES OF

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PROTECTION, ALL THAT'S COME OUT

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OF THESE CENTERS AND WE'VE HAD A

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B CELL MAPPING ON AND OFF FOR

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QUITE A WHILE.

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I'M GOING TO IMPRESS ON YOU THE

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IMPACT OF MAPPING STUDIES.

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I THINK WHEN YOU HEAR THAT YOU

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MIGHT THINK, OH, THIS MIGHT BE

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BORING.

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BUT IT'S NOT.

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IT'S ACTUALLY BEEN THE CRUX OF

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THE FIELD, I BELIEVE.

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SO, ONE OF THE THINGS ABOUT B

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CELL EPITOPE MAPPING OR ANTIBODY

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MAPPING, I THINK, IS THAT WE

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WERE AT A TIPPING POINT IN

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HISTORY WHERE ANTIBODIES ARE

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GOING TO START BEING ONE OF THE

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PRINCIPAL TOOLS WE USE IN

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EMERGING INFECTION MANAGEMENT.

200
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IN FACT, MAYBE IN ALL INFECTIOUS

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DISEASES, AND IT'S ODD THEY

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HAVEN'T BEEN BECAUSE YOU'LL

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00:08:44,400 --> 00:08:47,040
REMEMBER THE FIRST NOBEL PRIZE

204
00:08:47,040 --> 00:08:49,000
WAS GIVEN FOR ANTI-TOXINS, SO

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ANTIBODIES WERE DISCOVERED IN

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THE CONTEXT OF INFECTIOUS

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DISEASES, POLYCLONAL IMMUNE

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00:08:56,200 --> 00:08:57,880
GLOBULINS USED SINCE THE

209
00:08:57,880 --> 00:08:59,000
1880s, STARTING WITH RABIES

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AND TETANUS AND SO ON.

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BUT WHY DID CANCER INSTITUTE AND

212
00:09:06,200 --> 00:09:07,160
AUTOIMMUNITY COMMUNITIES, YOU

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00:09:07,160 --> 00:09:17,120
KNOW, THEY HAVE OVER 100

214
00:09:17,120 --> 00:09:17,920
LICENSED MONOCLONALS, ALL OF A

215
00:09:17,920 --> 00:09:22,720
SUNDAY YOU'LL SEE A -- SUDDEN

216
00:09:22,720 --> 00:09:24,040
YOU'LL SEE THEM COME INTO THE

217
00:09:24,040 --> 00:09:24,520
FACE.

218
00:09:24,520 --> 00:09:26,560
YOU ALREADY HAVE.

219
00:09:26,560 --> 00:09:28,520
THEY ACTUALLY COVER MULTIPLE

220
00:09:28,520 --> 00:09:29,600
DRUG CLASSES, SO ANTIBODIES, NOW

221
00:09:29,600 --> 00:09:33,760
WE KNOW, CAN BE USED FOR

222
00:09:33,760 --> 00:09:34,840
PREVENTION SO THE PRODUCT TIM

223
00:09:34,840 --> 00:09:36,840
MENTIONED CAME OUT OF OUR

224
00:09:36,840 --> 00:09:39,640
LABORATORY OUT OF OUR PROGRAM,

225
00:09:39,640 --> 00:09:42,280
CONVERTED BY ASTRAZENECA TO

226
00:09:42,280 --> 00:09:44,400
LONG-ACTING ANTIBODIES SO THE FC

227
00:09:44,400 --> 00:09:46,240
WAS MODIFIED, OVER A 90 DAY

228
00:09:46,240 --> 00:09:48,160
HALF-LIFE.

229
00:09:48,160 --> 00:09:51,600
WITH PROPER POTENCY IN FACT

230
00:09:51,600 --> 00:09:52,200
THESE ANTIBODIES OUTPERFORMED

231
00:09:52,200 --> 00:09:53,720
mRNA VACCINES IN TERMS OF

232
00:09:53,720 --> 00:09:54,640
EFFICACY AND DURABILITY, WHICH

233
00:09:54,640 --> 00:09:55,880
IS AMAZING.

234
00:09:55,880 --> 00:09:57,400
THEY ARE BETTER VACCINES THAN

235
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VACCINES.

236
00:09:57,760 --> 00:10:00,000
I KNOW YOU DON'T LIKE ME SAYING

237
00:10:00,000 --> 00:10:01,240
THAT, BUT IT'S THE TRUTH, IF YOU

238
00:10:01,240 --> 00:10:02,560
LOOK AT THE DATA.

239
00:10:02,560 --> 00:10:06,040
I THINK WE NEED TO GRAPPLE WITH

240
00:10:06,040 --> 00:10:07,680
THAT BECAUSE IN THE FUTURE

241
00:10:07,680 --> 00:10:09,440
ANTIBODIES FOR SMALL OUTBREAKS

242
00:10:09,440 --> 00:10:11,200
WILL BE QUICKER, BETTER, FASTER,

243
00:10:11,200 --> 00:10:13,240
THEY ALSO ARE -- YOU CAN USE

244
00:10:13,240 --> 00:10:15,120
THEM IN BABIES AND

245
00:10:15,120 --> 00:10:16,480
WASHINGTON-YEAR-OLD PEOPLE, STEM

246
00:10:16,480 --> 00:10:18,080
CELL TRANSPLANTS, MUCH MORE

247
00:10:18,080 --> 00:10:19,440
VERSATILE THAN VACCINES IN

248
00:10:19,440 --> 00:10:20,920
CERTAIN SITUATIONS AND THEY CAN

249
00:10:20,920 --> 00:10:23,320
BE MORE DURABLE AND EFFECTIVE.

250
00:10:23,320 --> 00:10:24,320
WE SAW THAT WITH COVID.

251
00:10:24,320 --> 00:10:28,240
YOU CAN USE THEM IN

252
00:10:28,240 --> 00:10:29,000
POST-EXPOSURE PROPHYLAXIS.

253
00:10:29,000 --> 00:10:30,120
WHICH MOST VACCINES DON'T WORK

254
00:10:30,120 --> 00:10:30,880
WELL.

255
00:10:30,880 --> 00:10:33,520
WE DO USE IT IN PERINATAL HEP B

256
00:10:33,520 --> 00:10:35,800
AND RABIES, PART OF THE REGIMEN,

257
00:10:35,800 --> 00:10:37,000
BUT ANTIBODIES REALLY CLEARLY

258
00:10:37,000 --> 00:10:39,960
CAN BE USED IN POST EXPOSURE

259
00:10:39,960 --> 00:10:40,840
PROPHYLAXIS, THAT'S BEEN SHOWN

260
00:10:40,840 --> 00:10:41,840
CLEARLY IN COVID.

261
00:10:41,840 --> 00:10:43,360
YOU CAN USE IT AS A TREATMENT

262
00:10:43,360 --> 00:10:48,600
LIKE YOU WOULD USE AN ANTI-VIRAL

263
00:10:48,600 --> 00:10:50,040
SMALL MOLECULE DRUG BUT THEY

264
00:10:50,040 --> 00:10:51,120
WILL WORK BETTER THAN DRUGS, AND

265
00:10:51,120 --> 00:10:54,400
YOU CAN TAKE THEM INTO THE

266
00:10:54,400 --> 00:10:58,680
HOSPITAL OR ONTO VENTILATED

267
00:10:58,680 --> 00:10:59,000
PATIENTS.

268
00:10:59,000 --> 00:11:01,400
EVUSHELL LONG ACTING DRUG WAS

269
00:11:01,400 --> 00:11:04,160
LOOKED AS IN ACTIV TRIAL

270
00:11:04,160 --> 00:11:06,360
SPONSORED BY NIH, CAUSED 30%

271
00:11:06,360 --> 00:11:11,280
REDUCTION IN MORTALITY AND

272
00:11:11,280 --> 00:11:11,760
HOSPITALIZED PATIENTS.

273
00:11:11,760 --> 00:11:16,120
SAME DRUG AS VACCINE WORKS AS

274
00:11:16,120 --> 00:11:16,880
ANTI-VIRAL THERAPIES, PRETTY

275
00:11:16,880 --> 00:11:17,520
IMPRESSIVE.

276
00:11:17,520 --> 00:11:19,960
I CAME UP WITH A GOOD PROFILE

277
00:11:19,960 --> 00:11:22,280
FOR VACCINE OR PREVENTION ON TOP

278
00:11:22,280 --> 00:11:24,000
IN BLUE AND TARGET PRODUCT

279
00:11:24,000 --> 00:11:26,760
PROFILE FOR TREATMENT LIKE A

280
00:11:26,760 --> 00:11:27,880
SMALL MOLECULE DRUG OR SOMETHING

281
00:11:27,880 --> 00:11:28,600
FOR COVID.

282
00:11:28,600 --> 00:11:30,120
I DON'T HAVE TIME TO TRICK YOU

283
00:11:30,120 --> 00:11:30,560
HERE.

284
00:11:30,560 --> 00:11:33,560
THESE ARE THE ACTUAL RESULTS OF

285
00:11:33,560 --> 00:11:35,280
THE PHASE 2 PHASE 3 PREVENTION

286
00:11:35,280 --> 00:11:37,720
TRIAL THAT MANY OF YOU KNOW OF

287
00:11:37,720 --> 00:11:40,640
AND WERE PART OF, AND BOTTOM IS

288
00:11:40,640 --> 00:11:42,200
THE TACKLE PHASE 3 RESULTS FROM

289
00:11:42,200 --> 00:11:43,680
SORT OF TREATMENT SCENARIO.

290
00:11:43,680 --> 00:11:45,120
AGAIN, IT'S THE SAME COMBINATION

291
00:11:45,120 --> 00:11:46,000
OF TWO ANTIBODIES.

292
00:11:46,000 --> 00:11:48,280
I'M GOING TO TELL YOU MORE ABOUT

293
00:11:48,280 --> 00:11:48,640
THEM.

294
00:11:48,640 --> 00:11:52,160
AT SIX MONTHS YOU GET AN 83%

295
00:11:52,160 --> 00:11:53,240
REDUCTION IN HIGH RISK

296
00:11:53,240 --> 00:11:54,080
INDIVIDUALS AGAINST ALL

297
00:11:54,080 --> 00:11:55,880
SYMPTOMS, THIS IS NOT JUST

298
00:11:55,880 --> 00:11:59,040
SEVERE DISEASE BUT THIS IS

299
00:11:59,040 --> 00:11:59,600
INCLUDING UPPER RESPIRATORY

300
00:11:59,600 --> 00:12:02,520
INFECTION, WHICH FAR EXCEEDS

301
00:12:02,520 --> 00:12:03,760
WHAT A TWO-DOSE mRNA VACCINE

302
00:12:03,760 --> 00:12:06,160
DOES IN HEALTHY PEOPLE AND COULD

303
00:12:06,160 --> 00:12:08,760
BE USED IN IMMUNE COMPROMISED,

304
00:12:08,760 --> 00:12:10,520
AND TREATMENT SCENARIO WHEN

305
00:12:10,520 --> 00:12:13,640
GIVEN EARLY, NOT LATE BUT EARLY,

306
00:12:13,640 --> 00:12:15,280
YOU GET 90% PROTECTION AGAINST

307
00:12:15,280 --> 00:12:17,120
PROGRESSION TO SEVERE COVID.

308
00:12:17,120 --> 00:12:19,080
I THINK THE VERSATILITY OF

309
00:12:19,080 --> 00:12:21,120
ANTIBODIES MAKES THEM WORTHY OF

310
00:12:21,120 --> 00:12:21,960
OUR ATTENTION.

311
00:12:21,960 --> 00:12:23,600
A LOT OF THINGS THAT HAPPENED IN

312
00:12:23,600 --> 00:12:26,120
THE LAST FIVE YEARS IN THE

313
00:12:26,120 --> 00:12:29,400
ANTIBODY SPACE, ONE IS SPEED.

314
00:12:29,400 --> 00:12:30,800
SO, THROUGH THE EPITOPE MAPPING

315
00:12:30,800 --> 00:12:33,000
PROGRAM WE DID GET SOME

316
00:12:33,000 --> 00:12:34,920
SUPPLEMENTAL FUNDING VERY EARLY,

317
00:12:34,920 --> 00:12:36,520
I THINK THE PROGRAM FLEXED TO

318
00:12:36,520 --> 00:12:40,200
COVID AND WE STARTED TALKING TO

319
00:12:40,200 --> 00:12:43,760
PROGRAM IN FEBRUARY OF 2020, AND

320
00:12:43,760 --> 00:12:45,480
WORK ON THIS SPACE.

321
00:12:45,480 --> 00:12:48,840
IN TERMS OF SPEED, THESE ARE TWO

322
00:12:48,840 --> 00:12:51,240
WORKFLOWS ON THE LEFT, 10X

323
00:12:51,240 --> 00:12:52,680
GENOMICS SINGLE CELL RNAseqO

324
00:12:52,680 --> 00:12:54,640
THE RIGHT IS A BERKELEY LIGHTS

325
00:12:54,640 --> 00:12:57,080
SINGLE CELL DEVICE.

326
00:12:57,080 --> 00:13:01,680
WE RAN TWO WORKFLOWS LIVE FIRE

327
00:13:01,680 --> 00:13:03,880
DURING COVID, TAKE PBMCs FROM

328
00:13:03,880 --> 00:13:06,480
SURVIVORS, ISOLATE B CELLS, USE

329
00:13:06,480 --> 00:13:10,720
FLOW CYTOMETRY TO LABEL CELLS

330
00:13:10,720 --> 00:13:12,600
WITH RECOMBINANT SPIKE PROTEIN,

331
00:13:12,600 --> 00:13:14,440
AND THEN SORT THOSE, WE EARED

332
00:13:14,440 --> 00:13:16,880
EXPANDED THEM IN T CELL-LIKE

333
00:13:16,880 --> 00:13:18,600
MILIEU OR JUST WENT TO SINGLE

334
00:13:18,600 --> 00:13:19,840
CELL RNAseq.

335
00:13:19,840 --> 00:13:22,240
I'M GOING TO CONTINUE THOSE

336
00:13:22,240 --> 00:13:25,120
WORKFLOWS, YOU END UP WITH GENES

337
00:13:25,120 --> 00:13:27,720
YOU SYNTHESIZE, PUT IN PLASMA,

338
00:13:27,720 --> 00:13:30,120
DO MICROSCOPE EXPRESSION, DO

339
00:13:30,120 --> 00:13:30,800
BONDING AND NEUTRALIZATION.

340
00:13:30,800 --> 00:13:33,000
ON THE RIGHT ON THE BEACON COULD

341
00:13:33,000 --> 00:13:36,600
SEE INDIVIDUAL CELLS MAKING

342
00:13:36,600 --> 00:13:38,800
ANTIBODY, AND EVEN WE DID SOME

343
00:13:38,800 --> 00:13:41,440
FUNCTIONAL TESTS, SINGLE CELL

344
00:13:41,440 --> 00:13:42,320
LEVEL, NEUTRALIZATION OR

345
00:13:42,320 --> 00:13:43,400
RECEPTOR BLOCKING AT THE SINGLE

346
00:13:43,400 --> 00:13:44,800
CELL LEVEL, REALLY FOR THE FIRST

347
00:13:44,800 --> 00:13:46,120
TIME THAT I'M EVER AWARE OF.

348
00:13:46,120 --> 00:13:52,160
ONE WAY OR THE OTHER, END UP

349
00:13:52,160 --> 00:13:52,720
WITH RECOMBINANT ANTIBODIES.

350
00:13:52,720 --> 00:13:55,640
AND SO THIS IS SORT OF A

351
00:13:55,640 --> 00:13:56,240
SCHEMATIC.

352
00:13:56,240 --> 00:13:57,400
B CELLS, MEMORY B CELLS, HAVE

353
00:13:57,400 --> 00:13:58,800
THE B CELL RECEPTOR ON THEIR

354
00:13:58,800 --> 00:14:00,040
SURFACE WHICH IS THE ANTIBODY

355
00:14:00,040 --> 00:14:01,720
THEY WILL LATER SECRETE.

356
00:14:01,720 --> 00:14:05,920
THAT'S HOW WE CAN LABEL THEM

357
00:14:05,920 --> 00:14:09,760
WITH A RECOMBINANT PROTEIN LIKE

358
00:14:09,760 --> 00:14:12,600
RBD OR SPIKE PROTEIN, ACTIVATE

359
00:14:12,600 --> 00:14:16,680
ON CD LIGAND AND IL-12 OUT OF

360
00:14:16,680 --> 00:14:17,960
BASIC SCIENCE STUDIES SPONSORED

361
00:14:17,960 --> 00:14:21,360
BY NIH WE USE THOSE TO STIMULATE

362
00:14:21,360 --> 00:14:22,360
A GERMINAL CENTER OR LYMPH NODE

363
00:14:22,360 --> 00:14:27,720
IN VITRO AND PUT THOSE ON THIS

364
00:14:27,720 --> 00:14:28,600
DEVICE, BERKELEY LIGHTS BEACON,

365
00:14:28,600 --> 00:14:29,800
THEY DROP SHIPPED US ONE.

366
00:14:29,800 --> 00:14:31,080
WE'VE NOW BOUGHT IT.

367
00:14:31,080 --> 00:14:35,040
FIRST TIME WE EVER USED IT WE

368
00:14:35,040 --> 00:14:38,760
MADE THE ANTIBODIES, PRETTY

369
00:14:38,760 --> 00:14:39,080
AMAZING.

370
00:14:39,080 --> 00:14:40,960
YOU LABEL BEADS, WITH SPIKE

371
00:14:40,960 --> 00:14:42,360
PROTEIN, AND THOSE ARE PUT OUT

372
00:14:42,360 --> 00:14:44,240
IN A CHANNEL AND YOU PUT A

373
00:14:44,240 --> 00:14:45,680
SINGLE B CELL IN EACH OF THE

374
00:14:45,680 --> 00:14:47,480
LITTLE WELLS, THEY CALL THEM

375
00:14:47,480 --> 00:14:49,160
PENS, AND THE CELLS ARE

376
00:14:49,160 --> 00:14:50,920
STIMULATED SO THEY FILL THIS

377
00:14:50,920 --> 00:14:53,040
VERY SMALL VOLUME, VERY RAPIDLY,

378
00:14:53,040 --> 00:14:54,240
SECRETED ANTIBODY, WHICH GETS

379
00:14:54,240 --> 00:14:57,800
OUT INTO THE CHANNEL.

380
00:14:57,800 --> 00:14:59,600
BEADS LIGHT UP, FLUORESCENTLY,

381
00:14:59,600 --> 00:15:00,960
YOU CAN DO MULTI-COLOR.

382
00:15:00,960 --> 00:15:02,520
WE DID RBD AND SPIKE AT THE SAME

383
00:15:02,520 --> 00:15:02,960
TIME.

384
00:15:02,960 --> 00:15:05,680
THIS IS A VIDEO OF ABOUT 30

385
00:15:05,680 --> 00:15:07,000
MINUTES ON THE INSTRUMENT

386
00:15:07,000 --> 00:15:09,200
LOOKING DOWN.

387
00:15:09,200 --> 00:15:10,720
THE CHIPS ACTUALLY HOLD ABOUT I

388
00:15:10,720 --> 00:15:14,040
THINK 18,000 OF THESE LITTLE

389
00:15:14,040 --> 00:15:15,440
PENS, SO EACH VERTICAL

390
00:15:15,440 --> 00:15:17,680
DISTINCTION IS A SINGLE CELL.

391
00:15:17,680 --> 00:15:19,400
AND I'M JUST GOING TO SHOW YOU A

392
00:15:19,400 --> 00:15:20,480
COUPLE HUNDRED HERE.

393
00:15:20,480 --> 00:15:21,800
OTHERWISE YOU LOSE RESOLUTION.

394
00:15:21,800 --> 00:15:25,000
THIS IS 30 MINUTES STARTING NOW.

395
00:15:25,000 --> 00:15:26,840
YOU SEE A PLUME, THIS IS A BLACK

396
00:15:26,840 --> 00:15:30,800
AND WHITE IMAGE, A PLUME OF

397
00:15:30,800 --> 00:15:32,320
ANTIBODY LABELING THE BEADS THAT

398
00:15:32,320 --> 00:15:35,960
ARE SPIKE OR RBD ON THE CHANNEL

399
00:15:35,960 --> 00:15:37,680
SO UNDERNEATH EACH OF THESE

400
00:15:37,680 --> 00:15:39,120
PLUMES LIKE A VOLCANO PLUME WE

401
00:15:39,120 --> 00:15:41,200
GO TO THE BOTTOM, SEE THE B

402
00:15:41,200 --> 00:15:42,240
CELL, THE INSTRUMENT, YOU

403
00:15:42,240 --> 00:15:43,680
SURROUND THE CELL WITH A SQUARE

404
00:15:43,680 --> 00:15:44,720
OF LIGHT AND THERE'S ENOUGH

405
00:15:44,720 --> 00:15:48,320
ENERGY IN THAT LIGHT BOX TO MOVE

406
00:15:48,320 --> 00:15:49,280
THE LIGHT, THERE'S ENOUGH ENERGY

407
00:15:49,280 --> 00:15:51,840
IN THAT LIGHT BOX TO MOVE THE

408
00:15:51,840 --> 00:15:53,480
CELL OUT.

409
00:15:53,480 --> 00:15:55,400
YOU GET THE ANTIBODY VARIABLE

410
00:15:55,400 --> 00:15:57,080
GENE SEQUENCES OUT.

411
00:15:57,080 --> 00:16:00,760
USING THE TWO WORK FLOWS PBMCs

412
00:16:00,760 --> 00:16:04,160
TO SINGLE CELL OR 10 X GENOMICS

413
00:16:04,160 --> 00:16:05,360
OR BERKELEY LIGHTS, GO TO NEXT

414
00:16:05,360 --> 00:16:10,840
GEN SEQUENCING PROTOCOL WHICH WE

415
00:16:10,840 --> 00:16:13,240
USE ILLUMINA, YOU COULD USE

416
00:16:13,240 --> 00:16:16,000
VARIOUS THINGS.

417
00:16:16,000 --> 00:16:18,920
WE FTP SEQUENCES ON THE SERVERS,

418
00:16:18,920 --> 00:16:22,240
TWIST, SYNTHESIZE, GAVE THEM OUR

419
00:16:22,240 --> 00:16:24,480
EXPRESSION VECTOR, ANTIBODY

420
00:16:24,480 --> 00:16:26,920
PLASMID, GIVES ASSEMBLY CLONE

421
00:16:26,920 --> 00:16:27,560
SYNTHESIZED DNA INTO THE PLASMA

422
00:16:27,560 --> 00:16:28,640
OF THE INSTRUMENT.

423
00:16:28,640 --> 00:16:31,520
WE OPEN THE FED EX BOX, THERE'S

424
00:16:31,520 --> 00:16:37,320
96 WELL PLATES WITH PLASMIDS

425
00:16:37,320 --> 00:16:41,920
READY TO GO, TRANSFECT AND WE'RE

426
00:16:41,920 --> 00:16:48,360
READY TO EXPRESS MONOCLONALS.

427
00:16:48,360 --> 00:16:49,440
POLY PEPTIDES, FUNCTIONAL

428
00:16:49,440 --> 00:16:52,200
MAPPING IS EXTREMELY IMPORTANT

429
00:16:52,200 --> 00:16:53,280
FOR THERAPEUTIC OR PROPHYLACTIC

430
00:16:53,280 --> 00:16:53,600
ANTIBODIES.

431
00:16:53,600 --> 00:16:55,560
FOR COVID THERE WAS NO TEST AT

432
00:16:55,560 --> 00:17:00,160
THE TIME WE DID THIS.

433
00:17:00,160 --> 00:17:02,920
SO ON THE FLY, IN MARCH 2022, WE

434
00:17:02,920 --> 00:17:08,600
DEVELOPED THIS TEST WHICH IS

435
00:17:08,600 --> 00:17:10,240
CALLED REALTIME ANALYSIS, AND

436
00:17:10,240 --> 00:17:14,200
WHAT THIS IS, IT'S A 384 PLATE,

437
00:17:14,200 --> 00:17:15,720
THERE'S ELECTRODES THAT MEASURE

438
00:17:15,720 --> 00:17:16,720
FLOW OF ELECTRICITY ACROSS THE

439
00:17:16,720 --> 00:17:16,920
WELL.

440
00:17:16,920 --> 00:17:19,200
IF YOU PUT CELLS ON THERE, A

441
00:17:19,200 --> 00:17:20,640
TISSUE CULTURE TREATED PLATE,

442
00:17:20,640 --> 00:17:21,960
CELLS BLOCK THE ELECTRICITY, AND

443
00:17:21,960 --> 00:17:25,040
YOU GET A PROPERTY CALLED

444
00:17:25,040 --> 00:17:25,680
IMPEDANCE.

445
00:17:25,680 --> 00:17:26,240
YOU BLOCK.

446
00:17:26,240 --> 00:17:29,200
AND SO FROM ZERO TO 80 HOURS ON

447
00:17:29,200 --> 00:17:31,520
X-AXIS YOU CAN SEE WE PUT CELLS

448
00:17:31,520 --> 00:17:34,920
ON AND SIGNAL GOES OUT BUT IT'S

449
00:17:34,920 --> 00:17:36,680
NORMALIZED CELL INDEX, IT'S

450
00:17:36,680 --> 00:17:37,440
IMPEDANCE OR BLOCKING

451
00:17:37,440 --> 00:17:37,880
ELECTRICITY.

452
00:17:37,880 --> 00:17:39,520
IF YOU ADD VIRUS IMPEDANCE GOES

453
00:17:39,520 --> 00:17:42,360
DOWN BECAUSE YOU GLOW UP THE

454
00:17:42,360 --> 00:17:43,680
CELLS, GET CYTOPATHIC EFFECT,

455
00:17:43,680 --> 00:17:44,440
ELECTRICITY FLOWS AGAIN.

456
00:17:44,440 --> 00:17:48,200
BUT IF YOU ADD VIRUS AND

457
00:17:48,200 --> 00:17:48,800
MONOCLONAL ANTIBODY, IT

458
00:17:48,800 --> 00:17:50,440
NEUTRALIZES THE VIRUS, WHEN THE

459
00:17:50,440 --> 00:17:53,600
INTEGRITY OF THE CELL MONOLAYER

460
00:17:53,600 --> 00:17:54,960
IS MAINTAINED, YOU MAINTAIN

461
00:17:54,960 --> 00:17:55,400
IMPEDANCE.

462
00:17:55,400 --> 00:17:58,760
WE DID THIS ACTUALLY IN ROUGH

463
00:17:58,760 --> 00:18:05,800
DILUTIONS IN QUADRANTS, 1 TO 20,

464
00:18:05,800 --> 00:18:08,400
500, USING CPE ASSAY IN REAL

465
00:18:08,400 --> 00:18:09,400
TIME WITHOUT REAGENTS.

466
00:18:09,400 --> 00:18:11,040
ALL WE HAD WAS VIRUS.

467
00:18:11,040 --> 00:18:11,560
AND CELLS.

468
00:18:11,560 --> 00:18:13,920
AND YOU PUT THOSE TWO THINGS

469
00:18:13,920 --> 00:18:17,720
TOGETHER AND DO NEUTRALIZATION

470
00:18:17,720 --> 00:18:20,240
WITHOUT ANY DETECTING

471
00:18:20,240 --> 00:18:28,440
MONOCLONALS, NO 

472
00:18:28,440 --> 00:18:29,040
NEUROFLUORESCENCE, 24-36 HOURS

473
00:18:29,040 --> 00:18:30,240
COULD SEE IT HAPPEN.

474
00:18:30,240 --> 00:18:30,920
IT'S AMAZING.

475
00:18:30,920 --> 00:18:32,360
ANOTHER PROPERTY THAT'S GOING TO

476
00:18:32,360 --> 00:18:33,680
BE REALLY IMPORTANT FOR RNA

477
00:18:33,680 --> 00:18:37,080
VIRUS THE IN THE FUTURE BECAUSE

478
00:18:37,080 --> 00:18:40,680
WE'RE ALL EXPERTS ON VARIANTS

479
00:18:40,680 --> 00:18:43,440
NOW, WE KNEW PROBABLY FOR RNA

480
00:18:43,440 --> 00:18:45,520
VIRUS THERE ARE GOING TO BE

481
00:18:45,520 --> 00:18:45,800
VARIANTS.

482
00:18:45,800 --> 00:18:46,840
POTENTIAL FOR ESCAPE.

483
00:18:46,840 --> 00:18:50,480
SO WE KNEW WE WANTED ANTIBODY

484
00:18:50,480 --> 00:18:51,760
COMBINATIONS TWO OR MORE, SO

485
00:18:51,760 --> 00:18:54,960
THAT WAS A GIVEN THAT WE WOULD

486
00:18:54,960 --> 00:18:56,160
HAVE NON-COMPETING ANTIBODIES IN

487
00:18:56,160 --> 00:18:58,800
THE COMBINATIONS THAT WE COULD

488
00:18:58,800 --> 00:19:00,400
USE FOR THERAPY OR PROPHYLAXIS.

489
00:19:00,400 --> 00:19:06,000
BUT ONE THING OUR GROUP IN

490
00:19:06,000 --> 00:19:06,600
PARTICULAR HAS BEEN

491
00:19:06,600 --> 00:19:11,000
INVESTIGATING IN THE RECENT

492
00:19:11,000 --> 00:19:12,200
MAPPING CONTRACT, FOR FLU,

493
00:19:12,200 --> 00:19:13,600
SARS-COV-2 AND SOME EBOLA STUFF

494
00:19:13,600 --> 00:19:16,680
I'LL SHOW YOU, IS GETTING

495
00:19:16,680 --> 00:19:17,800
SYNERGY OR COOPERATIVITY,

496
00:19:17,800 --> 00:19:20,400
MAPPING AREAS ON THE VIRAL

497
00:19:20,400 --> 00:19:22,160
GLYCOPROTEINS THAT CAN BE

498
00:19:22,160 --> 00:19:25,720
INTERROGATED WITH ANTIBODY, TO

499
00:19:25,720 --> 00:19:28,280
CHANGE THAT ENTIRE GLYCOPROTEIN

500
00:19:28,280 --> 00:19:29,520
BY THE BINDING OF FIRST ANTIBODY

501
00:19:29,520 --> 00:19:33,600
SO VIRUS IN SOME CASE THE

502
00:19:33,600 --> 00:19:34,600
GLYCOPROTEIN BECOMES MORE

503
00:19:34,600 --> 00:19:36,360
ACCESSIBLE OR SUSCEPTIBLE TO

504
00:19:36,360 --> 00:19:38,440
NEUTRALIZATION, BY THE SECOND

505
00:19:38,440 --> 00:19:38,680
ANTIBODY.

506
00:19:38,680 --> 00:19:39,840
SO THE BINDING OF THE FIRST

507
00:19:39,840 --> 00:19:41,480
MAKES THE ACTIVITY OF THE SECOND

508
00:19:41,480 --> 00:19:42,360
BETTER.

509
00:19:42,360 --> 00:19:47,480
THIS WAS CALLED SYNERGY.

510
00:19:47,480 --> 00:19:48,600
IT'S COMMONLY LOOKED FOR IN

511
00:19:48,600 --> 00:19:50,560
SMALL MOLECULE DRUGS AND DRUG

512
00:19:50,560 --> 00:19:50,920
INDUSTRY.

513
00:19:50,920 --> 00:19:52,680
YOU RARELY SEE IT BECAUSE NUMBER

514
00:19:52,680 --> 00:19:54,520
ONE IT'S RARE.

515
00:19:54,520 --> 00:19:56,320
YOU CAN'T BIND A GLYCOPROTEIN

516
00:19:56,320 --> 00:19:59,240
ANYWHERE ON THE SURFACE AND GET

517
00:19:59,240 --> 00:20:01,200
AN ALLOSTERIC EFFECT AT SITE OF

518
00:20:01,200 --> 00:20:01,560
VULNERABILITY.

519
00:20:01,560 --> 00:20:02,640
YOU HAVE TO MAP THAT.

520
00:20:02,640 --> 00:20:04,280
THAT'S WHAT WE DID.

521
00:20:04,280 --> 00:20:08,960
WE WENT THROUGH THOUSANDS OF ABS

522
00:20:08,960 --> 00:20:09,880
THAT -- ANTIBODIES THAT WE GOT

523
00:20:09,880 --> 00:20:11,200
FOR SARS-COV-2 AND LOOKED FOR

524
00:20:11,200 --> 00:20:14,560
COMPETITION FIRST AND HAD

525
00:20:14,560 --> 00:20:15,600
NON-COMPETING PAIRS, LOOKED AT

526
00:20:15,600 --> 00:20:16,640
NEUTRALIZATION WHEN YOU ADD

527
00:20:16,640 --> 00:20:16,880
TOGETHER.

528
00:20:16,880 --> 00:20:19,160
THIS IS A SYNERGY PLOT.

529
00:20:19,160 --> 00:20:21,000
IT'S A DOSE-RESPONSE.

530
00:20:21,000 --> 00:20:24,320
IF YOU GO FROM ZERO TO 250

531
00:20:24,320 --> 00:20:27,360
NANOGRAM ON THE X-AXIS OF 1

532
00:20:27,360 --> 00:20:29,120
ANTIBODY, THE SECOND ON THE

533
00:20:29,120 --> 00:20:30,360
Y-AXIS, CAN YOU SEE THERE'S

534
00:20:30,360 --> 00:20:34,040
CONCENTRATIONS WHERE FOR

535
00:20:34,040 --> 00:20:38,400
INSTANCE THIS ANTIBODY AT 8

536
00:20:38,400 --> 00:20:40,520
NANOGRAMS PER MILL NO

537
00:20:40,520 --> 00:20:43,800
NEUTRALIZATION, AND THIS 6 3, NO

538
00:20:43,800 --> 00:20:44,080
ACTIVITY.

539
00:20:44,080 --> 00:20:45,760
IF YOU COMBINE THEM AT THAT

540
00:20:45,760 --> 00:20:48,040
CONCENTRATION YOU GET NEARLY

541
00:20:48,040 --> 00:20:48,880
100% NEUTRALIZATION.

542
00:20:48,880 --> 00:20:51,240
SO YOU CAN SORT OF SEE IF YOU

543
00:20:51,240 --> 00:20:53,640
REVERSE THAT, YOU IS SEE A

544
00:20:53,640 --> 00:20:55,920
SYNERGY MAP OF A STOICHIOMETRY

545
00:20:55,920 --> 00:20:57,240
AND CONCENTRATION WHERE YOU GET

546
00:20:57,240 --> 00:20:57,480
ENERGY.

547
00:20:57,480 --> 00:20:59,200
THIS TURNED OUT TO BE VERY

548
00:20:59,200 --> 00:21:02,400
IMPORTANT SO HERE'S THE

549
00:21:02,400 --> 00:21:04,520
COMBINATION OF ANTIBODIES CALLED

550
00:21:04,520 --> 00:21:06,360
2196 AND 2130 WE DISCOVERED THAT

551
00:21:06,360 --> 00:21:11,520
ENDED UP IN THE ECUSHELL

552
00:21:11,520 --> 00:21:13,800
PROPERTY, THIS IS SINGLE

553
00:21:13,800 --> 00:21:14,560
RECONSTRUCTION AT VANDERBILT,

554
00:21:14,560 --> 00:21:16,320
BOTH BIND AT THE SAME TIME.

555
00:21:16,320 --> 00:21:17,240
RBD IS NOT VERY LARGE.

556
00:21:17,240 --> 00:21:18,840
YOU HAVE TO BE CAREFUL TO GET

557
00:21:18,840 --> 00:21:21,040
THE ANTIBODIES JUST RIGHT.

558
00:21:21,040 --> 00:21:22,240
THESE ANTIBODIES WERE

559
00:21:22,240 --> 00:21:22,680
SYNERGISTIC.

560
00:21:22,680 --> 00:21:26,600
WE WENT ON ABOUT A MONTH LATER

561
00:21:26,600 --> 00:21:27,880
AND GOT THE CRYSTAL STRUCTURE OF

562
00:21:27,880 --> 00:21:30,640
BOTH ANTIBODIES ON THE RBD,

563
00:21:30,640 --> 00:21:34,120
WE'RE SHOWING IT HERE IN

564
00:21:34,120 --> 00:21:36,880
COMPLEX -- WELL, IN CONTEXT OF

565
00:21:36,880 --> 00:21:38,760
THE TRIMER, WITH OPEN RBD, BUT

566
00:21:38,760 --> 00:21:41,480
WE CAN SEE HOW THESE WORK.

567
00:21:41,480 --> 00:21:45,640
THIS IS -- THIS TYPE OF MAPPING

568
00:21:45,640 --> 00:21:47,720
INCLUDING EM, CryoEM, OR HIGH

569
00:21:47,720 --> 00:21:48,840
RESOLUTION STUDIES WITH

570
00:21:48,840 --> 00:21:49,640
CRYSTALLOGRAPHY OF COMPLEXES HAS

571
00:21:49,640 --> 00:21:51,200
TURNED OUT TO BE A VERY

572
00:21:51,200 --> 00:21:53,160
IMPORTANT PART OF THE MAPPING

573
00:21:53,160 --> 00:21:56,680
ENTERPRISE SO THEN WE CAN GET

574
00:21:56,680 --> 00:21:58,280
CONTACT RESIDUES, POTENTIAL

575
00:21:58,280 --> 00:21:59,080
CONTACT RESIDUES, ANYTHING

576
00:21:59,080 --> 00:22:01,720
WITHIN 4 1/2 ANGSTROMS OF THE

577
00:22:01,720 --> 00:22:03,360
ANTIBODY AND THE VIRUS AND THEN

578
00:22:03,360 --> 00:22:05,440
WE CAN TAKE THOSE VIRAL CONTACT

579
00:22:05,440 --> 00:22:09,720
RESIDUES AND GO OUT TO NEXT

580
00:22:09,720 --> 00:22:11,360
STRAIN OR SOMEPLACE WHERE FIELD

581
00:22:11,360 --> 00:22:12,760
ISOLATES ARE BEING CATALOGED AND

582
00:22:12,760 --> 00:22:14,200
WE CAN PREDICT WHAT'S GOING ON

583
00:22:14,200 --> 00:22:17,800
IN TERMS OF ESCAPE OR FUNCTION.

584
00:22:17,800 --> 00:22:18,960
NOW, ANOTHER REALLY EXCITING

585
00:22:18,960 --> 00:22:21,560
THING WE DID IN THE MAPPING

586
00:22:21,560 --> 00:22:23,960
ENTERPRISE HERE, WE WORK WITH

587
00:22:23,960 --> 00:22:28,040
JESSIE BLOOM'S LAB AT FRED

588
00:22:28,040 --> 00:22:28,720
HUTCH.

589
00:22:28,720 --> 00:22:30,480
JESSIE PUT EVERY AMINO ACID, ALL

590
00:22:30,480 --> 00:22:32,280
20, AT EVERY POSITION OF THE RBD

591
00:22:32,280 --> 00:22:34,280
AND PUT THAT IN A YEAST LIBRARY.

592
00:22:34,280 --> 00:22:37,720
WE WERE ABLE TO DO SORT OF A

593
00:22:37,720 --> 00:22:38,320
THREE-STEP PROCESS.

594
00:22:38,320 --> 00:22:40,080
ONE, WHAT RESIDUES WERE

595
00:22:40,080 --> 00:22:41,480
TOLERATED SO THAT THE PROTEIN

596
00:22:41,480 --> 00:22:41,960
EVEN FOLDED?

597
00:22:41,960 --> 00:22:44,360
IF YOU PUT A RESIDUE IN, PROTEIN

598
00:22:44,360 --> 00:22:45,320
DOESN'T FOLD, THAT'S NOT A

599
00:22:45,320 --> 00:22:45,520
VIRUS.

600
00:22:45,520 --> 00:22:47,600
YOU DON'T HAVE TO WORRY ABOUT

601
00:22:47,600 --> 00:22:47,960
THAT.

602
00:22:47,960 --> 00:22:49,720
SECOND, JESSIE ALREADY MADE THE

603
00:22:49,720 --> 00:22:51,200
LIBRARY AND LOOKED FOR ACE-2

604
00:22:51,200 --> 00:22:53,400
BINDING SO IF THAT RECEPTOR

605
00:22:53,400 --> 00:22:54,720
BINDING DOMAIN DOES NOT MIND

606
00:22:54,720 --> 00:22:55,960
RECEPTOR THAT'S NOT GOING TO BE

607
00:22:55,960 --> 00:22:57,440
A VIRUS, THAT'S GONE.

608
00:22:57,440 --> 00:22:59,080
WE ALREADY CULLED THROUGH THE

609
00:22:59,080 --> 00:23:00,000
SEQUENCES.

610
00:23:00,000 --> 00:23:01,400
DOESN'T FOLD, DOESN'T BIND

611
00:23:01,400 --> 00:23:01,680
RECEPTOR.

612
00:23:01,680 --> 00:23:04,560
WHAT WAS LEFT, THEN WE COULD

613
00:23:04,560 --> 00:23:05,680
INTERROGATE ESCAPING THE TWO

614
00:23:05,680 --> 00:23:06,840
ANTIBODIES WE WERE FOCUSING ON,

615
00:23:06,840 --> 00:23:11,360
YOU CAN SEE ON THE BOTTOM 2196

616
00:23:11,360 --> 00:23:14,160
ON LEFT, 2130 ON RIGHT, WEB LOGO

617
00:23:14,160 --> 00:23:16,480
PLOTS OF AMINO ACIDS THAT WOULD

618
00:23:16,480 --> 00:23:18,000
ALLOW ESCAPE FRACTION WERE

619
00:23:18,000 --> 00:23:20,200
ALMOST NON-EXISTENT SO WE WERE

620
00:23:20,200 --> 00:23:21,600
CATALOGING OUR ANTIBODIES AND

621
00:23:21,600 --> 00:23:22,840
FOCUSING ON THE SYNERGISTIC

622
00:23:22,840 --> 00:23:24,680
PAIRS THAT COULD BIND

623
00:23:24,680 --> 00:23:25,360
SIMULTANEOUSLY AND SYNERGIZE AND

624
00:23:25,360 --> 00:23:31,400
WERE POTENT AND NEUTRALIZING,

625
00:23:31,400 --> 00:23:32,800
SELECTED DIFFICULT TO ESCAPE A

626
00:23:32,800 --> 00:23:33,080
PRIORI.

627
00:23:33,080 --> 00:23:34,080
YOU COULD PREDICT WHAT WAS GOING

628
00:23:34,080 --> 00:23:35,840
TO HAPPEN IN THE FUTURE,

629
00:23:35,840 --> 00:23:37,280
JESSIE'S GROUP COULD.

630
00:23:37,280 --> 00:23:38,680
WE SELECTED THESE ANTIBODIES.

631
00:23:38,680 --> 00:23:41,320
THE REST IS MORE CONVENTIONAL.

632
00:23:41,320 --> 00:23:43,160
MIKE DIAMOND, THERE WERE NO

633
00:23:43,160 --> 00:23:46,560
SMALL ANIMAL MODELS IN MARCH OF

634
00:23:46,560 --> 00:23:51,160
2020, SO MIKE IS A COLLABORATOR

635
00:23:51,160 --> 00:23:54,200
WITH ADENOVIRUS, HUMAN ACE-2

636
00:23:54,200 --> 00:23:56,320
RECEPTOR IN MICE, ISOTYPE

637
00:23:56,320 --> 00:23:57,400
CONTROL, TREATED MAINTAINED

638
00:23:57,400 --> 00:23:59,240
WEIGHT, YOU SEE HISTOPATHOLOGY

639
00:23:59,240 --> 00:24:01,560
IN UNTREATED, CLEAR LUNGS IN

640
00:24:01,560 --> 00:24:02,120
TREATED.

641
00:24:02,120 --> 00:24:06,480
WE WORKED WITH DAN BAROUCH'S LAB

642
00:24:06,480 --> 00:24:10,640
IN THE MONKEYS MODEL, GRAVE

643
00:24:10,640 --> 00:24:11,040
PROPHYLACTICALLY.

644
00:24:11,040 --> 00:24:12,480
LOOKED IN NOSE AND LUNGS

645
00:24:12,480 --> 00:24:13,600
CHALLENGED WITH ORIGINAL VIRUS,

646
00:24:13,600 --> 00:24:18,080
USE BE SUBGENOMIC RNA TEST,

647
00:24:18,080 --> 00:24:19,920
NEWLY MADE RNA, NOT A SINGLE

648
00:24:19,920 --> 00:24:25,000
MOLECULE OF NEWLY MADE RNA

649
00:24:25,000 --> 00:24:26,600
DETECTED IN PROPHYLAX

650
00:24:26,600 --> 00:24:27,040
ANTIBODIES.

651
00:24:27,040 --> 00:24:29,360
THE FINAL GO SIGNAL.

652
00:24:29,360 --> 00:24:30,360
THESE ANTIBODIES LOOK GREAT.

653
00:24:30,360 --> 00:24:34,280
AND NOW BACK TO THE SPEED THING

654
00:24:34,280 --> 00:24:40,640
I MENTIONED, WE GOT THE SAMPLE

655
00:24:40,640 --> 00:24:43,280
FROM THESE CONVALESCENT

656
00:24:43,280 --> 00:24:46,800
INDIVIDUALS INFECTED IN WUHAN

657
00:24:46,800 --> 00:24:48,880
CHINA IN DECEMBER 2019, TRAVELED

658
00:24:48,880 --> 00:24:51,160
TO NORTH AMERICA.

659
00:24:51,160 --> 00:24:53,040
SAMPLE ARRIVES IN NASHVILLE, BY

660
00:24:53,040 --> 00:24:57,520
APRIL 8 HAD GIVEN ASTRAZENECA

661
00:24:57,520 --> 00:24:58,040
THE SEQUENCES.

662
00:24:58,040 --> 00:25:00,040
WE THINK WE CAN TAKE IT DOWN TO

663
00:25:00,040 --> 00:25:01,880
MAYBE 14 DAYS, BUT WHO CARES,

664
00:25:01,880 --> 00:25:05,960
14,  25, THIS STUFF IS FAST.

665
00:25:05,960 --> 00:25:09,240
OTHER GROUPS DID IT AS WELL.

666
00:25:09,240 --> 00:25:10,560
YOU SAW REGENERON AND OTHER

667
00:25:10,560 --> 00:25:12,440
GROUPS THAT ARE IN COMMERCIAL

668
00:25:12,440 --> 00:25:15,080
SPACE WORK VERY QUICKLY TOO.

669
00:25:15,080 --> 00:25:18,880
AND THAT ENDED UP BEING THESE

670
00:25:18,880 --> 00:25:22,360
TWO ANTIBODIES, UNTIL THIS WEEK

671
00:25:22,360 --> 00:25:27,200
THE e-WAY WAS WITHDRAWN,

672
00:25:27,200 --> 00:25:29,360
ANTIBODIES COVERS EVERY VIRUS

673
00:25:29,360 --> 00:25:30,280
THROUGH BA.5.

674
00:25:30,280 --> 00:25:34,560
PEOPLE SAY ALEXANDRIA FAILED. A.

675
00:25:34,560 --> 00:25:36,840
THAT'S NOT TRUE.

676
00:25:36,840 --> 00:25:39,960
THEY LASTED LONGER THAN VACCINES

677
00:25:39,960 --> 00:25:41,200
AND ANTIBODIES.

678
00:25:41,200 --> 00:25:48,880
IF YOU CHECK AND  CHECK, WE GOT

679
00:25:48,880 --> 00:25:50,240
SEVERAL YEARS OUT OF THOSE

680
00:25:50,240 --> 00:25:53,160
ANTIBODIES WHICH IS AMAZING.

681
00:25:53,160 --> 00:25:56,040
AND THEN OTHER TOPIC I WANTED TO

682
00:25:56,040 --> 00:25:59,400
TALK ABOUT TODAY IS THE SCALE.

683
00:25:59,400 --> 00:26:01,600
SO THAT'S SHIFTED DURING THE

684
00:26:01,600 --> 00:26:03,160
CURRENT CONTRACT PERIOD, AT

685
00:26:03,160 --> 00:26:04,640
LEAST B CELL EPITOPE MAPPING.

686
00:26:04,640 --> 00:26:06,120
YOU CANNOT IMAGINE THE SCALE WE

687
00:26:06,120 --> 00:26:07,600
CAN WORK AT NOW.

688
00:26:07,600 --> 00:26:10,040
THIS IS EBOLA STUDIES THAT WERE

689
00:26:10,040 --> 00:26:11,040
SUPPORTED IN OUR CONTRACT.

690
00:26:11,040 --> 00:26:13,640
WE DO THE SAME THING, TAKE

691
00:26:13,640 --> 00:26:16,160
BLOOD, IN THIS CASE SURVIVOR

692
00:26:16,160 --> 00:26:18,240
FROM NIGERIA, WHO WAS A

693
00:26:18,240 --> 00:26:20,800
PHYSICIAN TAKING CARE OF A CASE

694
00:26:20,800 --> 00:26:23,880
AND BECAME INFECTED HIMSELF, IN

695
00:26:23,880 --> 00:26:24,920
2014.

696
00:26:24,920 --> 00:26:28,000
PBMCs WERE ISOLATED.

697
00:26:28,000 --> 00:26:33,760
B CELLS, PARAMAGNETICALLY, FLOW

698
00:26:33,760 --> 00:26:37,520
SHORT EBOLA GP, 10X WITH SINGLE

699
00:26:37,520 --> 00:26:37,800
CELL.

700
00:26:37,800 --> 00:26:42,000
WE SAW 100,000 EBOLA GP-SPECIFIC

701
00:26:42,000 --> 00:26:43,840
CELLS AND SORTED THEM, RECOVERED

702
00:26:43,840 --> 00:26:49,400
HEAVY AND LIGHT CHAIN FOR 15,000

703
00:26:49,400 --> 00:26:50,280
FROM ONE SAMPLE.

704
00:26:50,280 --> 00:26:52,040
SO MANY SEQUENCES, YOU CAN'T

705
00:26:52,040 --> 00:26:53,040
JUST MAKE ALL THOSE.

706
00:26:53,040 --> 00:26:54,360
YOU'RE TALKING ABOUT TENS OF

707
00:26:54,360 --> 00:27:04,840
MILLIONS OF DOLLARS JUST TO

708
00:27:05,720 --> 00:27:06,200
SYNTHESIZE DNA.

709
00:27:06,200 --> 00:27:08,280
WE CLUSTERED.

710
00:27:08,280 --> 00:27:10,040
SOME ANTIBODIES WERE RELATED,

711
00:27:10,040 --> 00:27:12,320
FAMILIES, CLONE OH TYPES, WE DID

712
00:27:12,320 --> 00:27:12,960
BIOINFORMATIC WORK.

713
00:27:12,960 --> 00:27:15,920
IF I SHOW YOU THE UNIVERSE OF

714
00:27:15,920 --> 00:27:18,320
15,000 ANTIBODIES COLOR CODED BY

715
00:27:18,320 --> 00:27:21,360
FUNCTION, SO ORANGE IS

716
00:27:21,360 --> 00:27:22,640
PAN-EBOLA, BLUE IS STRAIN

717
00:27:22,640 --> 00:27:28,200
SPECIFIC, THE SIZE OF THE CLONAL

718
00:27:28,200 --> 00:27:29,440
FAMILIES, AN AMAZING UNIVERSE.

719
00:27:29,440 --> 00:27:30,880
I COULD GO ON AND ON ABOUT THE

720
00:27:30,880 --> 00:27:36,040
TESTING THAT WAS PUT INTO THIS.

721
00:27:36,040 --> 00:27:40,200
AND EVEN THE RELATIONSHIPS

722
00:27:40,200 --> 00:27:40,960
GENETICALLY AND FUNCTIONALLY,

723
00:27:40,960 --> 00:27:41,560
BRINGING NEUTRALIZATION WITH

724
00:27:41,560 --> 00:27:42,320
SEQUENCE DIVERSITY, THERE'S A

725
00:27:42,320 --> 00:27:43,800
LOT GOING ON IN TERMS OF

726
00:27:43,800 --> 00:27:47,200
INFORMATICS IN THE SPACE.

727
00:27:47,200 --> 00:27:49,600
IT'S AN EXCITING FIELD,

728
00:27:49,600 --> 00:27:50,080
COMPUTATIONAL BIOLOGY.

729
00:27:50,080 --> 00:27:53,880
ANOTHER TECHNIQUE THAT'S COME

730
00:27:53,880 --> 00:27:57,160
INTO THE FIELD, CELL SIGNAL,

731
00:27:57,160 --> 00:27:59,160
GEORGE GIORGIO, CAN YOU CAPTURE

732
00:27:59,160 --> 00:28:01,880
ANTIBODIES NOT AS GENES FROM B

733
00:28:01,880 --> 00:28:05,080
CELLS OR PLASMA CELLS BUT GRAB

734
00:28:05,080 --> 00:28:06,480
THE ANTIBODIES, FROM PROTEIN OR

735
00:28:06,480 --> 00:28:11,080
SERUM, FROM THE SAME INDIVIDUAL

736
00:28:11,080 --> 00:28:11,640
WE CAPTURED 6,000 MONOCLONAL

737
00:28:11,640 --> 00:28:14,560
ANTIBODIES OUT OF THE PLASMA

738
00:28:14,560 --> 00:28:18,160
ONTO EBOLA GP, ELUTED THEM AS

739
00:28:18,160 --> 00:28:22,680
PROTEINS, SEQUENCED THEM BY MASS

740
00:28:22,680 --> 00:28:25,960
SPEC, YOU CAN COMPARE WITH

741
00:28:25,960 --> 00:28:26,280
PROTEINS.

742
00:28:26,280 --> 00:28:29,040
OPEN QUESTION, IS B CELL MEMORY

743
00:28:29,040 --> 00:28:32,400
POOL THE SAME AS PLASMA CELLS

744
00:28:32,400 --> 00:28:34,680
SECRETING INTO THE SERUM, VERY

745
00:28:34,680 --> 00:28:37,240
IMPORTANT. 

746
00:28:37,240 --> 00:28:38,080
WE SEE SUBSTANTIAL OVERLAP.

747
00:28:38,080 --> 00:28:42,400
THEY ARE NOT COMPLETELY

748
00:28:42,400 --> 00:28:43,480
OVERLAPPED BUT HIGHLY

749
00:28:43,480 --> 00:28:43,920
OVERLAPPED.

750
00:28:43,920 --> 00:28:47,200
I THINK MY TAKE ON THIS IS THAT

751
00:28:47,200 --> 00:28:49,480
B CELL MEMORY DOES TO A LARGE

752
00:28:49,480 --> 00:28:51,360
EXTENT REFLECT AT LEAST THE POOL

753
00:28:51,360 --> 00:28:54,520
FROM WHICH LONG LIVED PLASMA

754
00:28:54,520 --> 00:28:56,680
CELLS ARE RECOVERED.

755
00:28:56,680 --> 00:28:57,800
NOW, AM I OUT OF TIME?

756
00:28:57,800 --> 00:29:00,360
DO I NEED TO END?

757
00:29:00,360 --> 00:29:02,440
THESE ARE THREE OF THE CLONES IN

758
00:29:02,440 --> 00:29:03,200
THIS INDIVIDUAL.

759
00:29:03,200 --> 00:29:06,600
IT'S AMAZING ON THE TOP IS HEAVY

760
00:29:06,600 --> 00:29:07,680
CHAINS.

761
00:29:07,680 --> 00:29:08,800
THESE ARE POINT MUTATIONS, SO

762
00:29:08,800 --> 00:29:11,000
THIS IS JUST INTERESTING THAT

763
00:29:11,000 --> 00:29:15,280
INDIVIDUALS MAKE NOT ONLY A

764
00:29:15,280 --> 00:29:15,920
MONOCLONAL, IN THE LINEAGE,

765
00:29:15,920 --> 00:29:18,200
SYME'S THEY ARE MAKING --

766
00:29:18,200 --> 00:29:19,640
SOMETIMES THEY ARE MAKING

767
00:29:19,640 --> 00:29:21,160
HUNDREDS OF VARIANTS, WE WORRY

768
00:29:21,160 --> 00:29:24,160
ABOUT VIRAL VARIANTS BUT YOU SEE

769
00:29:24,160 --> 00:29:28,280
EQUIVALENT OR GREATER EXTENT OF

770
00:29:28,280 --> 00:29:29,000
ANTIBODY VARIANTS.

771
00:29:29,000 --> 00:29:31,440
NOW, SINCE WE HAD SO MANY

772
00:29:31,440 --> 00:29:35,840
ANTIBODY SEQUENCES, 15,000 FROM

773
00:29:35,840 --> 00:29:37,640
THIS INDIVIDUAL, TWO INDIVIDUALS

774
00:29:37,640 --> 00:29:39,920
REPRESENTED HERE IN THE CIRCOS

775
00:29:39,920 --> 00:29:40,400
PLOT.

776
00:29:40,400 --> 00:29:43,080
WE WERE ABLE TO COMPARE DATA

777
00:29:43,080 --> 00:29:46,480
FROM EMORY GROUP, SCOTT BOYD AND

778
00:29:46,480 --> 00:29:48,320
RAFAEL MADDEN AND OTHERS HAVE

779
00:29:48,320 --> 00:29:52,160
LOOKED AT REPERTOIRE OF EBOLA

780
00:29:52,160 --> 00:29:59,560
SURVIVORS AND OTHERS VSV

781
00:29:59,560 --> 00:30:01,760
VACCINEES, CHIMP, THE LINE

782
00:30:01,760 --> 00:30:02,760
CONNECTS.

783
00:30:02,760 --> 00:30:04,040
IT'S GRATIFYING TO SEE NATURAL

784
00:30:04,040 --> 00:30:05,680
IMMUNITY OVERLAPS WITH THAT OF

785
00:30:05,680 --> 00:30:06,720
VACCINE-INDUCED IMMUNITY.

786
00:30:06,720 --> 00:30:07,680
THEY ARE NOT COMPLETELY

787
00:30:07,680 --> 00:30:08,080
DIFFERENT.

788
00:30:08,080 --> 00:30:10,640
THERE'S A LOT OF PUBLIC

789
00:30:10,640 --> 00:30:11,240
CLONOTYPES.

790
00:30:11,240 --> 00:30:12,240
THAT'S SOMETHING THAT'S HAPPENED

791
00:30:12,240 --> 00:30:15,600
IN THE CURRENT CONTRACT LOTS

792
00:30:15,600 --> 00:30:15,800
 OF

793
00:30:15,800 --> 00:30:17,560
PEOPLE ARE SEEING, YOU AND I

794
00:30:17,560 --> 00:30:19,520
SHARE AN ANTIBODY SEQUENCE OR

795
00:30:19,520 --> 00:30:20,960
LINEAGE, USED TO BE THOUGHT

796
00:30:20,960 --> 00:30:23,240
RARE, NOW WE SEE IT'S THE NORM.

797
00:30:23,240 --> 00:30:25,440
LOTS OF OVERLAP.

798
00:30:25,440 --> 00:30:36,000
YOU CAN TAKE THOSE PUBLIC CLONE

799
00:30:39,600 --> 00:30:40,640
CLONOTYPES AND DO FUNCTIONAL

800
00:30:40,640 --> 00:30:41,080
GRIDS.

801
00:30:41,080 --> 00:30:43,400
THE AMOUNT OF INFORMATION WE'RE

802
00:30:43,400 --> 00:30:44,400
GETTING IS ENORMOUS.

803
00:30:44,400 --> 00:30:46,880
WE CAN TAKE IT BACK TO MORE

804
00:30:46,880 --> 00:30:50,640
CONVENTIONAL MAPPING THINGS, AND

805
00:30:50,640 --> 00:30:53,080
WE TOOK THE TOP 15 CLONOTYPES

806
00:30:53,080 --> 00:30:58,920
SHARED BETWEEN INDIVIDUALS BEING

807
00:30:58,920 --> 00:31:00,800
VACCINATED OR INFECTED, DID E.M.

808
00:31:00,800 --> 00:31:01,040
STUDIES.

809
00:31:01,040 --> 00:31:03,760
YOU CAN SEE THESE INDIVIDUALS

810
00:31:03,760 --> 00:31:05,800
ARE DECORATING THE ENTIRE

811
00:31:05,800 --> 00:31:07,240
GLYCOPROTEIN, TOP, SIDE, BOTTOM,

812
00:31:07,240 --> 00:31:07,680
STEM.

813
00:31:07,680 --> 00:31:08,320
THESE INDIVIDUALS MAKE

814
00:31:08,320 --> 00:31:10,200
ANTIBODIES TO EVERYWHERE ON THE

815
00:31:10,200 --> 00:31:12,480
GP WHICH IS VERY COOL.

816
00:31:12,480 --> 00:31:13,800
BECAUSE THE MONOCLONALS ARE

817
00:31:13,800 --> 00:31:14,080
SNAPSHOTS.

818
00:31:14,080 --> 00:31:15,880
WHEN YOU MAKE THEM AT THIS SCALE

819
00:31:15,880 --> 00:31:17,520
YOU SEE HOW BIG IT IS.

820
00:31:17,520 --> 00:31:22,080
WE TOOK A LOT OF CLONOTYPES INTO

821
00:31:22,080 --> 00:31:26,600
MOUSE STUDIES, SO THIS IS EBOLA

822
00:31:26,600 --> 00:31:27,360
ZAIRE, LETHAL INFECTION,

823
00:31:27,360 --> 00:31:28,680
CONTROLS ALL DIED.

824
00:31:28,680 --> 00:31:31,640
BUT MANY OF THESE

825
00:31:31,640 --> 00:31:33,720
MONOTHERAPY-TREATED GROUPS WITH

826
00:31:33,720 --> 00:31:35,920
PUBLIC CLONOTYPES ARE COMPLETELY

827
00:31:35,920 --> 00:31:36,160
PROTECTED.

828
00:31:36,160 --> 00:31:41,360
I THINK THIS IS REASSURING, LOTS

829
00:31:41,360 --> 00:31:49,800
OF PEOPLE MAKE THE SAME

830
00:31:49,800 --> 00:31:50,600
ANTIBODIES AND ARE PROTECTED

831
00:31:50,600 --> 00:31:51,640
AGAINST EBOLA.

832
00:31:51,640 --> 00:31:54,840
THE HUMAN SYSTEM IS COMPLEX AND

833
00:31:54,840 --> 00:31:55,080
CAPABLE.

834
00:31:55,080 --> 00:31:58,400
I WANT TO REEMPHASIZE THE

835
00:31:58,400 --> 00:32:00,200
REVOLUTION IN CryoEM, A LOT OF

836
00:32:00,200 --> 00:32:02,720
MAPPINGS GOING ON AT VERY HIGH

837
00:32:02,720 --> 00:32:05,240
RESOLUTION OF ANTIBODIES AND

838
00:32:05,240 --> 00:32:08,520
COMPLEX PARTICLES, BUT ALSO HGX,

839
00:32:08,520 --> 00:32:12,040
YOU KNOW, PROTEOMIC STUDIES,

840
00:32:12,040 --> 00:32:13,960
SINGLE PARTICLE RECONSTRUCTION,

841
00:32:13,960 --> 00:32:18,480
CO-CRYSTAL STRUCTURES, SO MUCH

842
00:32:18,480 --> 00:32:19,280
STRUCTURAL GOING ON.

843
00:32:19,280 --> 00:32:25,640
WE CAN FIND ANTIBODIES EXTREMELY

844
00:32:25,640 --> 00:32:28,640
FAST, USED AS VACCINES TO

845
00:32:28,640 --> 00:32:29,080
PREVENT.

846
00:32:29,080 --> 00:32:30,080
EVUSHELL WAS GIVEN IM, WE

847
00:32:30,080 --> 00:32:31,800
LEARNED IV IS A LOSING STRATEGY,

848
00:32:31,800 --> 00:32:34,240
WE DON'T HAVE ENOUGH INFUSION

849
00:32:34,240 --> 00:32:36,600
SYSTEMS BUT IM IS COMPLETELY

850
00:32:36,600 --> 00:32:36,880
POSSIBLE.

851
00:32:36,880 --> 00:32:38,720
WE CAN GET INTO CLINIC RAPIDLY

852
00:32:38,720 --> 00:32:40,480
WITH ANTIBODIES.

853
00:32:40,480 --> 00:32:46,920
I HAVE A PROGRAM, WE'RE TRYING

854
00:32:46,920 --> 00:32:48,120
TO MAKE ANTIBODIES FOR 100 AHEAD

855
00:32:48,120 --> 00:32:51,960
OF TIME, DON'T  HAVE TO WAIT.

856
00:32:51,960 --> 00:32:55,200
NOW YOU MAY KNOW THAT WE DID A

857
00:32:55,200 --> 00:32:58,400
STUDY WITH MODERNA, THE FIRST

858
00:32:58,400 --> 00:33:00,440
ANTIBODY BY mRNA INTO HUMANS,

859
00:33:00,440 --> 00:33:10,920
IT'S BEEN DONE IN HUMANS, WE

860
00:33:14,680 --> 00:33:19,520
WORKING TOWARD NEBULIZED, $10 A

861
00:33:19,520 --> 00:33:20,960
DOSE, ANTIBODIES ARE THE FUTURE.

862
00:33:20,960 --> 00:33:22,800
YOU'RE GOING TO SAY DO I WANT A

863
00:33:22,800 --> 00:33:23,800
VACCINE, ANTIBODY, BOTH?

864
00:33:23,800 --> 00:33:26,400
IT'S NOT EITHER/OR.

865
00:33:26,400 --> 00:33:27,200
IT'S BOTH/AND.

866
00:33:27,200 --> 00:33:29,360
ANTIBODIES ARE GOING TO RISE IN

867
00:33:29,360 --> 00:33:30,040
PROMINENCE AND USE, I THINK

868
00:33:30,040 --> 00:33:30,760
YOU'LL SEE THAT.

869
00:33:30,760 --> 00:33:34,520
THIS IS A PICTURE OF MY GROUP AT

870
00:33:34,520 --> 00:33:37,920
VANDERBILT. 

871
00:33:37,920 --> 00:33:45,520
I MENTIONED MIKE DIAMOND, JESSIE

872
00:33:45,520 --> 00:33:47,440
BAROUCH, A LOT OF COMPANIES

873
00:33:47,440 --> 00:33:47,720
HELPED US.

874
00:33:47,720 --> 00:33:49,000
NIH HAS BEEN OUR PRINCIPAL

875
00:33:49,000 --> 00:33:53,360
FUNDING SOURCE FOR THE MAPPING

876
00:33:53,360 --> 00:33:54,800
STUDIES, BUT DOLLEY PARTON GOT

877
00:33:54,800 --> 00:33:56,000
US GOING, OUR LOCAL CELEBRITY,

878
00:33:56,000 --> 00:33:59,080
WHO HELPED US GET GOING ON

879
00:33:59,080 --> 00:33:59,280
COVID.

880
00:33:59,280 --> 00:34:00,160
I'LL STOP THERE AND MAY HAVE

881
00:34:00,160 --> 00:34:02,120
USED MY TIME BUT I'M HAPPY TO

882
00:34:02,120 --> 00:34:05,640
ANSWER QUESTIONS IF THERE IS

883
00:34:05,640 --> 00:34:05,840
TIME.

884
00:34:05,840 --> 00:34:06,840
>>JIM, THANK YOU.

885
00:34:06,840 --> 00:34:08,760
THAT WAS TERRIFIC.

886
00:34:08,760 --> 00:34:10,040
WE'RE PAST THE TIME.

887
00:34:10,040 --> 00:34:17,320
YOU SAID YOU HAD ANOTHER

888
00:34:17,320 --> 00:34:17,760
COMMITMENT.

889
00:34:17,760 --> 00:34:21,360
IF THAT'S CHANGED, WE HAVE TIME.

890
00:34:21,360 --> 00:34:26,200
>>I THINK I'VE GOT
MINUTES.

891
00:34:26,200 --> 00:34:27,120
LET'S DO IT.

892
00:34:27,120 --> 00:34:31,800
>>QUESTIONS FROM COUNCIL

893
00:34:31,800 --> 00:34:32,800
MEMBERS?

894
00:34:32,800 --> 00:34:33,000
>>JIM?

895
00:34:33,000 --> 00:34:33,960
>>YEAH, JIM, TERRIFIC.

896
00:34:33,960 --> 00:34:36,920
I WAS INTERESTED IN YOUR

897
00:34:36,920 --> 00:34:38,040
PRESENTATION OF SYNERGY, AND HOW

898
00:34:38,040 --> 00:34:41,000
FAR DOES THAT GO?

899
00:34:41,000 --> 00:34:41,800
DO YOU SEE SYNERGISTIC

900
00:34:41,800 --> 00:34:42,840
INTERACTIONS WHERE AN ANTIBODY

901
00:34:42,840 --> 00:34:49,640
CAN ACTUALLY OPEN UP AN EPITOPE

902
00:34:49,640 --> 00:34:50,320
THAT'S OTHERWISE INACCESSIBLE?

903
00:34:50,320 --> 00:34:54,680
>>YES, YOU CAN SEE THAT.

904
00:34:54,680 --> 00:34:55,960
IN THE PREVIOUS ITERATION OF

905
00:34:55,960 --> 00:34:59,760
THIS CONTRACT WE WERE MAPPING

906
00:34:59,760 --> 00:35:02,680
FLU ANTIBODIES AND DISCOVERED

907
00:35:02,680 --> 00:35:05,400
TRIMER INTERFACE ANTIBODIES.

908
00:35:05,400 --> 00:35:08,920
SO IN OLIGOMERS LIKE FLU,

909
00:35:08,920 --> 00:35:11,000
TRIMERS, SURFACES ARE OBSCURED,

910
00:35:11,000 --> 00:35:12,520
YOU CAN'T SEE THEM IN CRYSTAL

911
00:35:12,520 --> 00:35:13,960
STRUCTURE BUT FOUND ANTIBODIES

912
00:35:13,960 --> 00:35:15,920
THAT WOULD RECOGNIZE THOSE SITES

913
00:35:15,920 --> 00:35:18,040
AND WORK IN VIVO AND ARE

914
00:35:18,040 --> 00:35:18,480
PROTECTIVE.

915
00:35:18,480 --> 00:35:19,760
WE'VE BEEN LOOKING.

916
00:35:19,760 --> 00:35:22,160
THERE'S SOME DYNAMICS THEREFORE

917
00:35:22,160 --> 00:35:23,720
TO HA, THEY OPEN DURING FUSION

918
00:35:23,720 --> 00:35:25,680
BUT TURNS OUT EVEN BEFORE FUSION

919
00:35:25,680 --> 00:35:26,960
THEY ARE MOVING AROUND, CRYSTAL

920
00:35:26,960 --> 00:35:28,680
STRUCTURES WE THINK OF THEM AS

921
00:35:28,680 --> 00:35:30,040
MARBLE STATUES BUT THEY ARE NOT

922
00:35:30,040 --> 00:35:31,160
LIKE THAT.

923
00:35:31,160 --> 00:35:34,400
THESE THINGS ARE WIGGLING AND

924
00:35:34,400 --> 00:35:34,800
OPENING.

925
00:35:34,800 --> 00:35:42,640
SINCE THAT TIME WE FOUND SIMILAR

926
00:35:42,640 --> 00:35:43,520
ANTIBODIES FOR NEAPA, DIMERS

927
00:35:43,520 --> 00:35:45,720
BIND DOWN, NOT SHOWN ON THE

928
00:35:45,720 --> 00:35:47,480
SURFACE OF THE CRYSTAL STRUCTURE

929
00:35:47,480 --> 00:35:53,520
OF DIMER BUT THOSE ARE EVEN

930
00:35:53,520 --> 00:35:56,120
NEUTRALIZING AND WE SEE

931
00:35:56,120 --> 00:35:57,560
ANTIBODIES TO OTHER SURFACES

932
00:35:57,560 --> 00:36:00,080
PROLONG OPENNESS THAT'S ALREADY

933
00:36:00,080 --> 00:36:01,760
THERE, IT'S NOT JUST PROVOKING

934
00:36:01,760 --> 00:36:03,600
IT, LIKE IT'S ALREADY THERE,

935
00:36:03,600 --> 00:36:09,280
SORT OF LOCKS IT MORE OPEN OR

936
00:36:09,280 --> 00:36:14,600
TENDS TO BE MORE OPENNEN.

937
00:36:14,600 --> 00:36:17,160
DIMER, TRIMER, TETRA VIRUS,

938
00:36:17,160 --> 00:36:18,680
PROBABLY EVERY VIRUS HAS

939
00:36:18,680 --> 00:36:19,880
INTERFACE EPITOPES NOT

940
00:36:19,880 --> 00:36:21,440
UNDERSTOOD YET, AND THESE

941
00:36:21,440 --> 00:36:22,720
COMBINATIONS ARE PLAYING WITH

942
00:36:22,720 --> 00:36:23,400
THAT.

943
00:36:23,400 --> 00:36:26,360
THEY ARE CHANGING DYNAMICS OF

944
00:36:26,360 --> 00:36:27,760
THE OLIGOMERS, THAT'S AN

945
00:36:27,760 --> 00:36:30,400
IMPORTANT FUTURE DIRECTION, HOW

946
00:36:30,400 --> 00:36:33,080
TO HARNESS THAT.

947
00:36:33,080 --> 00:36:34,320
>>GREAT.

948
00:36:34,320 --> 00:36:34,600
THANK YOU.

949
00:36:34,600 --> 00:36:39,360
>>JIM, THERE'S A LOT BEEN

950
00:36:39,360 --> 00:36:40,240
PUBLISHED RECENTLY ABOUT

951
00:36:40,240 --> 00:36:42,200
VACCINAL EFFECTS WITH HIV,

952
00:36:42,200 --> 00:36:44,200
BROADLY NEUTRALIZING ANTIBODIES.

953
00:36:44,200 --> 00:36:45,400
WONDERING IF YOU'VE HAD THE

954
00:36:45,400 --> 00:36:48,880
OPPORTUNITY TO LOOK AT THAT WITH

955
00:36:48,880 --> 00:36:49,800
SOME OF THE SARS-COV-2

956
00:36:49,800 --> 00:36:53,200
ANTIBODIES AND ANY OTHER

957
00:36:53,200 --> 00:36:56,480
THOUGHTS ON ENGINEERING YOUR

958
00:36:56,480 --> 00:37:00,000
ANTIBODIES TO ENHANCE A VACCINAL

959
00:37:00,000 --> 00:37:01,200
EFFECT IF YOU'VE DONE THAT OR

960
00:37:01,200 --> 00:37:03,280
HAVE PLANS TO DO THAT?

961
00:37:03,280 --> 00:37:04,440
>>YEAH, I'M HESITANT TO
ANSWER

962
00:37:04,440 --> 00:37:06,640
BECAUSE I'M AN OUTLIER IN THIS

963
00:37:06,640 --> 00:37:07,400
FIELD.

964
00:37:07,400 --> 00:37:08,840
WHEN WE PUT EVERYTHING TOGETHER

965
00:37:08,840 --> 00:37:11,360
WITH AZ, WE ELECTED TO KNOCK OUT

966
00:37:11,360 --> 00:37:13,400
ALL FC GAMMA RECEPTOR

967
00:37:13,400 --> 00:37:13,760
INTERACTIONS.

968
00:37:13,760 --> 00:37:16,920
OF COURSE THERE WAS CONCERN

969
00:37:16,920 --> 00:37:18,360
ABOUT ADE, HIGHER REPLICATION AT

970
00:37:18,360 --> 00:37:19,600
THAT TIME BUT IT TURNED OUT I

971
00:37:19,600 --> 00:37:22,280
THINK TO BE THE RIGHT THING.

972
00:37:22,280 --> 00:37:23,960
IF YOU LOOK AT HOSPITALIZED

973
00:37:23,960 --> 00:37:25,360
PATIENTS THE ONLY ANTIBODY DID

974
00:37:25,360 --> 00:37:30,400
NOT FAIL FOR FUTILITY AS YOU

975
00:37:30,400 --> 00:37:36,480
WELL KNOW WAS EVU SHELL AND

976
00:37:36,480 --> 00:37:36,920
CAUSED 30%.

977
00:37:36,920 --> 00:37:39,320
YOU DON'T NEED FC MEDIATED, YOU

978
00:37:39,320 --> 00:37:40,520
23450ED NEUTRALIZATION.

979
00:37:40,520 --> 00:37:41,840
IF YOU HAVE EARLY OUTPATIENT

980
00:37:41,840 --> 00:37:44,280
MILD DISEASE AND LOW NUMBER OF

981
00:37:44,280 --> 00:37:46,560
INFECTED CELLS, PROBABLY IN YOUR

982
00:37:46,560 --> 00:37:48,680
UPPER AIRWAY, SURE, HAVE AT IT,

983
00:37:48,680 --> 00:37:50,000
KILL ALL THE CELLS, MAYBE TUNING

984
00:37:50,000 --> 00:37:52,400
UP IS A GOOD IDEA BECAUSE YOU

985
00:37:52,400 --> 00:37:54,840
WANT TO ELIMINATE THE FACTORIES.

986
00:37:54,840 --> 00:37:56,440
WHEN YOUR LUNG IS HIGHLY

987
00:37:56,440 --> 00:37:58,000
INFECTED, YOU'RE IN THE HOSPITAL

988
00:37:58,000 --> 00:37:58,920
BECAUSE YOU HAVE LUNG

989
00:37:58,920 --> 00:38:00,880
INFLAMMATION OR YOU'RE ON THE

990
00:38:00,880 --> 00:38:02,880
VENTILATOR, DO YOU WANT TO POUR

991
00:38:02,880 --> 00:38:05,080
OIL ON THE INFLAMMATORY MILIEU

992
00:38:05,080 --> 00:38:06,200
BY BRINGING IN EFFECTOR CELLS

993
00:38:06,200 --> 00:38:07,160
AND TURNING THEM UP?

994
00:38:07,160 --> 00:38:11,440
I THINK THE ANSWER IS NO.

995
00:38:11,440 --> 00:38:12,960
YOU WANT TO TURN THEM OFF,

996
00:38:12,960 --> 00:38:22,800
THAT'S WERE PEOPLE WERE USING

997
00:38:22,800 --> 00:38:24,600
GLUCOCORTICOIDS, YOU ALREADY

998
00:38:24,600 --> 00:38:25,680
HAVE INFLAMMATION, MY OWN

999
00:38:25,680 --> 00:38:26,880
OPINION WHICH NOT MANY PEOPLE

1000
00:38:26,880 --> 00:38:28,080
SHARE, I DON'T THINK, IS YOU

1001
00:38:28,080 --> 00:38:31,240
WANT TO TURN IT OFF.

1002
00:38:31,240 --> 00:38:32,800
YOU WANT A SILENT ANTIBODY.

1003
00:38:32,800 --> 00:38:43,360
BUT TAKE IT FOR WHAT IT'S WORTH 

1004
00:38:48,080 --> 00:38:49,560
>>JIM -- I'M SORRY.

1005
00:38:49,560 --> 00:38:50,200
>>GO AHEAD.

1006
00:38:50,200 --> 00:38:51,960
>>I WANT TO FOLLOW UP.

1007
00:38:51,960 --> 00:38:54,360
THANK YOU VERY MUCH, A GREAT

1008
00:38:54,360 --> 00:38:54,800
PRESENTATION.

1009
00:38:54,800 --> 00:38:58,720
TO FOLLOW UP ON DAN'S QUESTION,

1010
00:38:58,720 --> 00:39:00,920
COULDN'T YOU HAVE DIFFERENT

1011
00:39:00,920 --> 00:39:03,960
ANTIBODIES FOR DIFFERENT STAGES?

1012
00:39:03,960 --> 00:39:05,280
SO MAYBE FOR PREVENTIVE

1013
00:39:05,280 --> 00:39:06,360
MONOCLONAL MAYBE YOU DO WANT

1014
00:39:06,360 --> 00:39:09,480
SOMETHING THAT HAS A VACCINAL

1015
00:39:09,480 --> 00:39:11,080
EFFECT BECAUSE THEN YOU'RE

1016
00:39:11,080 --> 00:39:12,840
NEUTRALIZING BUT THEN YOU'RE

1017
00:39:12,840 --> 00:39:14,240
ALSO MAYBE -- WHEN PEOPLE GET

1018
00:39:14,240 --> 00:39:16,680
EXPOSED YOU COULD BE EXPANDING

1019
00:39:16,680 --> 00:39:18,960
THE RESPONSE IF YOU WERE GETTING

1020
00:39:18,960 --> 00:39:23,440
SOME KIND OF VACCINAL EFFECT?

1021
00:39:23,440 --> 00:39:25,720
YOU WOULDN'T WANT TO USE THAT

1022
00:39:25,720 --> 00:39:26,960
WHEN SOMEBODY IS IN THE

1023
00:39:26,960 --> 00:39:27,360
HOSPITAL, RIGHT?

1024
00:39:27,360 --> 00:39:28,560
>>I AGREE WITH THAT.

1025
00:39:28,560 --> 00:39:32,400
THIS TOUCHES ON -- THERE'S A

1026
00:39:32,400 --> 00:39:34,720
LARGE LITERATURE ON

1027
00:39:34,720 --> 00:39:35,280
PASSIVE/ACTIVE IMMUNIZATION,

1028
00:39:35,280 --> 00:39:38,240
VERY POPULAR IN THE '60s.

1029
00:39:38,240 --> 00:39:40,760
ACTUALLY DID SOME WORK IN THE

1030
00:39:40,760 --> 00:39:44,480
INTRAMURAL PROGRAM IN

1031
00:39:44,480 --> 00:39:47,160
CHIMPANZEES WITH A POLYCLONAL

1032
00:39:47,160 --> 00:39:50,880
ADDING LIVE ATTENUATED VACCINES.

1033
00:39:50,880 --> 00:39:51,520
IF ANTIBODY NEUTRALIZATION TITER

1034
00:39:51,520 --> 00:39:53,600
IS HIGH IN SETTING OF

1035
00:39:53,600 --> 00:39:54,600
VACCINATION YOU SUPPRESS PRIMARY

1036
00:39:54,600 --> 00:39:55,040
RESPONSE.

1037
00:39:55,040 --> 00:39:58,120
IT'S NOT GOOD FOR THE PRIME.

1038
00:39:58,120 --> 00:40:00,400
WELL, THE ANTIBODY RESPONSE TO

1039
00:40:00,400 --> 00:40:01,080
THE PRIME.

1040
00:40:01,080 --> 00:40:04,240
BUT IF YOU GET THE STOICHIOMETRY

1041
00:40:04,240 --> 00:40:05,880
JUST RIGHT YOU ENHANCE THE

1042
00:40:05,880 --> 00:40:07,080
PRIMING AND ENHANCE THE MEMORY

1043
00:40:07,080 --> 00:40:08,800
RESPONSE TO A SECOND DOSE OF

1044
00:40:08,800 --> 00:40:09,160
VACCINE.

1045
00:40:09,160 --> 00:40:10,680
THAT WAS WORKED OUT WITH

1046
00:40:10,680 --> 00:40:13,680
MEASLES, WHEN THE VACCINE WAS

1047
00:40:13,680 --> 00:40:18,560
TOO HOT, PEOPLE WERE GIVEN

1048
00:40:18,560 --> 00:40:19,440
IMMUNOGLOBULIN AND VACCINE, CHOP

1049
00:40:19,440 --> 00:40:20,440
DID STUDIES.

1050
00:40:20,440 --> 00:40:23,920
IF ANTIBODIES ARE HIGH,

1051
00:40:23,920 --> 00:40:24,360
SUPPRESS.

1052
00:40:24,360 --> 00:40:26,240
IS IT STOICHIOMETRY IS PERFECT

1053
00:40:26,240 --> 00:40:27,760
YOU GET ENHANCEMENT.

1054
00:40:27,760 --> 00:40:28,960
WHEN ANTIBODIES ARE LOW YOU

1055
00:40:28,960 --> 00:40:31,360
DON'T SEE ANY EFFECT.

1056
00:40:31,360 --> 00:40:35,400
PART IS NOT JUST TIMING BUT

1057
00:40:35,400 --> 00:40:37,080
UNDERSTANDING THE FUNCTIONAL

1058
00:40:37,080 --> 00:40:37,560
STOICHIOMETRY.

1059
00:40:37,560 --> 00:40:39,800
AND MAYBE -- SOME PEOPLE TRIED

1060
00:40:39,800 --> 00:40:42,800
TO COUPLE THE ANTIBODY IN

1061
00:40:42,800 --> 00:40:49,480
VACCINE TO TARGET DEN  DENDRITIC

1062
00:40:49,480 --> 00:40:49,760
CELLS.

1063
00:40:49,760 --> 00:40:52,640
YES, FOR VACCINATION THERE'S A

1064
00:40:52,640 --> 00:40:57,240
SWEET SPOT OF ANTIBODIES THAT'S

1065
00:40:57,240 --> 00:40:58,320
BETTER THAN ANTI-GEN ALONE,

1066
00:40:58,320 --> 00:41:00,800
EXACTLY WHY I'M NOT SURE.

1067
00:41:00,800 --> 00:41:03,320
>>IS THERE ANYTHING IN
THE

1068
00:41:03,320 --> 00:41:06,080
OFFING THAT WOULD, YOU KNOW,

1069
00:41:06,080 --> 00:41:09,720
LEAD TO A NEW TECHNOLOGY OR

1070
00:41:09,720 --> 00:41:11,000
PLATFORM FOR ENHANCING ANTIBODY

1071
00:41:11,000 --> 00:41:11,920
DURABILITY THAT, YOU KNOW,

1072
00:41:11,920 --> 00:41:13,000
THERE'S SOME NICE ADVANCES THERE

1073
00:41:13,000 --> 00:41:15,960
ALREADY BUT IS THERE ANYTHING

1074
00:41:15,960 --> 00:41:20,320
YOU'RE AWARE OF THAT'S COMING IN

1075
00:41:20,320 --> 00:41:20,960
THE FUTURE?

1076
00:41:20,960 --> 00:41:24,600
>>THE CURRENT THINGS
BEING USED

1077
00:41:24,600 --> 00:41:27,240
LIKE YTELS, THOSE GET YOU TO,

1078
00:41:27,240 --> 00:41:29,960
WELL, EACH ANTIBODY IS DIFFERENT

1079
00:41:29,960 --> 00:41:32,680
BECAUSE THE FV INTERACTS WITH

1080
00:41:32,680 --> 00:41:34,640
FCRN SO DEPENDING ON THE

1081
00:41:34,640 --> 00:41:38,720
SEQUENCE BUT YOU MIGHT ENVISION

1082
00:41:38,720 --> 00:41:40,160
110 PHYSICAL -- 110 SOMEDAY

1083
00:41:40,160 --> 00:41:41,760
PHYSICAL HALF-LIFE, WHERE YOU

1084
00:41:41,760 --> 00:41:43,000
TOP OUT, THE BENEFITS HERE, I

1085
00:41:43,000 --> 00:41:45,280
DIDN'T HAVE TIME TO TALK ABOUT

1086
00:41:45,280 --> 00:41:48,680
OUR PROGRAM, I WANTED TO, WE'VE

1087
00:41:48,680 --> 00:41:50,640
DONE DISCOVERY WHERE YOU CAN

1088
00:41:50,640 --> 00:41:56,960
FIND ANTIBODIES, SOME FOR RIP

1089
00:41:56,960 --> 00:42:00,680
WHERE POTENCY IS .01 NANOGRAM

1090
00:42:00,680 --> 00:42:02,000
PER mL.

1091
00:42:02,000 --> 00:42:04,520
THE PREDICTED, WE DOSE DOWN IN

1092
00:42:04,520 --> 00:42:05,120
ANIMALS, PREDICTED EFFECTIVE

1093
00:42:05,120 --> 00:42:08,520
DOSE IN HUMAN IS LESS THAN 1

1094
00:42:08,520 --> 00:42:09,400
MILLIGRAM, IT'S 700 MICROGRAMS.

1095
00:42:09,400 --> 00:42:13,480
SO IF YOU GAVE A HUMAN BEING 300

1096
00:42:13,480 --> 00:42:15,160
MILLIGRAMS STANDARD DOSE OF THAT

1097
00:42:15,160 --> 00:42:17,640
ANTIBODY, YOU ALREADY HAVE A

1098
00:42:17,640 --> 00:42:20,800
HALF-LIFE THAT'S ENORMOUS, IT'S

1099
00:42:20,800 --> 00:42:21,000
YEARS.

1100
00:42:21,000 --> 00:42:23,120
IF YOU ADDED YTE TO THAT NOW

1101
00:42:23,120 --> 00:42:25,000
YOU'RE OUT TO 5 TO 10 YEARS.

1102
00:42:25,000 --> 00:42:29,840
I THINK THE POTENTIAL GAINS ARE

1103
00:42:29,840 --> 00:42:33,520
NOT NECESSARILY ENGINEERING THE

1104
00:42:33,520 --> 00:42:34,720
FCRN FOR PHYSICAL HALF-LIFE,

1105
00:42:34,720 --> 00:42:37,840
IT'S ACHIEVING A LONGER

1106
00:42:37,840 --> 00:42:39,560
FUNCTIONAL HALF-LIFE BY DROPPING

1107
00:42:39,560 --> 00:42:41,520
THE IC 50, INCREASE POTENCY, YOU

1108
00:42:41,520 --> 00:42:42,520
HAVE A LONGER FUNCTIONAL

1109
00:42:42,520 --> 00:42:43,600
HALF-LIFE RATHER THAN PHYSICAL

1110
00:42:43,600 --> 00:42:44,160
HALF-LIFE.

1111
00:42:44,160 --> 00:42:50,000
THAT'S WHERE THE GAINS ARE TO BE

1112
00:42:50,000 --> 00:42:51,160
MADE.

1113
00:42:51,160 --> 00:42:53,960
>>GREAT.

1114
00:42:53,960 --> 00:42:54,320
THANK YOU.

1115
00:42:54,320 --> 00:42:54,640
>>EXCELLENT.

1116
00:42:54,640 --> 00:42:56,120
>>TIM, SEEMS LIKE WE
SHOULD

1117
00:42:56,120 --> 00:42:56,600
MOVE ON.

1118
00:42:56,600 --> 00:42:59,240
>>THANK YOU FOR HAVING
ME.

1119
00:42:59,240 --> 00:43:01,200
>>I'LL SEE SOME OF YOU
TOMORROW

1120
00:43:01,200 --> 00:43:02,480
AT THE ZIKA MEETING.

1121
00:43:02,480 --> 00:43:03,880
>>SEE YOU THEN.

1122
00:43:03,880 --> 00:43:04,240
>>THANKS, JIM.

1123
00:43:04,240 --> 00:43:06,880
>>ALL RIGHT.

1124
00:43:06,880 --> 00:43:11,040
SO OUR NEXT PRESENTATION IS FROM

1125
00:43:11,040 --> 00:43:13,960
DR. SETEE, PROFESSOR IN CENTER

1126
00:43:13,960 --> 00:43:15,720
FOR AUTOIMMUNITY AND

1127
00:43:15,720 --> 00:43:17,360
INFLAMMATION AND CENTER FOR

1128
00:43:17,360 --> 00:43:19,480
INFECTIOUS DISEASE AND VACCINE

1129
00:43:19,480 --> 00:43:22,160
RESEARCH AT LA JOLLA INSTITUTE

1130
00:43:22,160 --> 00:43:23,200
FOR IMMUNOLOGY.

1131
00:43:23,200 --> 00:43:25,800
AND ALEX, ARE YOU READY?

1132
00:43:25,800 --> 00:43:31,280
>>YES. 

1133
00:43:31,280 --> 00:43:32,960
LET ME SHARE MY SCREEN.

1134
00:43:32,960 --> 00:43:38,640
AND HOPEFULLY YOU CAN SEE IT.

1135
00:43:38,640 --> 00:43:44,680
AND LET ME GO ON PRESENTATION

1136
00:43:44,680 --> 00:43:47,080
MODE. 

1137
00:43:47,080 --> 00:43:48,400
OOPS.

1138
00:43:48,400 --> 00:43:49,600
YOU SEE THE SCREEN?

1139
00:43:49,600 --> 00:43:51,320
>>LOOKS GREAT, ALEX.

1140
00:43:51,320 --> 00:43:52,560
>>OKAY, GOOD.

1141
00:43:52,560 --> 00:43:57,240
WHAT I THOUGHT I WOULD DO IS

1142
00:43:57,240 --> 00:43:58,480
TALK ABOUT TWO DIFFERENT

1143
00:43:58,480 --> 00:44:00,200
EXAMPLES OF WHAT HAS BEEN

1144
00:44:00,200 --> 00:44:04,240
ACCOMPLISHED IN THE CONTEXT OF

1145
00:44:04,240 --> 00:44:05,880
THE EPITOPE IDENTIFICATION AND

1146
00:44:05,880 --> 00:44:09,400
DISCOVERY, ONE RELATED TO

1147
00:44:09,400 --> 00:44:14,640
DENGUE, THE OTHER SARS-COV-2

1148
00:44:14,640 --> 00:44:18,280
MORE RECENTLY.

1149
00:44:18,280 --> 00:44:20,240
AND SPECIFICALLY, FIRST HAVE A

1150
00:44:20,240 --> 00:44:22,120
SHORT OVERVIEW OF APPROACHES FOR

1151
00:44:22,120 --> 00:44:24,320
T CELL EPITOPE IDENTIFICATION

1152
00:44:24,320 --> 00:44:26,480
AND VALIDATION AND GO INTO TWO

1153
00:44:26,480 --> 00:44:28,560
SPECIFIC EXAMPLES HERE.

1154
00:44:28,560 --> 00:44:30,640
SO, YOU ALL KNOW DIFFERENT

1155
00:44:30,640 --> 00:44:36,120
ASSAYS ARE UTILIZED TO MEASURE

1156
00:44:36,120 --> 00:44:39,400
T-CELL RESPONSES, SO PROBABLY

1157
00:44:39,400 --> 00:44:43,480
THE MOST SIMPLE BUT CONVERSELY

1158
00:44:43,480 --> 00:44:47,520
LESS INFORMATIVE ASSAY IS THE

1159
00:44:47,520 --> 00:44:52,000
WHOLE BLOG INTERFERON GAMMA

1160
00:44:52,000 --> 00:44:56,040
RELEASE ASSAY, USED IN TB AS

1161
00:44:56,040 --> 00:44:57,560
QUANTUM THEOREM ASSAY, IT WORKS

1162
00:44:57,560 --> 00:45:00,160
BUT DOESN'T TELL WHAT YOU KIND

1163
00:45:00,160 --> 00:45:01,440
OF CELLS ARE PRODUCING

1164
00:45:01,440 --> 00:45:03,520
INTERFERON GAMMA.

1165
00:45:03,520 --> 00:45:08,680
NEXT STEP UP IS THE ELISPOT

1166
00:45:08,680 --> 00:45:10,200
ASSAYS, ROBUST, RELATIVELY

1167
00:45:10,200 --> 00:45:10,840
HIGH-THROUGHPUT, BUT FAR LESS

1168
00:45:10,840 --> 00:45:13,040
SENSITIVE OF SOME OF THE MORE

1169
00:45:13,040 --> 00:45:13,720
SECOND GENERATION ASSAYS THAT

1170
00:45:13,720 --> 00:45:15,680
I'M GOING TO DISCUSS IN A

1171
00:45:15,680 --> 00:45:16,040
SECOND.

1172
00:45:16,040 --> 00:45:19,840
AND ALSO THEY DON'T GIVE ANY

1173
00:45:19,840 --> 00:45:21,000
INFORMATION ABOUT THE PHENOTYPE

1174
00:45:21,000 --> 00:45:22,360
OF A RESPONDING T CELL WHERE

1175
00:45:22,360 --> 00:45:30,800
THEY ARE CD4 OR CD8 AND SO

1176
00:45:30,800 --> 00:45:31,000
FORTH.

1177
00:45:31,000 --> 00:45:34,200
EXTRACELLULAR CYTOKINE STAINING

1178
00:45:34,200 --> 00:45:37,280
INSTEAD DETECT FUNCTIONAL

1179
00:45:37,280 --> 00:45:39,560
RESPONSES, AND THEY ARE -- THEY

1180
00:45:39,560 --> 00:45:42,760
GENERATE PHENOTYPIC INFORMATION.

1181
00:45:42,760 --> 00:45:44,240
NOT ONLY YOU DETECT INTERFERON

1182
00:45:44,240 --> 00:45:47,560
GAMMA OR IL-5 OR IL-10 BUT ALSO

1183
00:45:47,560 --> 00:45:49,720
KNOW WHAT IS THE CELL THAT MAKES

1184
00:45:49,720 --> 00:45:57,120
CD4, CD8, YOU CAN MEASURE ALSO

1185
00:45:57,120 --> 00:46:02,440
OTHER PHENOACTIVIC MARKERS ON

1186
00:46:02,440 --> 00:46:04,400
THE CELL SURFACE.

1187
00:46:04,400 --> 00:46:09,720
POTENTIAL PROBLEM IS ICS DETECTS

1188
00:46:09,720 --> 00:46:12,200
PRODUCTION OF CYTOKINE, A

1189
00:46:12,200 --> 00:46:14,240
PROBLEM, IN THE CASE FOR EXAMPLE

1190
00:46:14,240 --> 00:46:18,560
OF FOLLICULAR T HELPER CELLS

1191
00:46:18,560 --> 00:46:19,520
BECAUSE NOTORIOUSLY BOTH CELLS

1192
00:46:19,520 --> 00:46:21,720
DON'T MAKE A LOT OF CYTOKINES.

1193
00:46:21,720 --> 00:46:26,360
YOU WOULDN'T DETECT, IN FACT WE

1194
00:46:26,360 --> 00:46:32,920
DEVELOP THIS AIM  ASSAY IN

1195
00:46:32,920 --> 00:46:33,800
COLLABORATION WITH SHANE CROWLEY

1196
00:46:33,800 --> 00:46:34,760
THE MAIN DRIVING FORCE TO

1197
00:46:34,760 --> 00:46:39,160
OVERCOME THE ISSUES. 

1198
00:46:39,160 --> 00:46:41,120
AIM ASSAY DETECTS UPREGULATION

1199
00:46:41,120 --> 00:46:47,680
OF MARKERS WHEN THE T CELL IS

1200
00:46:47,680 --> 00:46:48,680
ENCOUNTERED THE COGNATE ANTIGEN,

1201
00:46:48,680 --> 00:46:51,760
IT'S NOT DEPEND ON DETECTING

1202
00:46:51,760 --> 00:46:53,280
CYTOKINES, THE OTHER PROBLEM IF

1203
00:46:53,280 --> 00:46:55,240
YOU RUN AN ICS FOR INTERFERON

1204
00:46:55,240 --> 00:46:57,320
GAMMA, THE CELL IS NOT MAKING

1205
00:46:57,320 --> 00:47:02,680
INTERFERON GAMMA BUT MAKING A

1206
00:47:02,680 --> 00:47:05,200
DIFFERENT CYTOKINE, YOU WOULD

1207
00:47:05,200 --> 00:47:05,560
MISS.

1208
00:47:05,560 --> 00:47:09,040
THERE ARE OTHER ASSAYS SUCH AS

1209
00:47:09,040 --> 00:47:10,000
TETRIMERS, TCR SEQUENCING WHICH

1210
00:47:10,000 --> 00:47:14,960
I'M NOT GOING TO DISCUSS HERE

1211
00:47:14,960 --> 00:47:17,120
TODAY, I TRUST DAVID WHO FOLLOWS

1212
00:47:17,120 --> 00:47:20,080
ME, NEXT SPEAKER, WILL DISCUSS

1213
00:47:20,080 --> 00:47:23,920
SOME OF THIS, ALSO VERY GOOD.

1214
00:47:23,920 --> 00:47:28,280
ONE POINT I WANT TO TOUCH ON IS

1215
00:47:28,280 --> 00:47:32,760
BEYOND WHAT PARTICULAR ASSAY YOU

1216
00:47:32,760 --> 00:47:34,880
MAY USE, YOU HAVE TO CONSIDER

1217
00:47:34,880 --> 00:47:38,600
DIFFERENT FORMATS TO BE

1218
00:47:38,600 --> 00:47:39,560
CONSIDERED.

1219
00:47:39,560 --> 00:47:41,320
SO, ONE FORMAT IS EX VIVO

1220
00:47:41,320 --> 00:47:41,880
ASSAYS.

1221
00:47:41,880 --> 00:47:45,040
SO THAT IS A FORMAT WHERE YOU

1222
00:47:45,040 --> 00:47:51,840
JUST ASSAY FRESH CELLS OR FROZEN

1223
00:47:51,840 --> 00:47:53,480
PBMCs, WITHOUT ANY IN VITRO

1224
00:47:53,480 --> 00:47:53,920
EXPANSION.

1225
00:47:53,920 --> 00:47:56,440
THIS IS OBVIOUSLY MOST

1226
00:47:56,440 --> 00:47:59,600
PHYSIOLOGICALLY BECAUSE DOESN'T

1227
00:47:59,600 --> 00:48:00,040
ALTER PHENOTYPE.

1228
00:48:00,040 --> 00:48:02,440
THESE ARE LIVE CELLS, CAN BE

1229
00:48:02,440 --> 00:48:06,280
SORTED AND ISOLATED, SO IT'S

1230
00:48:06,280 --> 00:48:08,440
VERY AMENABLE TO DOWNSTREAM

1231
00:48:08,440 --> 00:48:09,240
ANALYSIS WITH TRANSCRIPTOMICS,

1232
00:48:09,240 --> 00:48:11,560
SINGLE CELL AND SO FORTH.

1233
00:48:11,560 --> 00:48:18,000
IT DOES REQUIRE A LITTLE BIT

1234
00:48:18,000 --> 00:48:21,080
MORE CELLSN IN COMPARISON TO IN

1235
00:48:21,080 --> 00:48:21,560
VITRO.

1236
00:48:21,560 --> 00:48:22,360
WHAT'S TYPICALLY DONE, ONE- OR

1237
00:48:22,360 --> 00:48:25,000
TWO- WEEK IN VITRO CULTURE, AND

1238
00:48:25,000 --> 00:48:27,800
THIS IS VERY EFFECTIVE IN

1239
00:48:27,800 --> 00:48:30,520
EXPANDING ANTIGENS FOR T CELLS.

1240
00:48:30,520 --> 00:48:34,240
THAT'S ALLOWING YOU TO DETECT

1241
00:48:34,240 --> 00:48:39,560
WEAK RESPONSES, YOU CAN STILL DO

1242
00:48:39,560 --> 00:48:42,960
TCR SEQUENCING, YOU CAN DO IT EX

1243
00:48:42,960 --> 00:48:43,480
VIVO.

1244
00:48:43,480 --> 00:48:46,560
IT'S MORE LABORIOUS, CERTAIN

1245
00:48:46,560 --> 00:48:48,240
CELL TYPES LIKE TREG DO NOT

1246
00:48:48,240 --> 00:48:53,360
EXPAND REEL IN VITRO.

1247
00:48:53,360 --> 00:48:55,120
PHENOTYPE IS ALTERED.

1248
00:48:55,120 --> 00:48:57,120
THE LAST THING TO CONSIDER IS

1249
00:48:57,120 --> 00:48:59,600
WHAT ANTIGEN ARE YOU GOING TO

1250
00:48:59,600 --> 00:49:02,480
USE TO CONFRONT THE T CELLS IN

1251
00:49:02,480 --> 00:49:05,440
THE ASSAY FORMAT AND IN SPECIFIC

1252
00:49:05,440 --> 00:49:05,840
ASSAY.

1253
00:49:05,840 --> 00:49:13,680
AND I'M GOING TO DISCUSS THIS A

1254
00:49:13,680 --> 00:49:14,880
LITTLE BIT FURTHER BECAUSE WE

1255
00:49:14,880 --> 00:49:16,400
NEED TO ANSWER THE QUESTION OF

1256
00:49:16,400 --> 00:49:18,480
WHAT ANTIGENS ARE WE GOING TO

1257
00:49:18,480 --> 00:49:22,520
USE AND WHAT IS A RELEVANT

1258
00:49:22,520 --> 00:49:24,600
ANTIGEN TO USE IN MOST

1259
00:49:24,600 --> 00:49:28,560
SITUATIONS, WHAT PROMPTED US TO

1260
00:49:28,560 --> 00:49:31,200
DEVELOP THIS MEGAPOOL APPROACH.

1261
00:49:31,200 --> 00:49:35,040
THIS STARTS FROM CONSIDERATION

1262
00:49:35,040 --> 00:49:36,600
THAT IN REALITY HUMAN T CELLS

1263
00:49:36,600 --> 00:49:40,720
RECOGNIZE A LOT OF DIFFERENT

1264
00:49:40,720 --> 00:49:43,960
ANTIGENS, SO YOU GO FROM 25

1265
00:49:43,960 --> 00:49:45,240
DIFFERENT POTENTIAL ANTIGENS, IN

1266
00:49:45,240 --> 00:49:47,880
THE CASE OF SARS-COV-2, TO

1267
00:49:47,880 --> 00:49:50,600
HUNDREDS OF DIFFERENT EXPRESSED

1268
00:49:50,600 --> 00:49:52,920
IN POXVIRUSES OR HERPES VIRUSES,

1269
00:49:52,920 --> 00:49:54,240
TO THOUSANDS OF DIFFERENT

1270
00:49:54,240 --> 00:50:04,760
ANTIGENS EXPRESSED IN THE CASE

1271
00:50:05,760 --> 00:50:09,680
OF BACTERIA SUCH TUBERCULOSIS,

1272
00:50:09,680 --> 00:50:14,120
BORE DA TELL A, SO  THIS IS

1273
00:50:14,120 --> 00:50:19,920
FURTHER COMPLICATED BY THE FACT

1274
00:50:19,920 --> 00:50:21,760
HUMANS EXPRESS HLA TYPES, SIX

1275
00:50:21,760 --> 00:50:24,720
DIFFERENT IN MOST HUMANS, SIX

1276
00:50:24,720 --> 00:50:27,040
DIFFERENT CLASS 1, EIGHT CLASS 2

1277
00:50:27,040 --> 00:50:28,600
TYPES.

1278
00:50:28,600 --> 00:50:32,080
SO IT'S A VERY LARGE DEGREE OF

1279
00:50:32,080 --> 00:50:35,760
HETEROGENEITY WHICH PROMPTED US

1280
00:50:35,760 --> 00:50:41,600
TO REALLY PUSH THE TECHNOLOGY TO

1281
00:50:41,600 --> 00:50:44,240
SEE HOW MANY DIFFERENT PEPTIDES

1282
00:50:44,240 --> 00:50:46,280
AND CANDIDATE EPITOPES WE COULD

1283
00:50:46,280 --> 00:50:50,760
COMBINE A SINGLE POOL, HAD TO

1284
00:50:50,760 --> 00:50:52,200
USE SEQUENTIAL STRATEGY TO AVOID

1285
00:50:52,200 --> 00:50:53,880
TOXICITY AND NOW CAN ROUTINELY

1286
00:50:53,880 --> 00:50:55,920
USE POOLS OF HUNDREDS OF

1287
00:50:55,920 --> 00:50:57,000
DIFFERENT PEPTIDES.

1288
00:50:57,000 --> 00:50:57,800
DEPENDING ON THE PARTICULAR

1289
00:50:57,800 --> 00:51:01,640
APPLICATION, YOU CAN USE

1290
00:51:01,640 --> 00:51:03,160
OVERLAPPING PEPTIDES, SPANNING

1291
00:51:03,160 --> 00:51:07,960
THE ENTIRE SEQUENCE OF ANTIGEN

1292
00:51:07,960 --> 00:51:09,520
OF INTEREST, OR IF THE NUMBER OF

1293
00:51:09,520 --> 00:51:12,360
ANTIGENS 

1294
00:51:12,360 --> 00:51:14,760
ANTIGENS TO BE CONSIDERED IS TOO

1295
00:51:14,760 --> 00:51:15,600
LARGE OR CONVERSELY AVAILABLE TO

1296
00:51:15,600 --> 00:51:23,720
STUDIES TOO SMALL YOU CAN USE

1297
00:51:23,720 --> 00:51:27,360
PREDICTIONS MAKING SURE YOU DO A

1298
00:51:27,360 --> 00:51:29,640
GOOD JOB REPRESENTING IT, IN THE

1299
00:51:29,640 --> 00:51:31,320
DIFFERENT LOCI OR IF THE TARGET

1300
00:51:31,320 --> 00:51:34,360
IS STUDIED EXTENSIVELY AND THE

1301
00:51:34,360 --> 00:51:35,880
EPITOPES RECOGNIZED BY HUMAN T

1302
00:51:35,880 --> 00:51:38,960
CELLS ARE ALREADY KNOWN TO A

1303
00:51:38,960 --> 00:51:40,800
LARGE EXTENT, YOU CAN USE

1304
00:51:40,800 --> 00:51:44,760
UNDATED EVIDENCE.

1305
00:51:44,760 --> 00:51:46,480
THIS MEGAPOOL APPROACH HAS BEEN

1306
00:51:46,480 --> 00:51:51,200
DESCRIBED AND VALIDATED FOR MANY

1307
00:51:51,200 --> 00:51:55,880
DIFFERENT VIRUSES BUT MICRO

1308
00:51:55,880 --> 00:52:00,080
BACTERIA, ALLERGENS, 

1309
00:52:00,080 --> 00:52:00,880
AUTOIMMUNITY.

1310
00:52:00,880 --> 00:52:04,880
AS WAS MENTIONED EARLIER, WE

1311
00:52:04,880 --> 00:52:09,680
HAVE DEVELOPED REAGENTS, AND

1312
00:52:09,680 --> 00:52:12,400
SHARED THESE REAGENTS WORLDWIDE

1313
00:52:12,400 --> 00:52:14,160
WITH STARTING COLLABORATIONS,

1314
00:52:14,160 --> 00:52:15,920
SOMETIMES SENDING TO PEPTIDES,

1315
00:52:15,920 --> 00:52:17,440
IN THE CASE OF SARS-COV-2 THIS

1316
00:52:17,440 --> 00:52:20,400
WAS IMPORTANT TO CATALYZE BASIC

1317
00:52:20,400 --> 00:52:21,800
AND APPLIED RESEARCH, WE SHARED

1318
00:52:21,800 --> 00:52:28,040
THIS WITH HUNDREDS OF LABS IN

1319
00:52:28,040 --> 00:52:29,680
163 DIFFERENT LABS, SIX

1320
00:52:29,680 --> 00:52:30,920
CONTINENTS, IF YOU KNOW OF

1321
00:52:30,920 --> 00:52:33,760
ANYBODY THAT HAS A LAB IN

1322
00:52:33,760 --> 00:52:37,040
ANTARCTICA WE'LL HAVE HAVE EVERY

1323
00:52:37,040 --> 00:52:40,320
CONTINENT WHERE WE SENT THE

1324
00:52:40,320 --> 00:52:40,600
MEGAPOOLS.

1325
00:52:40,600 --> 00:52:45,000
LET ME GIVE AN EXAMPLES OF HOW

1326
00:52:45,000 --> 00:52:47,280
WE USE THESE APPROACHES TO

1327
00:52:47,280 --> 00:52:53,680
CHARACTERIZE T CELLS IN THE CASE

1328
00:52:53,680 --> 00:52:57,400
OF DENGUE IS, A MAJOR HEALTH

1329
00:52:57,400 --> 00:53:01,320
PROBLEM, A MEMBER OF THE

1330
00:53:01,320 --> 00:53:04,080
FLAVIVIRUS GENUS, WHICH HAS

1331
00:53:04,080 --> 00:53:05,840
SEVERAL VIRUSES OF PUBLIC HEALTH

1332
00:53:05,840 --> 00:53:07,680
CONCERN SUCH AS ZIKA, YELLOW

1333
00:53:07,680 --> 00:53:12,160
FEVER, WEST NILE, SO FORTH.

1334
00:53:12,160 --> 00:53:16,440
AND DENGUE IS -- THERE ARE FOUR

1335
00:53:16,440 --> 00:53:17,560
SEROTYPES, ONE THROUGH FOUR,

1336
00:53:17,560 --> 00:53:23,240
HUNDREDS OF MILLIONS OF

1337
00:53:23,240 --> 00:53:26,880
INFECTIONS PER YEAR, AND LIKELY

1338
00:53:26,880 --> 00:53:28,840
THE LIFE-THREATENING SEVERE

1339
00:53:28,840 --> 00:53:31,920
DISEASE IS LIMITED TO SMALL

1340
00:53:31,920 --> 00:53:34,840
FRACTION OF THOSE CASES, AND

1341
00:53:34,840 --> 00:53:38,600
CURIOUSLY THIS SEVERE DISEASE IS

1342
00:53:38,600 --> 00:53:40,320
ASSOCIATED WITH AN HETEROLOGOUS

1343
00:53:40,320 --> 00:53:40,560
SETTING.

1344
00:53:40,560 --> 00:53:42,080
SOMEONE GETS INFECTED WITH

1345
00:53:42,080 --> 00:53:44,600
DENGUE 2 AT FIRST TIME,

1346
00:53:44,600 --> 00:53:46,360
REINFECTED A SECOND TIME WITH

1347
00:53:46,360 --> 00:53:49,560
SAY DENGUE 3, THE RISK FOR

1348
00:53:49,560 --> 00:53:54,160
SEVERE DISEASE IS HIGHEST.

1349
00:53:54,160 --> 00:53:59,000
WE STUDIED QUITE A BIT DENGUE IN

1350
00:53:59,000 --> 00:54:03,000
TWO ENDEMIC AREAS, ONE

1351
00:54:03,000 --> 00:54:04,040
NICARAGUA, THE OTHER SRI LANKA,

1352
00:54:04,040 --> 00:54:08,320
BY DESIGN BECAUSE WE WANTED TO

1353
00:54:08,320 --> 00:54:10,080
STUDY TWO COMPLETELY DIFFERENT

1354
00:54:10,080 --> 00:54:15,000
POPULATIONS ASSOCIATED WITH

1355
00:54:15,000 --> 00:54:20,360
DIFFERENT HEALTH CARE, DIFFERENT

1356
00:54:20,360 --> 00:54:21,000
ETHNICITIES, HLA DISTRIBUTIONS,

1357
00:54:21,000 --> 00:54:24,120
TO FOLLOWING BUT REALLY FINDINGS

1358
00:54:24,120 --> 00:54:27,080
THAT WOULD BE TRUE AND VERIFIED

1359
00:54:27,080 --> 00:54:29,960
IN SUCH DIVERSE SETTINGS WOULD

1360
00:54:29,960 --> 00:54:35,000
BE REALLY UNIVERSAL. 

1361
00:54:35,000 --> 00:54:38,560
SO, WE APPLIED ETHICAL

1362
00:54:38,560 --> 00:54:41,040
IDENTIFICATION STRATEGIES AND WE

1363
00:54:41,040 --> 00:54:45,040
EVENTUALLY DEFINED ABOUT 300

1364
00:54:45,040 --> 00:54:47,200
EPITOPES IN NICARAGUA ENDEMIC

1365
00:54:47,200 --> 00:54:48,640
AREA POPULATION AREA, ABOUT 400

1366
00:54:48,640 --> 00:54:53,520
IN SRI LANKA, AND THEN WE LOOKED

1367
00:54:53,520 --> 00:54:56,520
AT THE OVERLAP AND WE ZOOM IN ON

1368
00:54:56,520 --> 00:55:00,000
ABOUT 250 DIFFERENT EPITOPES

1369
00:55:00,000 --> 00:55:01,880
WHICH ACCOUNTED FOR 90% OF

1370
00:55:01,880 --> 00:55:06,480
ACTIVITY, IN BOTH  POPULATIONS

1371
00:55:06,480 --> 00:55:12,960
ABLE TO GENERATE A CD8 MEGAPOOL,

1372
00:55:12,960 --> 00:55:14,040
WE THEN SHOWED THIS MEGAPOOL

1373
00:55:14,040 --> 00:55:16,360
COULD BE USE TO DETECT T-CELL

1374
00:55:16,360 --> 00:55:17,680
RESPONSES IN ANY POPULATION, IF

1375
00:55:17,680 --> 00:55:20,520
YOU WENT IN BRAZIL, INDIA OR

1376
00:55:20,520 --> 00:55:24,040
WHATEVER, STILL WERE ABLE TO USE

1377
00:55:24,040 --> 00:55:27,000
THIS MEGAPOOL TO DETECT

1378
00:55:27,000 --> 00:55:30,520
RESPONSES AND SIMILAR EPITOPE

1379
00:55:30,520 --> 00:55:31,160
IDENTIFICATION STUDIES WHICH I'M

1380
00:55:31,160 --> 00:55:32,680
NOT GOING TO DISCUSS FOR

1381
00:55:32,680 --> 00:55:36,120
INTEREST OF TIME LED TO

1382
00:55:36,120 --> 00:55:38,760
DEFINITION OF MEGA POOL AT CD4

1383
00:55:38,760 --> 00:55:40,200
EPITOPES RECOGNIZED IN HUMAN

1384
00:55:40,200 --> 00:55:44,240
POPULATIONS AND ENCODED BY

1385
00:55:44,240 --> 00:55:44,560
DENGUE.

1386
00:55:44,560 --> 00:55:45,640
SO, ONE IMPORTANT THING THAT

1387
00:55:45,640 --> 00:55:52,240
CAME OUT OF THIS STUDY, NOW WE

1388
00:55:52,240 --> 00:55:56,920
COULD ACTUALLY MEASURE RELIABLY

1389
00:55:56,920 --> 00:55:59,440
HUMAN T-CELL RESPONSES IN

1390
00:55:59,440 --> 00:56:04,800
PATIENT POPULATIONS WITHOUT

1391
00:56:04,800 --> 00:56:07,280
HAVING JUST ONE EPITOPE OR

1392
00:56:07,280 --> 00:56:09,840
PARTIAL PRESENTATIONS, AND THIS

1393
00:56:09,840 --> 00:56:11,040
WAS RELEVANT BECAUSE I'VE BEEN

1394
00:56:11,040 --> 00:56:15,760
IN THE FIELD FOR A LONG TIME,

1395
00:56:15,760 --> 00:56:20,160
THIS CONCEPT, BUT WAS ACTUALLY

1396
00:56:20,160 --> 00:56:21,240
NOT REALLY SUPPORTED

1397
00:56:21,240 --> 00:56:23,800
EXPERIMENTALLY BY SOLID DATA, IN

1398
00:56:23,800 --> 00:56:27,920
MY OPINION, THAT T CELLS WERE

1399
00:56:27,920 --> 00:56:29,120
RESPONSIBLE FOR THE SEVERE

1400
00:56:29,120 --> 00:56:30,880
DISEASE IN ACUTE PHASE AND THAT

1401
00:56:30,880 --> 00:56:33,840
THE T CELLS WERE THE BAD ACTORS.

1402
00:56:33,840 --> 00:56:38,120
IN FACT IN MY OPINION ALSO

1403
00:56:38,120 --> 00:56:39,200
SOMEWHAT REALLY UNFORTUNATE

1404
00:56:39,200 --> 00:56:40,400
CONSEQUENCES BECAUSE IN THE

1405
00:56:40,400 --> 00:56:43,480
VACCINE SETTING PEOPLE SENDED TO

1406
00:56:43,480 --> 00:56:44,800
SHY AWAY FROM INDUCING T-CELL

1407
00:56:44,800 --> 00:56:45,040
RESPONSES.

1408
00:56:45,040 --> 00:56:49,160
BUT THEN WE WERE ABLE TO

1409
00:56:49,160 --> 00:56:50,600
ACTUALLY ISOLATE THE

1410
00:56:50,600 --> 00:56:51,680
ANTIGEN-SPECIFIC CD4 AND CD8 T

1411
00:56:51,680 --> 00:56:53,320
CELLS AND ASK THE QUESTION, IS

1412
00:56:53,320 --> 00:56:57,680
THERE A DIFFERENCE IN IMMUNE

1413
00:56:57,680 --> 00:56:58,040
SIGNATURE?

1414
00:56:58,040 --> 00:57:00,440
ARE THEY CAUSING HAVOC IN THE

1415
00:57:00,440 --> 00:57:01,520
ACUTE PHASE AND SEVERE DISEASE?

1416
00:57:01,520 --> 00:57:04,160
AND THAT WAS NOT TRUE.

1417
00:57:04,160 --> 00:57:05,800
BOTH FOR CD4 AND CD8.

1418
00:57:05,800 --> 00:57:13,160
SO THIS WAS A VERY IMPORTANT

1419
00:57:13,160 --> 00:57:15,200
ADVANCE, IN MY OPINIONS,

1420
00:57:15,200 --> 00:57:15,800
UNDERSTANDING IMMUNOPATHOLOGY

1421
00:57:15,800 --> 00:57:19,400
ASSOCIATED WITH SEVERE DENGUE

1422
00:57:19,400 --> 00:57:19,640
INFECTION.

1423
00:57:19,640 --> 00:57:21,560
FURTHERMORE, WHEN YOU LOOK AT

1424
00:57:21,560 --> 00:57:25,200
THE TARGETS OF IMMUNE RESPONSES,

1425
00:57:25,200 --> 00:57:28,120
TURNS OUT THAT IMMUNE RESPONSES

1426
00:57:28,120 --> 00:57:31,240
ON TOP OF CD8 AND ON THE BOTTOM

1427
00:57:31,240 --> 00:57:38,120
IS CD4,  FOR SAKE OF

1428
00:57:38,120 --> 00:57:39,640
ILLUSTRATION, IS THAT THE

1429
00:57:39,640 --> 00:57:42,920
ENVELOPE PROTEIN WHICH IS THE

1430
00:57:42,920 --> 00:57:45,080
TARGET OF ANTIBODY RESPONSES,

1431
00:57:45,080 --> 00:57:48,040
WHICH ARE OF INTEREST, TO

1432
00:57:48,040 --> 00:57:50,000
PREVENT INFECTION, IS ACTUALLY

1433
00:57:50,000 --> 00:57:54,000
NOT A GOOD TARGET FOR EITHER CD4

1434
00:57:54,000 --> 00:57:56,120
AND T CELLS.

1435
00:57:56,120 --> 00:58:00,240
IN THE CD4 T CELLS ACTUALLY

1436
00:58:00,240 --> 00:58:04,800
RECOGNIZE CAPSID AND NS 3 MOST

1437
00:58:04,800 --> 00:58:09,200
DOMINANTLY, CD8 SIMILARLY NS3 IS

1438
00:58:09,200 --> 00:58:11,680
DOMINANT TARGET FOLLOWED BY NS5.

1439
00:58:11,680 --> 00:58:15,320
THIS IS RELEVANT IN THE CONTEXT

1440
00:58:15,320 --> 00:58:16,960
OF VACCINE DEVELOPMENT.

1441
00:58:16,960 --> 00:58:23,760
AND SO THERE ARE THREE DIFFERENT

1442
00:58:23,760 --> 00:58:27,000
MAIN VACCINE CONSTRUCTS AND

1443
00:58:27,000 --> 00:58:30,640
DESIGNS THAT HAVE BEEN DEVELOPED

1444
00:58:30,640 --> 00:58:40,080
FOR DENGUE AND ONE IS DENGVAXIA

1445
00:58:40,080 --> 00:58:44,680
DEVELOPED BY SANOFI PASTEUR, ONE

1446
00:58:44,680 --> 00:58:52,240
BY TAKEDA, AND TV003 FOLLOWING

1447
00:58:52,240 --> 00:58:56,400
THE WORK OF STEVE WHITEHEAD AT

1448
00:58:56,400 --> 00:58:58,000
NIAID, AND THEN MERCK.

1449
00:58:58,000 --> 00:59:01,000
ALL RELY ON FOUR DIFFERENT

1450
00:59:01,000 --> 00:59:03,040
ENVELOPES FROM FOUR DENGUE

1451
00:59:03,040 --> 00:59:06,360
SEROTYPES. 

1452
00:59:06,360 --> 00:59:10,640
IN THE CASE OF THE DENGVAXIA THE

1453
00:59:10,640 --> 00:59:20,040
BACKBONE OF YELLOW FEVER WHILE

1454
00:59:20,040 --> 00:59:23,520
TAKEDA AND NIAID USED THEM

1455
00:59:23,520 --> 00:59:23,920
(INDISCERNIBLE).

1456
00:59:23,920 --> 00:59:25,960
I WANT TO REMIND YOU WHAT I

1457
00:59:25,960 --> 00:59:36,600
SHOWED IN THE PREVIOUS SLIDE ACY

1458
00:59:43,240 --> 00:59:47,240
HUMAN T CELLS NOT RECOGNIZED

1459
00:59:47,240 --> 00:59:48,760
ENVELOPE VERY WELL, THERE WAS

1460
00:59:48,760 --> 00:59:51,160
ALSO ANOTHER STUDY TO GET TO THE

1461
00:59:51,160 --> 00:59:54,440
BOTTOM WHERE WE LOOKED AT

1462
00:59:54,440 --> 00:59:57,720
WHETHER THE T CELLS INDUCED BY

1463
00:59:57,720 --> 01:00:06,040
YELLOW FEVER WOULD RECOGNIZE

1464
01:00:06,040 --> 01:00:06,600
DENGUE SEQUENCING.

1465
01:00:06,600 --> 01:00:09,880
THIS SAYS IF YOU WANT T CELLS,

1466
01:00:09,880 --> 01:00:12,400
IF YOU WANT ALSO CD8 TO KILL

1467
01:00:12,400 --> 01:00:16,800
INFECTED VIRUS, CD4 TO SUPPORT

1468
01:00:16,800 --> 01:00:19,200
THE ANTIBODY RESPONSE, ENVELOPE

1469
01:00:19,200 --> 01:00:22,280
BY ITSELF AND/OR ENVELOPE BY

1470
01:00:22,280 --> 01:00:25,440
ITSELF OR A YELLOW FEVER

1471
01:00:25,440 --> 01:00:30,480
CONSTRUCT IS NOTE  -- NOT GOINGE

1472
01:00:30,480 --> 01:00:32,560
ENOUGH.

1473
01:00:32,560 --> 01:00:35,600
WE EVALUATED T-CELL RESPONSES

1474
01:00:35,600 --> 01:00:38,440
INDUCED BY 003 TETRAVALENT

1475
01:00:38,440 --> 01:00:42,080
VACCINE, THAT INDUCES STRONG

1476
01:00:42,080 --> 01:00:44,360
T-CELL RESPONSES, ACTUALLY EVEN

1477
01:00:44,360 --> 01:00:48,120
HIGHER THAN WHAT WE'RE SEEING IN

1478
01:00:48,120 --> 01:00:53,840
CONVALESCENT PEOPLE FROM

1479
01:00:53,840 --> 01:00:56,440
NICARAGUA AND OTHER AREAS.

1480
01:00:56,440 --> 01:00:58,080
ALSO MOST T-CELL RESPONSE

1481
01:00:58,080 --> 01:01:03,680
OBSERVED IN THE CONTEXT OF

1482
01:01:03,680 --> 01:01:04,760
TETRAVALENT VACCINE WAS AGAINST

1483
01:01:04,760 --> 01:01:09,560
SEQUENCES SHARED BY FOUR

1484
01:01:09,560 --> 01:01:10,880
SEROTYPES.

1485
01:01:10,880 --> 01:01:13,960
SO REALLY INTERESTING FINDING,

1486
01:01:13,960 --> 01:01:17,680
SUCH AS COMBINATION OF DIFFERENT

1487
01:01:17,680 --> 01:01:28,240
DENGUE BACKBONES REALLY FOCUSES

1488
01:07:34,680 --> 01:07:34,880
 BY FAR

1489
01:07:34,880 --> 01:07:36,080
THE BEST.

1490
01:07:36,080 --> 01:07:37,640
ALSO EARLY CD8 RESPONSE

1491
01:07:37,640 --> 01:07:41,000
CORRELATED, IF YOU LOOK AT EARLY

1492
01:07:41,000 --> 01:07:42,880
RESPONSE, ANTIBODIES DO NOT

1493
01:07:42,880 --> 01:07:44,640
CORRELATE WITH A PARTICULARLY

1494
01:07:44,640 --> 01:07:46,920
MILDER OUTCOME.

1495
01:07:46,920 --> 01:07:48,920
THIS WAS CONFIRMED BY THE GROUP

1496
01:07:48,920 --> 01:07:52,360
IN SINGAPORE WHICH ADDED THE

1497
01:07:52,360 --> 01:07:54,800
FACT THAT EARLY T-CELL RESPONSES

1498
01:07:54,800 --> 01:08:03,560
WERE ASSOCIATED WITH LOWER VIRAL

1499
01:08:03,560 --> 01:08:06,440
LOAD, USING SAMPLES FROM

1500
01:08:06,440 --> 01:08:09,600
OUTBREAK, EARLY WUHAN EARLY IN

1501
01:08:09,600 --> 01:08:12,120
ITALY IN 2020, WE SAMPLED,

1502
01:08:12,120 --> 01:08:17,920
CONFIRMED WITH LARGER COHORT AND

1503
01:08:17,920 --> 01:08:19,440
SAW THIS IMPORTANT PHENOMENON

1504
01:08:19,440 --> 01:08:20,400
THAT ANOTHER IMPORTANT CORRELATE

1505
01:08:20,400 --> 01:08:23,800
OF MILD DISEASE WAS TO HAVE A

1506
01:08:23,800 --> 01:08:25,000
POLYFUNCTIONAL RESPONSE, SO

1507
01:08:25,000 --> 01:08:26,120
PEOPLE WITH T-CELL RESPONSE NOT

1508
01:08:26,120 --> 01:08:32,040
ONLY AGAINST SPIKE BUT ALSO

1509
01:08:32,040 --> 01:08:32,880
AGAINST OTHER ANTIGENS DID MUCH

1510
01:08:32,880 --> 01:08:35,400
BETTER THAN THE RESPONSE FOCUSED

1511
01:08:35,400 --> 01:08:37,480
ON SPIKE, A RECENT DATA BUT FOR

1512
01:08:37,480 --> 01:08:40,080
EMPHASIZE IN CERTAIN CONDITIONS

1513
01:08:40,080 --> 01:08:44,840
YOU CAN EVEN HAVE A PROTECTION

1514
01:08:44,840 --> 01:08:48,000
ASSOCIATED WITH T CELLS FROM

1515
01:08:48,000 --> 01:08:49,080
INFECTION.

1516
01:08:49,080 --> 01:08:59,240
SO, AT THIS POINT, WE MOVED TO

1517
01:08:59,240 --> 01:09:01,640
MEASURE RESPONSES AGAINST

1518
01:09:01,640 --> 01:09:04,480
VACCINATION, USING THE MEGAPOOLS

1519
01:09:04,480 --> 01:09:09,880
DEVELOPED IN THE PREVIOUS

1520
01:09:09,880 --> 01:09:20,320
STUDIES, COMPARED TWO mRNA

1521
01:09:21,200 --> 01:09:21,800
PLATFORMS, PROTEIN ADJUVANT

1522
01:09:21,800 --> 01:09:25,440
VACCINE, THIS IS A NICE STUDY IN

1523
01:09:25,440 --> 01:09:29,040
MY OPINION, SUBJECTS THAT WERE

1524
01:09:29,040 --> 01:09:31,480
ALL RECRUITED AND DONATED BLOOD

1525
01:09:31,480 --> 01:09:34,720
IN OUR CLINICAL CORE AND ALL

1526
01:09:34,720 --> 01:09:36,800
ASSAYS RUN ON THE SAME

1527
01:09:36,800 --> 01:09:38,240
INSTRUMENT, SAME DAYS, BY THE

1528
01:09:38,240 --> 01:09:40,640
SAME PEOPLE.

1529
01:09:40,640 --> 01:09:42,440
IT'S TIGHTLY COMPARABLE, AND

1530
01:09:42,440 --> 01:09:45,040
WHAT YOU SEE HERE THE THE

1531
01:09:45,040 --> 01:09:49,640
ANTIBODY RESPONSE GOES UP AND

1532
01:09:49,640 --> 01:09:52,720
DOWN, RISK WANES OVER SIX MONTHS

1533
01:09:52,720 --> 01:09:55,200
FOR BOTH mRNA PLATFORM, THE

1534
01:09:55,200 --> 01:09:57,320
VIRAL VECTOR IS NEVER AS GOOD IN

1535
01:09:57,320 --> 01:09:59,360
TERMS OF NEUTRALIZING ANTIBODY

1536
01:09:59,360 --> 01:10:07,240
BUT HAS A DIFFERENT KINETIC AND

1537
01:10:07,240 --> 01:10:08,360
GOOD NEUTRALIZING SIMILAR TO

1538
01:10:08,360 --> 01:10:08,720
mRNA.

1539
01:10:08,720 --> 01:10:11,640
I WANT TO POINT OUT THE

1540
01:10:11,640 --> 01:10:19,400
DIFFERENCE IN KINETICS OF T-CELL

1541
01:10:19,400 --> 01:10:20,200
RESPONSES, FOR DIFFERENT

1542
01:10:20,200 --> 01:10:23,240
PLATFORMS ARE MUCH MORE DURABLE.

1543
01:10:23,240 --> 01:10:26,200
THEY WANE MUCH LESS RAPIDLY.

1544
01:10:26,200 --> 01:10:30,240
NOW, THIS FITS WITH WHAT WAS

1545
01:10:30,240 --> 01:10:31,880
OBSERVED BEFORE THE VARIANTS

1546
01:10:31,880 --> 01:10:32,760
BECAME PREVALENT, WERE ALREADY

1547
01:10:32,760 --> 01:10:36,200
IN A NUMBER OF STUDIES FOR

1548
01:10:36,200 --> 01:10:38,680
EXAMPLE KAISER PERMANENTE WAS

1549
01:10:38,680 --> 01:10:40,880
OBSERVED THAT THE RESPONSE

1550
01:10:40,880 --> 01:10:42,960
INDUCED BY VACCINATION OR

1551
01:10:42,960 --> 01:10:44,560
NATURAL INFECTION TENDED TO PAIN

1552
01:10:44,560 --> 01:10:49,640
IN TERMS OF PROTECTION AGAINST

1553
01:10:49,640 --> 01:10:52,800
INFECTION, BUT THE VACCINES

1554
01:10:52,800 --> 01:10:54,000
STILL RETAINED SUBSTANTIAL

1555
01:10:54,000 --> 01:10:59,480
PROTECTION AGAINST SEVERE

1556
01:10:59,480 --> 01:11:00,560
DISEASE AND DEATH.

1557
01:11:00,560 --> 01:11:02,320
WHAT ABOUT VARIANTS?

1558
01:11:02,320 --> 01:11:05,280
WE DID STUDIES TO IDENTIFY CD4

1559
01:11:05,280 --> 01:11:09,440
AND CD8 EPITOPES, AND WE ENDED

1560
01:11:09,440 --> 01:11:13,040
UP DEFINING CLOSE TO A THOUSAND

1561
01:11:13,040 --> 01:11:16,880
EPITOPES, WE'RE NOT THE ONLY ONE

1562
01:11:16,880 --> 01:11:18,440
DOING THE STUDIES.

1563
01:11:18,440 --> 01:11:20,440
IF YOU MAKE A MEGA ANALYSIS OF

1564
01:11:20,440 --> 01:11:24,240
ALL THE DATA THAT WAS CONTAINED

1565
01:11:24,240 --> 01:11:28,160
IN THE IDP IN EARLY 2021,

1566
01:11:28,160 --> 01:11:33,520
ALREADY 2,000 DIFFERENT CD4, CD8

1567
01:11:33,520 --> 01:11:35,600
EPITOPE EXPERIMENTALLY DETECTED

1568
01:11:35,600 --> 01:11:36,480
IN HUMANS.

1569
01:11:36,480 --> 01:11:39,760
BY NOW WE'RE ABOUT 3,000

1570
01:11:39,760 --> 01:11:40,040
EPITOPES.

1571
01:11:40,040 --> 01:11:42,600
SO WHY AM I HARPING ON THIS

1572
01:11:42,600 --> 01:11:45,120
LARGE NUMBER OF EPITOPES BEING

1573
01:11:45,120 --> 01:11:45,400
RECOGNIZED?

1574
01:11:45,400 --> 01:11:48,400
BECAUSE THIS IS DIFFERENT FROM

1575
01:11:48,400 --> 01:11:51,360
WHAT YOU HEARD JIM TELLING YOU

1576
01:11:51,360 --> 01:11:56,240
WITH THE RBD REGION IS SMALL, SO

1577
01:11:56,240 --> 01:11:59,240
RELATIVELY FEW MUTATIONS IN THE

1578
01:11:59,240 --> 01:12:01,200
REGIONS THAT ARE RECOGNIZED BY

1579
01:12:01,200 --> 01:12:04,480
NEUTRALIZING ANTIBODIES CAN LEAD

1580
01:12:04,480 --> 01:12:09,720
TO A SUBSTANTIAL LOSS OF

1581
01:12:09,720 --> 01:12:12,040
ANTIBODY OVERACTIVITY OF

1582
01:12:12,040 --> 01:12:13,560
NEUTRALIZING ANTIBODIES.

1583
01:12:13,560 --> 01:12:17,400
AND CONVERSELY FOR T CELLS THIS

1584
01:12:17,400 --> 01:12:19,480
IS NOT REALLY FEASIBLE BECAUSE

1585
01:12:19,480 --> 01:12:21,240
SARS-COV-2 WOULD HAVE TO MUTATE

1586
01:12:21,240 --> 01:12:23,640
CONSTANTLY FROM EPITOPES TO

1587
01:12:23,640 --> 01:12:26,840
COMPLETELY ESCAPE HUMAN T CELL

1588
01:12:26,840 --> 01:12:27,200
RECOGNITION.

1589
01:12:27,200 --> 01:12:30,440
SO, IN FACT, THAT'S EXACTLY WHAT

1590
01:12:30,440 --> 01:12:31,320
YOU SEE.

1591
01:12:31,320 --> 01:12:32,960
WE SAW IN THIS STUDY WHERE WE

1592
01:12:32,960 --> 01:12:37,240
LOOKED AT ALL DIFFERENT VARIANTS

1593
01:12:37,240 --> 01:12:39,720
FROM ALPHA TO OMICRON, BUT

1594
01:12:39,720 --> 01:12:41,200
ESSENTIALLY 85% OR MORE OF T

1595
01:12:41,200 --> 01:12:46,120
CELL ACTIVITY WAS PRESERVED WITH

1596
01:12:46,120 --> 01:12:47,320
DIFFERENT VARIANTS.

1597
01:12:47,320 --> 01:12:49,760
THE LARGE MAJORITY OF T CELL

1598
01:12:49,760 --> 01:12:50,920
EPITOPES WERE 100% CONSERVED.

1599
01:12:50,920 --> 01:12:55,520
AND IN FACT IF WE DID REPERTOIRE

1600
01:12:55,520 --> 01:12:56,760
STUDIES WE ALSO SHOWED IN

1601
01:12:56,760 --> 01:12:58,280
INDIVIDUAL SUBJECTS THE MAJORITY

1602
01:12:58,280 --> 01:13:01,560
OF T CELL EPITOPES RECOGNIZED IN

1603
01:13:01,560 --> 01:13:03,240
THAT PARTICULAR SUBJECT WERE NOT

1604
01:13:03,240 --> 01:13:05,360
IMPACTED BY MUTATIONS IN THE

1605
01:13:05,360 --> 01:13:05,760
VARIANTS.

1606
01:13:05,760 --> 01:13:07,880
THIS WAS IN CONTRAST TO WHAT WAS

1607
01:13:07,880 --> 01:13:12,160
SEEN IN THE CASE OF NEUTRALIZING

1608
01:13:12,160 --> 01:13:16,120
ANTIBODIES, DRAMATICALLY

1609
01:13:16,120 --> 01:13:16,400
IMPACTED.

1610
01:13:16,400 --> 01:13:18,840
THIS WAS DONE, WAS CONFIRMED IN

1611
01:13:18,840 --> 01:13:22,640
MANY DIFFERENT STUDIES IN

1612
01:13:22,640 --> 01:13:23,640
COLLABORATION THAT INVOLVED LABS

1613
01:13:23,640 --> 01:13:25,840
ALL OVER THE WORLD, AND AT THIS

1614
01:13:25,840 --> 01:13:34,520
POINT IT'S I THINK WELL

1615
01:13:34,520 --> 01:13:35,520
ESTABLISHED THIS DICHOTOMY,

1616
01:13:35,520 --> 01:13:38,120
IMPACT IS MUCH GREATER AT THE

1617
01:13:38,120 --> 01:13:39,360
LEVEL OF NEUTRALIZING ANTIBODIES

1618
01:13:39,360 --> 01:13:40,800
WHILE T CELL ACTIVITY IS

1619
01:13:40,800 --> 01:13:45,720
ESSENTIALLY PRESERVED AT THE

1620
01:13:45,720 --> 01:13:46,440
POPULATION LEVEL.

1621
01:13:46,440 --> 01:13:47,880
THIS FITS WITH WHAT WE'RE

1622
01:13:47,880 --> 01:13:48,360
SEEING.

1623
01:13:48,360 --> 01:13:57,280
WE ALL SEE EVERY DAY WHERE NOW

1624
01:13:57,280 --> 01:13:59,440
THE VARIANTS HAVE PROTECTION

1625
01:13:59,440 --> 01:14:05,120
INDUCED BY VACCINE OR EFFECT OF

1626
01:14:05,120 --> 01:14:05,680
DIFFERENT VARIANTS IS MUCH

1627
01:14:05,680 --> 01:14:07,120
DECREASED IF YOU LOOK AT

1628
01:14:07,120 --> 01:14:08,880
PROTECTION FROM INFECTION, BUT

1629
01:14:08,880 --> 01:14:12,280
PROTECTION FROM SEVERE DISEASE

1630
01:14:12,280 --> 01:14:20,360
AND FROM DEATH IS MUCH -- IT'S

1631
01:14:20,360 --> 01:14:21,120
STILL LARGELY PRESERVED.

1632
01:14:21,120 --> 01:14:23,240
WHERE DO WE GO?

1633
01:14:23,240 --> 01:14:25,600
THIS IS ILLUSTRATING SOME OF THE

1634
01:14:25,600 --> 01:14:27,400
MEGAPOOLS WE CONTINUE TO

1635
01:14:27,400 --> 01:14:27,920
OPTIMIZE.

1636
01:14:27,920 --> 01:14:30,560
THIS IS A COMBINATION OF POOLS

1637
01:14:30,560 --> 01:14:34,840
THAT WE HAVE USED TO DETECT

1638
01:14:34,840 --> 01:14:39,120
IMMUNE RESPONSES, SO IT'S

1639
01:14:39,120 --> 01:14:43,040
DAYS BASICALLY A MEGA POOL THAT

1640
01:14:43,040 --> 01:14:43,720
DETECTS SPIKE, ANOTHER ONE THE

1641
01:14:43,720 --> 01:14:45,800
REST OF THE GENOME.

1642
01:14:45,800 --> 01:14:48,520
THIS COMBINATION PLOTS TWO

1643
01:14:48,520 --> 01:14:49,720
DIMENSIONAL -- IN TWO DIMENSIONS

1644
01:14:49,720 --> 01:14:52,360
CAN ACTUALLY TELL YOU A HISTORY

1645
01:14:52,360 --> 01:14:54,000
OF INFECTION.

1646
01:14:54,000 --> 01:14:55,640
SO PEOPLE ARE VACCINATED ONLY

1647
01:14:55,640 --> 01:14:59,800
REACT ONLY AGAINST SPIKE.

1648
01:14:59,800 --> 01:15:03,320
PEOPLE THAT HAVE BEEN INFECTED

1649
01:15:03,320 --> 01:15:05,280
BUT NOT VACCINATED OF COURSE SEE

1650
01:15:05,280 --> 01:15:09,080
BOTH SPIKE AND THE REST OF THE

1651
01:15:09,080 --> 01:15:09,680
GENOME.

1652
01:15:09,680 --> 01:15:12,400
PEOPLE THAT HAVE BREAKTHROUGH

1653
01:15:12,400 --> 01:15:14,240
INFECTION, FOR EXAMPLE, OR

1654
01:15:14,240 --> 01:15:16,560
HYBRID IMMUNITY, WE'VE SEEN BOTH

1655
01:15:16,560 --> 01:15:17,640
SPIKE TWICE, ONE BECAUSE OF

1656
01:15:17,640 --> 01:15:18,840
VACCINATION, ONE BECAUSE OF

1657
01:15:18,840 --> 01:15:20,480
INFECTION, THEY HAVE SO TO SPEAK

1658
01:15:20,480 --> 01:15:22,560
A HIGHER CONTENT OF SPIKE.

1659
01:15:22,560 --> 01:15:24,200
WE CAN ACTUALLY DO THIS AND

1660
01:15:24,200 --> 01:15:28,280
WE'VE SHOWN THIS IS MUCH MORE

1661
01:15:28,280 --> 01:15:30,200
SENSITIVE AT ANY SEROLOGICAL

1662
01:15:30,200 --> 01:15:30,400
ASSAY.

1663
01:15:30,400 --> 01:15:40,440
I WANT TO CLOSE HERE WITH THE

1664
01:15:40,440 --> 01:15:44,040
NOTION THAT ALL THIS DATA TELLS

1665
01:15:44,040 --> 01:15:47,560
US THAT A T CELL INDUCING

1666
01:15:47,560 --> 01:15:53,120
VACCINE COMPONENT COULD HAVE

1667
01:15:53,120 --> 01:15:56,440
REAL VALUE, TO ENHANCE

1668
01:15:56,440 --> 01:15:58,160
PREPAREDNESS AGAINST FUTURE

1669
01:15:58,160 --> 01:16:06,160
POSSIBLE PANDEMICS, AGAIN IN THE

1670
01:16:06,160 --> 01:16:11,840
CONTEXT OF PREVENTING SEVERE

1671
01:16:11,840 --> 01:16:12,840
DISEASE, NOT INFECTION,

1672
01:16:12,840 --> 01:16:14,880
SYNERGISTIC, THIS COULD BE

1673
01:16:14,880 --> 01:16:17,840
APPLICABLE TO MANY DIFFERENT

1674
01:16:17,840 --> 01:16:19,640
VIRUS FAMILIES THAT ARE PANDEMIC

1675
01:16:19,640 --> 01:16:20,920
CONCERN LISTED HERE WHERE YOU

1676
01:16:20,920 --> 01:16:25,200
COULD FOCUS ON WHAT ARE THE

1677
01:16:25,200 --> 01:16:29,720
CONSERVEED T CELL EPITOPES TO

1678
01:16:29,720 --> 01:16:31,760
DEVELOP BROADLY APPLICABLE

1679
01:16:31,760 --> 01:16:35,480
PANDEMIC PREPAREDNESS REAGENT.

1680
01:16:35,480 --> 01:16:37,360
SO, WHERE WE REMAINING

1681
01:16:37,360 --> 01:16:38,680
CHALLENGES AND TARGETS EMERGING

1682
01:16:38,680 --> 01:16:40,520
AND REEMERGING TARGETS I DID NOT

1683
01:16:40,520 --> 01:16:44,440
HAVE TIME TO GO INTO Mpox.

1684
01:16:44,440 --> 01:16:47,840
WE PUBLISHED A STUDY AT THE END

1685
01:16:47,840 --> 01:16:49,280
OF A YEAR, CHARACTERIZING AND

1686
01:16:49,280 --> 01:16:50,400
DESCRIBING THE FIRST ROUND OF

1687
01:16:50,400 --> 01:16:54,080
POOLS THAT CAN BE USED TO

1688
01:16:54,080 --> 01:16:56,280
DEVELOP -- TO DETECT RESPONSES

1689
01:16:56,280 --> 01:16:58,040
AGAINST Mpox IN THE

1690
01:16:58,040 --> 01:17:00,320
VACCINATION INFECTION SETTING,

1691
01:17:00,320 --> 01:17:04,560
PANDEMIC PREPAREDNESS, ALSO

1692
01:17:04,560 --> 01:17:06,560
BACTERIAL TARGETS LESS WELL

1693
01:17:06,560 --> 01:17:09,080
CHARACTERIZED, ALSO MANY OF THE

1694
01:17:09,080 --> 01:17:11,280
VACCINE TARGETS THAT ARE

1695
01:17:11,280 --> 01:17:15,440
REGISTERED OR IN DEVELOPMENT ARE

1696
01:17:15,440 --> 01:17:15,960
LESS WELL CHARACTERIZED.

1697
01:17:15,960 --> 01:17:16,960
I'D LIKE TO THANK THE PEOPLE

1698
01:17:16,960 --> 01:17:22,200
THAT HAVE BEEN INVOLVED IN THESE

1699
01:17:22,200 --> 01:17:30,840
STUDIES, STRONG COLLABORATION

1700
01:17:30,840 --> 01:17:35,760
WITH SHANE CROWLEY, AND MANY

1701
01:17:35,760 --> 01:17:37,320
OTHERS, THE IDP, AND THANK YOU

1702
01:17:37,320 --> 01:17:41,160
ALL AND I'LL TAKE QUESTIONS.

1703
01:17:41,160 --> 01:17:42,760
>>THANK YOU VERY MUCH,
ALEX.

1704
01:17:42,760 --> 01:17:45,280
I'D LIKE TO OPEN THIS UP FOR

1705
01:17:45,280 --> 01:17:45,880
QUESTIONS.

1706
01:17:45,880 --> 01:17:49,680
ARE THERE ANY QUESTIONS FROM THE

1707
01:17:49,680 --> 01:17:53,120
COUNCIL MEMBERS OR FROM THE

1708
01:17:53,120 --> 01:17:55,920
OTHER ATTENDEES? 

1709
01:17:55,920 --> 01:18:04,560
>>THIS IS JIM.

1710
01:18:04,560 --> 01:18:06,320
YOU MADE THE POINT PUTTING BROAD

1711
01:18:06,320 --> 01:18:08,400
RANGE OF T CELL EPITOPES COULD

1712
01:18:08,400 --> 01:18:11,360
BE HELPFUL FOR DURABILITY OF

1713
01:18:11,360 --> 01:18:13,560
PROTECTION AGAINST SEVERE

1714
01:18:13,560 --> 01:18:14,560
DISEASE.

1715
01:18:14,560 --> 01:18:16,280
WHAT ABOUT HOST CHARACTERISTICS?

1716
01:18:16,280 --> 01:18:19,800
AND ARE THERE SPECIAL

1717
01:18:19,800 --> 01:18:21,600
CONSIDERATIONS, YOU KNOW, FOR

1718
01:18:21,600 --> 01:18:23,040
DIFFERENT CATEGORIES OF HIGH

1719
01:18:23,040 --> 01:18:25,360
RISK INDIVIDUALS THAT YOU NEED

1720
01:18:25,360 --> 01:18:28,600
TO FACTOR INTO THEIR APPROACH.

1721
01:18:28,600 --> 01:18:30,960
>>YEAH, THAT'S A VERY
GOOD

1722
01:18:30,960 --> 01:18:32,680
QUESTION.

1723
01:18:32,680 --> 01:18:35,000
CERTAINLY ONE THING THAT IS

1724
01:18:35,000 --> 01:18:38,680
IMPORTANT TO CONSIDER, I MEAN,

1725
01:18:38,680 --> 01:18:43,080
PRAGMATICALLY IF YOU SEE NOW THE

1726
01:18:43,080 --> 01:18:44,720
PEOPLE THAT THE MAJORITY OF

1727
01:18:44,720 --> 01:18:50,120
PEOPLE THAT HAVE SEVERE DISEASE

1728
01:18:50,120 --> 01:18:51,560
TODAY ARE OLDER PEOPLE, PEOPLE

1729
01:18:51,560 --> 01:18:54,680
THAT DIDN'T ALL GET BOOSTED, IF

1730
01:18:54,680 --> 01:18:57,280
YOU WANT TO BE OVERGENERALIZING.

1731
01:18:57,280 --> 01:18:59,400
THAT ALREADY SUGGESTS WHAT ARE

1732
01:18:59,400 --> 01:19:02,560
SOME OF THE TARGETS FOR

1733
01:19:02,560 --> 01:19:03,040
INTERVENTION.

1734
01:19:03,040 --> 01:19:05,720
WHICH LEAD TO YOUR QUESTION --

1735
01:19:05,720 --> 01:19:07,080
WHICH LINK TO YOUR QUESTION, FOR

1736
01:19:07,080 --> 01:19:08,920
EXAMPLE, IS THERE A DIFFERENCE

1737
01:19:08,920 --> 01:19:10,760
IN T-CELL RESPONSE AND MEMORY

1738
01:19:10,760 --> 01:19:17,560
T-CELL RESPONSE IN OLDER PEOPLE?

1739
01:19:17,560 --> 01:19:20,640
IT'S A COMPLICATED THING.

1740
01:19:20,640 --> 01:19:24,000
OLDER PEOPLE MAY RESPOND LESS,

1741
01:19:24,000 --> 01:19:24,200
RIGHT?

1742
01:19:24,200 --> 01:19:26,840
JUST BECAUSE THEY ARE OLDER.

1743
01:19:26,840 --> 01:19:27,600
CONVERSELY OLDER PEOPLE BECAUSE

1744
01:19:27,600 --> 01:19:31,000
WE TEND TO HAVE MORE SEVERE

1745
01:19:31,000 --> 01:19:31,920
DISEASE MAY GET MORE ANTIGEN

1746
01:19:31,920 --> 01:19:38,240
LOAD SO WHEN YOU LOOK AT SOME OF

1747
01:19:38,240 --> 01:19:41,000
THE CONVALESCENT THERE'S

1748
01:19:41,000 --> 01:19:44,600
INDICATION THEY HAVE BETTER

1749
01:19:44,600 --> 01:19:45,480
T-CELL RESPONSE BECAUSE

1750
01:19:45,480 --> 01:19:48,560
(INDISCERNIBLE) BY THE VIRUS,

1751
01:19:48,560 --> 01:19:51,600
THAT OPENS THE QUESTION HOW LONG

1752
01:19:51,600 --> 01:19:53,680
DOES THIS IMMUNE RESPONSE -- DO

1753
01:19:53,680 --> 01:19:56,520
THEY -- IS THERE A DIFFERENCE IN

1754
01:19:56,520 --> 01:20:01,320
HOW QUICKLY OR STABLE THEIR

1755
01:20:01,320 --> 01:20:05,000
T-CELL RESPONSE EVOLVES OVER

1756
01:20:05,000 --> 01:20:05,200
TIME?

1757
01:20:05,200 --> 01:20:08,120
SO THOSE ARE VERY GOOD

1758
01:20:08,120 --> 01:20:08,440
QUESTIONS.

1759
01:20:08,440 --> 01:20:15,040
STILL I THINK OPEN TO A LARGE

1760
01:20:15,040 --> 01:20:15,280
DEGREE.

1761
01:20:15,280 --> 01:20:16,440
>>THANK YOU.

1762
01:20:16,440 --> 01:20:20,120
ARE THERE ANY OTHER QUESTIONS? 

1763
01:20:20,120 --> 01:20:25,520
>>YEAH, TIM, I HAD A
QUESTION.

1764
01:20:25,520 --> 01:20:27,520
ALEX, YOU ALLUDED TO PANDEMIC

1765
01:20:27,520 --> 01:20:27,840
PREPAREDNESS.

1766
01:20:27,840 --> 01:20:29,680
I'M WONDERING WHAT YOUR THOUGHTS

1767
01:20:29,680 --> 01:20:34,160
ARE ON WHERE ARE THE

1768
01:20:34,160 --> 01:20:38,560
BOTTLENECKS, AND SHOULD WE BE,

1769
01:20:38,560 --> 01:20:44,480
YOU KNOW, ASSEMBLING PEPTIDE

1770
01:20:44,480 --> 01:20:45,240
MEGAPOOLS FOR FUTURE

1771
01:20:45,240 --> 01:20:47,320
POSSIBILITIES OR IS IT

1772
01:20:47,320 --> 01:20:50,280
SUFFICIENT TO GET THINGS GOING

1773
01:20:50,280 --> 01:20:54,520
VERY QUICKLY WHEN THE NEXT

1774
01:20:54,520 --> 01:20:55,520
PATHOGEN EMERGES?

1775
01:20:55,520 --> 01:20:57,320
>>RIGHT.

1776
01:20:57,320 --> 01:20:59,040
I BELIEVE CERTAINLY A LOT OF

1777
01:20:59,040 --> 01:21:07,400
GROUND WORK COULD BE DONE TO

1778
01:21:07,400 --> 01:21:09,680
DEFINE THE EPITOPES POTENTIALLY

1779
01:21:09,680 --> 01:21:12,640
SHARED BETWEEN DIFFERENT

1780
01:21:12,640 --> 01:21:14,240
FAMILIES OF CONCERN, AND HAVE

1781
01:21:14,240 --> 01:21:16,120
BEEN VALIDATE AND READY TO GO.

1782
01:21:16,120 --> 01:21:22,600
OBVIOUSLY YOU CAN DO THAT AFTER

1783
01:21:22,600 --> 01:21:24,480
THE FACT, BUT YOU COULD DO THE

1784
01:21:24,480 --> 01:21:25,680
WORK AND HAVE INFORMATION READY

1785
01:21:25,680 --> 01:21:28,080
AND AVAILABLE AND READY TO GO,

1786
01:21:28,080 --> 01:21:33,320
OBVIOUSLY IN THE CONTEXT OF

1787
01:21:33,320 --> 01:21:35,960
PANDEMIC PREPAREDNESS, WE --

1788
01:21:35,960 --> 01:21:37,240
DEVIL'S ARGUMENT, WE DON'T KNOW

1789
01:21:37,240 --> 01:21:38,880
WHERE THE PANDEMIC CAN COME

1790
01:21:38,880 --> 01:21:39,160
FROM.

1791
01:21:39,160 --> 01:21:43,040
WELL, YES, BUT IF WE CAN COVER

1792
01:21:43,040 --> 01:21:46,360
SEVEN OR EIGHT FAMILIES THAT ARE

1793
01:21:46,360 --> 01:21:47,240
OF REASONABLE CONCERN THAT'S

1794
01:21:47,240 --> 01:21:50,240
ALREADY OF VALUE.

1795
01:21:50,240 --> 01:21:56,960
I MEAN, CERTAINLY IF ONE -- ONE

1796
01:21:56,960 --> 01:22:00,680
COULD EVEN ENVISION THAT THESE

1797
01:22:00,680 --> 01:22:03,520
ANTIGENS OR FRAGMENTS OF DOMAIN

1798
01:22:03,520 --> 01:22:05,040
IDENTIFIED OF BEING OF

1799
01:22:05,040 --> 01:22:05,920
PARTICULAR INTEREST, ARE

1800
01:22:05,920 --> 01:22:07,560
IDENTIFIED, ONE CAN DO LIMITED

1801
01:22:07,560 --> 01:22:12,480
PHASE 1 TRIALS TO SEE IF

1802
01:22:12,480 --> 01:22:13,280
DIFFERENT VACCINES ENCODING THEM

1803
01:22:13,280 --> 01:22:14,560
WORK OR SOMETHING LIKE THAT.

1804
01:22:14,560 --> 01:22:16,080
BUT CERTAINLY THE GROUND WORK

1805
01:22:16,080 --> 01:22:17,520
COULD BE DONE AND I THINK BE A

1806
01:22:17,520 --> 01:22:21,080
LOT OF VALUE IN DOING IT.

1807
01:22:21,080 --> 01:22:23,840
>>THANK YOU.

1808
01:22:23,840 --> 01:22:24,720
 

1809
01:22:24,720 --> 01:22:29,320
>>THANK YOU VERY MUCH.

1810
01:22:29,320 --> 01:22:31,000
ARE THERE ANY OTHER QUESTIONS

1811
01:22:31,000 --> 01:22:32,080
BEFORE ALEX GOES?

1812
01:22:32,080 --> 01:22:34,040
IF NOT, I WANT TO THANK YOU,

1813
01:22:34,040 --> 01:22:36,920
ALEX, FOR A GREAT PRESENTATION.

1814
01:22:36,920 --> 01:22:39,960
WE APPRECIATE IT.

1815
01:22:39,960 --> 01:22:44,680
NEXT SPEAKER TODAY IS DR. DAVID

1816
01:22:44,680 --> 01:22:46,240
KOELLE, THE PROFESSOR AT -- A

1817
01:22:46,240 --> 01:22:48,960
PROFESSOR AT THE UNIVERSITY OF

1818
01:22:48,960 --> 01:22:49,600
WASHINGTON, DEPARTMENT OF

1819
01:22:49,600 --> 01:22:51,680
MEDICINE, DIVISION OF ALLERGY

1820
01:22:51,680 --> 01:22:55,840
AND INFECTIOUS DISEASES. 

1821
01:22:55,840 --> 01:22:58,680
HE'S AN ADJUNCT PROFESSOR OF

1822
01:22:58,680 --> 01:23:01,640
GLOBAL HEALTH, AND A JOINT

1823
01:23:01,640 --> 01:23:03,080
PROFESSOR IN LABORATORY OF

1824
01:23:03,080 --> 01:23:05,680
MEDICINE IN DEPARTMENT OF

1825
01:23:05,680 --> 01:23:06,240
MEDICINE.

1826
01:23:06,240 --> 01:23:09,280
HE'S ALSO AFFILIATE INVESTIGATOR

1827
01:23:09,280 --> 01:23:12,920
AT THE FRED HUTCHINSON CANCER

1828
01:23:12,920 --> 01:23:15,200
RESEARCH CENTER.

1829
01:23:15,200 --> 01:23:17,600
AND DAVID'S SLIDES LOOK GREAT.

1830
01:23:17,600 --> 01:23:20,440
DAVID, IF YOU'RE READY?

1831
01:23:20,440 --> 01:23:24,200
 

1832
01:23:24,200 --> 01:23:24,800
>>THANK YOU.

1833
01:23:24,800 --> 01:23:26,480
CAN YOU HEAR ME?

1834
01:23:26,480 --> 01:23:26,760
>>GREAT.

1835
01:23:26,760 --> 01:23:27,800
>>THANKS FOR THE
INVITATION.

1836
01:23:27,800 --> 01:23:30,480
IT'S A TALL ORDER TO FOLLOW JIM

1837
01:23:30,480 --> 01:23:36,000
AND ALEX BUT I'LL TRY MY BEST. 

1838
01:23:36,000 --> 01:23:39,320
I'M GOING TO SHIFT EMPHASIS A

1839
01:23:39,320 --> 01:23:40,920
LITTLE BIT TOWARDS T-CELL

1840
01:23:40,920 --> 01:23:46,280
RECEPTOR SIDE OF THINGS, AS WELL

1841
01:23:46,280 --> 01:23:49,360
AS EPITOPE DISCOVERY, FORTUNATE

1842
01:23:49,360 --> 01:23:53,680
TO HAVE A CYCLE, AND TURNING TO

1843
01:23:53,680 --> 01:23:54,600
HOST SITE AND ACKNOWLEDGMENT

1844
01:23:54,600 --> 01:23:57,200
SLIDE TO SHOW A COUPLE FOLKS

1845
01:23:57,200 --> 01:23:59,000
WHOSE WORK I'M GOING TO

1846
01:23:59,000 --> 01:24:00,640
EMPHASIZE TODAY.

1847
01:24:00,640 --> 01:24:04,640
MY TITLE INCLUDED THE CONCEPT OF

1848
01:24:04,640 --> 01:24:05,760
TISSUE T CELLS, AND BECAUSE

1849
01:24:05,760 --> 01:24:08,480
NATURE DOES A NICE THING FOR US,

1850
01:24:08,480 --> 01:24:09,680
WHICH IS ANTIGEN SPECIFIC T

1851
01:24:09,680 --> 01:24:12,000
CELLS AT THE SITE OF THE

1852
01:24:12,000 --> 01:24:16,000
DISORDER, SO RATHER THAN

1853
01:24:16,000 --> 01:24:18,120
NECESSARILY FISHING RARE T CELLS

1854
01:24:18,120 --> 01:24:21,560
OUT OF THE BLOOD OR SENSITIVE

1855
01:24:21,560 --> 01:24:22,960
TECHNIQUES CAN SOMETIMES BIOPSY

1856
01:24:22,960 --> 01:24:26,120
THE SITE AND USE THIS

1857
01:24:26,120 --> 01:24:26,760
PRESUMPTIVE NATURAL ENRICHMENT,

1858
01:24:26,760 --> 01:24:28,760
AND IF I HAVE TIME I'LL SHOW YOU

1859
01:24:28,760 --> 01:24:39,280
WORK FROM SYPHILIS, CARCINOMA,

1860
01:24:40,400 --> 01:24:42,080
SHINGLES BUT STARTING WITH

1861
01:24:42,080 --> 01:24:43,200
COVID, ANTIGEN SPECIFIC T CELLS

1862
01:24:43,200 --> 01:24:45,640
IN THE NOSE, I BELIEVE.

1863
01:24:45,640 --> 01:24:47,120
ON THE RIGHT OF COURSE THIS IS

1864
01:24:47,120 --> 01:24:49,320
WHAT WE'RE TALKING ABOUT.

1865
01:24:49,320 --> 01:24:51,600
WITH ADVANCEMENTS IN SEQUENCING

1866
01:24:51,600 --> 01:24:56,440
CAN USE THE SEQUENCE OF CDR 3

1867
01:24:56,440 --> 01:24:58,280
REGION AS A BARCODE TO HELP US

1868
01:24:58,280 --> 01:24:59,920
TRACK T CELLS FROM THE BLOOD TO

1869
01:24:59,920 --> 01:25:02,600
TISSUES AND BACK AND FORTH.

1870
01:25:02,600 --> 01:25:05,960
SO, OUR STRATEGY OVER THE YEARS

1871
01:25:05,960 --> 01:25:07,920
HAS STARTED WITH BLOOD AND

1872
01:25:07,920 --> 01:25:09,800
TISSUE, WHEN WE START WITH BLOOD

1873
01:25:09,800 --> 01:25:11,960
WE TEND TO ENRICH RARE

1874
01:25:11,960 --> 01:25:13,960
PATHOGEN-SPECIFIC T CELLS OUT OF

1875
01:25:13,960 --> 01:25:15,680
THE BLOOD, GUARANTEEING THE T

1876
01:25:15,680 --> 01:25:17,560
CELLS WE'RE STUDYING REACT TO

1877
01:25:17,560 --> 01:25:18,240
THE WHOLE PATHOGEN.

1878
01:25:18,240 --> 01:25:20,320
SO IT'S NOT JUST A CIRCULAR

1879
01:25:20,320 --> 01:25:23,040
ARGUMENT WHERE YOU ENRICH WITH

1880
01:25:23,040 --> 01:25:24,560
PEPTIDE, TEST WITH PEPTIDE, WE

1881
01:25:24,560 --> 01:25:30,600
HAVE THE PATHOGEN IN THE CYCLE,

1882
01:25:30,600 --> 01:25:31,680
EXPAND OR EXPRESS REPORTER CELLS

1883
01:25:31,680 --> 01:25:34,760
AND GO TO ANTIGEN AND EPITOPE

1884
01:25:34,760 --> 01:25:35,000
DISCOVERY.

1885
01:25:35,000 --> 01:25:36,880
WITH TISSUE-BASED SYSTEM WE CAN

1886
01:25:36,880 --> 01:25:46,880
USE THIS NATURAL IN SITU ENRICH.

1887
01:25:46,880 --> 01:25:49,040
-MENT.

1888
01:25:49,040 --> 01:25:54,400
WE CAN EXPAND CELLS OR SEQUENCE

1889
01:25:54,400 --> 01:25:57,520
AND GO TO DISCOVERY.

1890
01:25:57,520 --> 01:25:59,480
THIS IS BLOOD EMPHASIS.

1891
01:25:59,480 --> 01:26:01,440
WE USE AIM.

1892
01:26:01,440 --> 01:26:02,760
ALEX INTRODUCED AIM, IN THE

1893
01:26:02,760 --> 01:26:04,960
EARLY DAYS WERE USING CD137 AS

1894
01:26:04,960 --> 01:26:06,160
OUR MARKER.

1895
01:26:06,160 --> 01:26:09,760
HERE IS A BLOOD SAMPLE, SOME

1896
01:26:09,760 --> 01:26:12,160
CELLS ARE EXPRESSING IN RESPONSE

1897
01:26:12,160 --> 01:26:14,440
TO ANTIGEN I MENTIONED.

1898
01:26:14,440 --> 01:26:24,920
AND WHEN WE  EXPAND WE'RE 50%

1899
01:26:24,920 --> 01:26:26,280
ANTIGEN REACTIVE, FROM .1 OUT OF

1900
01:26:26,280 --> 01:26:29,680
THE BODY TO NOW 50%, NOW

1901
01:26:29,680 --> 01:26:33,680
DISCOVERING EPITOPES, IT'S LIKE

1902
01:26:33,680 --> 01:26:34,760
SHOOTING FISH IN A BARREL.

1903
01:26:34,760 --> 01:26:37,360
WE CAN GO ON TO FULLY DEFINE

1904
01:26:37,360 --> 01:26:42,320
WHAT ANTIGENS AND EPITOPES ARE

1905
01:26:42,320 --> 01:26:43,160
IDENTIFIED.

1906
01:26:43,160 --> 01:26:47,680
THIS IS A SCREEN, GENOME WIDE

1907
01:26:47,680 --> 01:26:54,680
SCREEN FOR EVERY IN THE ZOSTER,

1908
01:26:54,680 --> 01:26:56,760
HERE IS THE SCREEN BEFORE THE

1909
01:26:56,760 --> 01:26:57,880
VACCINE, 28 DAYS AFTER THE

1910
01:26:57,880 --> 01:26:58,200
VACCINE.

1911
01:26:58,200 --> 01:27:01,560
YOU CAN SEE THERE DOES SEEM TO

1912
01:27:01,560 --> 01:27:04,320
BE A VACCINE RESPONSE, THIS IS A

1913
01:27:04,320 --> 01:27:11,640
WHOLE VIRUS VACCINE, THE

1914
01:27:11,640 --> 01:27:14,800
ATTENUATED OLD ZOSTRAVAX.

1915
01:27:14,800 --> 01:27:16,440
HERE IS DAY ZERO ON THE LEFT,

1916
01:27:16,440 --> 01:27:19,400
YOU CAN SEE WHEN WE GO TO DAY

1917
01:27:19,400 --> 01:27:21,840
28, A ONE-DOSE VACCINE, WE HAVE

1918
01:27:21,840 --> 01:27:24,320
A LOT BROADER RECOGNITION AFTER

1919
01:27:24,320 --> 01:27:28,400
DAY 28 AND THIS LASTS OUT TO DAY

1920
01:27:28,400 --> 01:27:28,680
182.

1921
01:27:28,680 --> 01:27:30,680
MECHANISM OF ACTION FOR THIS

1922
01:27:30,680 --> 01:27:31,480
VACCINE AND NEWER SHINGLES

1923
01:27:31,480 --> 01:27:33,720
VACCINE IS THOUGHT TO BE A T

1924
01:27:33,720 --> 01:27:36,040
CELL MECHANISM OF ACTION, IN

1925
01:27:36,040 --> 01:27:38,000
CONTRAST TO ALMOST ALL VACCINES

1926
01:27:38,000 --> 01:27:39,960
THAT WE TALKED ABOUT PREVIOUSLY,

1927
01:27:39,960 --> 01:27:41,320
PROBABLY IT'S THE T CELLS THAT

1928
01:27:41,320 --> 01:27:42,160
MATTER HERE.

1929
01:27:42,160 --> 01:27:44,960
WHEN WE HAVE HITS AT THE OPEN

1930
01:27:44,960 --> 01:27:47,840
LEVEL, OR GENE LEVEL, EXAMPLE

1931
01:27:47,840 --> 01:27:51,800
FROM GENE 68, THE GLYCOPROTEIN,

1932
01:27:51,800 --> 01:27:53,240
FAIRLY ROUTINE, FIGURING OUT

1933
01:27:53,240 --> 01:28:00,880
WHAT THE PEPTIDES ARE.

1934
01:28:00,880 --> 01:28:06,560
YOU CAN FIGURE OUT

1935
01:28:06,560 --> 01:28:07,880
HLA-RESTRICTING LOCUS, USEEL

1936
01:28:07,880 --> 01:28:14,000
SINGLE ANTIGEN PRESENTING T

1937
01:28:14,000 --> 01:28:15,320
CELLS, ANTIGEN PRESENTING,

1938
01:28:15,320 --> 01:28:16,760
PARDON ME.

1939
01:28:16,760 --> 01:28:22,640
ONLY ANTIGEN PRESENTING CELLS

1940
01:28:22,640 --> 01:28:25,200
THAT EXPRESS WERE ABLE TO

1941
01:28:25,200 --> 01:28:26,240
PRESENT THE EPITOPE.

1942
01:28:26,240 --> 01:28:28,440
ONE OF THE PAIN POINTS IS WHAT

1943
01:28:28,440 --> 01:28:30,440
ARE YOU GOING TO USE TO ENRICH

1944
01:28:30,440 --> 01:28:31,840
YOUR T CELLS OUT OF THE BLOOD.

1945
01:28:31,840 --> 01:28:33,600
WE WOULD LIKE TO START WITH

1946
01:28:33,600 --> 01:28:34,680
WHOLE PATHOGEN.

1947
01:28:34,680 --> 01:28:37,280
WE WANT OUR T CELLS TO SEE THE

1948
01:28:37,280 --> 01:28:41,120
WHOLE PATHOGEN.

1949
01:28:41,120 --> 01:28:42,960
PREVIOUS EXAMPLE USING CD137,

1950
01:28:42,960 --> 01:28:46,280
ANOTHER FROM ANOTHER PAPER WITH

1951
01:28:46,280 --> 01:28:49,240
ZIKA, CD137, STARTED GETTING

1952
01:28:49,240 --> 01:28:52,920
MORE PICKY, COVID WORK, REQUIRED

1953
01:28:52,920 --> 01:28:55,400
COORDINATE EXPRESSION OF 69 AND

1954
01:28:55,400 --> 01:28:59,560
137, SORTING CELLS, HERE IS

1955
01:28:59,560 --> 01:29:01,640
WHOLE KILL VIRUS.

1956
01:29:01,640 --> 01:29:03,720
WITH HERPES VIRUS CAN CAUSE

1957
01:29:03,720 --> 01:29:05,800
SEVERE DISEASE IN IMMUNE

1958
01:29:05,800 --> 01:29:06,680
COMPROMISED PEOPLE REQUIRED

1959
01:29:06,680 --> 01:29:07,960
COORDINATED EXPRESSION OF THREE

1960
01:29:07,960 --> 01:29:10,800
MARKERS IN ORDER TO SELECT THE

1961
01:29:10,800 --> 01:29:12,120
FINAL CELLS FOR DOWNSTREAM

1962
01:29:12,120 --> 01:29:12,480
STUDY.

1963
01:29:12,480 --> 01:29:14,520
IN THE LAST THREE YEARS WITH

1964
01:29:14,520 --> 01:29:15,640
SARS-COV-2 AND MANY PEOPLE

1965
01:29:15,640 --> 01:29:16,960
WORKING IN THE FIELD THERE'S

1966
01:29:16,960 --> 01:29:20,680
BEEN SORT OF A LITERATURE

1967
01:29:20,680 --> 01:29:21,560
EXPLOSION OF THESE

1968
01:29:21,560 --> 01:29:22,200
ACTIVATION-INDUCED MARKERS THAT

1969
01:29:22,200 --> 01:29:24,520
PEOPLE USED TO ENRICH NOW CELLS

1970
01:29:24,520 --> 01:29:27,920
OUT OF THE BLOOD. 

1971
01:29:27,920 --> 01:29:30,400
I WON'T SHOW DOWNSTREAM WORK BUT

1972
01:29:30,400 --> 01:29:32,520
I'LL SUMMARIZE THAT IT MATTERS

1973
01:29:32,520 --> 01:29:34,600
WHICH MARKERS YOU USE IN TERMS

1974
01:29:34,600 --> 01:29:40,720
OF THE PHENOTYPE OF THE

1975
01:29:40,720 --> 01:29:41,840
DOWNSTREAM CELLS AND

1976
01:29:41,840 --> 01:29:44,760
SPECIFICITY, THE GROUP USING

1977
01:29:44,760 --> 01:29:48,160
COMBINATION, ICS WITH SURFACE

1978
01:29:48,160 --> 01:29:52,320
MARKER, COMBINATION, AIM ICS AND

1979
01:29:52,320 --> 01:29:53,400
MATTERS HOW LONG YOU STIMULATE

1980
01:29:53,400 --> 01:29:56,040
BEFORE YOU SORT AND DO

1981
01:29:56,040 --> 01:29:56,960
DOWNSTREAM STUDIES, AN

1982
01:29:56,960 --> 01:30:01,760
INTERESTING PAIN POINT OR

1983
01:30:01,760 --> 01:30:03,960
CONTROVERSY POINT GOING FORWARD.

1984
01:30:03,960 --> 01:30:06,360
SWITCHING GEARS TO COVID,

1985
01:30:06,360 --> 01:30:08,640
GETTING INTO TRMs, TISSUE T

1986
01:30:08,640 --> 01:30:10,040
CELLS, GOOD LUCK TO FOLLOW

1987
01:30:10,040 --> 01:30:12,680
COHORT OF PEOPLE FOR TWO-YEAR

1988
01:30:12,680 --> 01:30:14,320
PERIOD, WITH HYBRID IMMUNITY.

1989
01:30:14,320 --> 01:30:18,480
INFECTED EARLY IN THE PANDEMIC,

1990
01:30:18,480 --> 01:30:21,800
GOT ROUTINE TWO-DOSE mRNA

1991
01:30:21,800 --> 01:30:22,920
VACCINATION, A YEAR LATER A

1992
01:30:22,920 --> 01:30:25,520
BOOSER, AT THE END WE DID A

1993
01:30:25,520 --> 01:30:27,520
NASAL SWAB LOOKING FOR

1994
01:30:27,520 --> 01:30:29,480
SARS-COV-2-SPECIFIC T CELLS.

1995
01:30:29,480 --> 01:30:33,080
THIS IS USING T-CELL RECEPTOR

1996
01:30:33,080 --> 01:30:36,800
BARCODES FOR TRACKING RATHER

1997
01:30:36,800 --> 01:30:39,000
THAN AS FUNCTIONAL ASSAY.

1998
01:30:39,000 --> 01:30:42,280
A PLOT OF EVENTS, THESE

1999
01:30:42,280 --> 01:30:45,440
INDIVIDUALS, 53 INDIVIDUALS.

2000
01:30:45,440 --> 01:30:46,680
THIS IS THE VACCINATIONS, THE

2001
01:30:46,680 --> 01:30:47,960
CIRCLE HERE.

2002
01:30:47,960 --> 01:30:50,280
TIME OF FIRST VACCINE, ABOUT A

2003
01:30:50,280 --> 01:30:52,320
YEAR AFTER THEIR INFECTION, SOME

2004
01:30:52,320 --> 01:30:54,200
PEOPLE HOSPITALIZED IN PURPLE

2005
01:30:54,200 --> 01:30:55,640
BAR, MOST PEOPLE WEREN'T

2006
01:30:55,640 --> 01:30:55,960
HOSPITALIZED.

2007
01:30:55,960 --> 01:30:57,920
EACH ONE OF THE MARKERS

2008
01:30:57,920 --> 01:31:02,200
BASICALLY IS A TIME POINT WE

2009
01:31:02,200 --> 01:31:04,360
HAVE FOR BLOOD SAMPLE ON THESE

2010
01:31:04,360 --> 01:31:04,760
PEOPLE.

2011
01:31:04,760 --> 01:31:05,800
WE DID CAREFUL SEROLOGY TRACKING

2012
01:31:05,800 --> 01:31:07,880
ON THESE INDIVIDUALS TO MAKE

2013
01:31:07,880 --> 01:31:11,080
SURE THEY REALLY DID HAVE HYBRID

2014
01:31:11,080 --> 01:31:13,040
IMMUNITY.

2015
01:31:13,040 --> 01:31:20,920
ONE PERSON SNUCK IN WHO PROBLEM

2016
01:31:20,920 --> 01:31:23,080
WASN'T INFECTED.

2017
01:31:23,080 --> 01:31:26,520
IN LATE 2020, TITERS WENT UP.

2018
01:31:26,520 --> 01:31:27,720
EVERYBODY ELSE ALSO HAD, WENT UP

2019
01:31:27,720 --> 01:31:28,800
WITH VACCINE.

2020
01:31:28,800 --> 01:31:31,320
WE CAN ALSO SEE THREE PEOPLE WHO

2021
01:31:31,320 --> 01:31:33,760
HAD BREAKTHROUGH INFECTIONS EVEN

2022
01:31:33,760 --> 01:31:37,200
AFTER VACCINATION, THEY HAD

2023
01:31:37,200 --> 01:31:39,600
COVID, GOT THEIR VACCINES,

2024
01:31:39,600 --> 01:31:43,040
ANTI-TITER WENT UP, EXCLUDED

2025
01:31:43,040 --> 01:31:44,720
FROM DOWNSTREAM ANALYSIS WHO

2026
01:31:44,720 --> 01:31:46,640
WERE OUTLIERS IN THE COHORT.

2027
01:31:46,640 --> 01:31:49,560
HOW ARE WE GOING TO NOMINATE

2028
01:31:49,560 --> 01:31:51,240
T-CELL RECEPTORS OR T CELLS AS

2029
01:31:51,240 --> 01:31:59,680
CANDIDATE SPIKE-T CELLS?

2030
01:31:59,680 --> 01:32:02,280
WE DID SEQUENCING WITH

2031
01:32:02,280 --> 01:32:03,600
IN-PERSON, ANALYZE DIFFERENCE

2032
01:32:03,600 --> 01:32:04,480
BETWEEN BEFORE VACCINE DOSE 1

2033
01:32:04,480 --> 01:32:06,600
AND THIS WAS ABOUT THREE WEEKS

2034
01:32:06,600 --> 01:32:07,920
AFTER VACCINE DOSE 2.

2035
01:32:07,920 --> 01:32:09,440
SO SHOWN HERE ON THESE RED

2036
01:32:09,440 --> 01:32:10,720
ARROWS ON THE LEFT.

2037
01:32:10,720 --> 01:32:13,600
WE GOT BLOOD ON THE X-AXIS FROM

2038
01:32:13,600 --> 01:32:15,360
BEFORE THE VACCINE WAS GIVEN,

2039
01:32:15,360 --> 01:32:16,360
THEY HAD MEMORY.

2040
01:32:16,360 --> 01:32:19,280
AND THEN AFTER TWO DOSES OF

2041
01:32:19,280 --> 01:32:22,920
VACCINATION, EACH DOT IS A T

2042
01:32:22,920 --> 01:32:25,080
CELL PROTOTYPE THAT'S AT THE

2043
01:32:25,080 --> 01:32:27,160
BETA CHAIN THAT'S DETECTED BY

2044
01:32:27,160 --> 01:32:30,760
NEXT GENERATION SEQUENCING USING

2045
01:32:30,760 --> 01:32:31,520
ADAPTIVE BIOTECHNOLOGIES

2046
01:32:31,520 --> 01:32:31,800
PLATFORM.

2047
01:32:31,800 --> 01:32:34,160
YOU SEE LOG SCALE HERE, ONE OUT

2048
01:32:34,160 --> 01:32:37,120
OF 100 T CELLS, ONE OUT OF

2049
01:32:37,120 --> 01:32:40,840
100,000 T CELLS, 10 TO THE MINUS

2050
01:32:40,840 --> 01:32:41,040
FIFTH.

2051
01:32:41,040 --> 01:32:44,120
ALL RED DOTS HAVE EXPANDED BY

2052
01:32:44,120 --> 01:32:46,960
FACTORS OF SOMETIMES 100, 1,000,

2053
01:32:46,960 --> 01:32:48,760
EVEN 10,000, TEMPORALLY IN

2054
01:32:48,760 --> 01:32:50,160
RESPONSE TO VACCINATION.

2055
01:32:50,160 --> 01:32:52,920
THESE ARE CANDIDATE VACCINE

2056
01:32:52,920 --> 01:32:54,000
REACTIVE T-CELL RECEPTORS.

2057
01:32:54,000 --> 01:32:57,400
IF WE LOOK BRIEFLY AT TWO

2058
01:32:57,400 --> 01:33:01,200
INDIVIDUALS, NOW LOOKING AT THE

2059
01:33:01,200 --> 01:33:03,280
KINETICS, THREE OR FOUR WEEKS

2060
01:33:03,280 --> 01:33:04,920
APART, THIS PERSON HAD A NICE

2061
01:33:04,920 --> 01:33:06,800
BUMP BEFORE AND AFTER FIRST

2062
01:33:06,800 --> 01:33:10,160
DOSE, FURTHER BUMP AFTER THE

2063
01:33:10,160 --> 01:33:13,920
SECOND DOSE, ALL OF THESE HERE.

2064
01:33:13,920 --> 01:33:15,880
IF YOU SUMMARIZE ACROSS BOTH

2065
01:33:15,880 --> 01:33:18,040
DOSES NICE RESPONSE ACROSS BOTH

2066
01:33:18,040 --> 01:33:19,480
DOSES, SO THE INDIVIDUAL HERE

2067
01:33:19,480 --> 01:33:21,680
DID NOT HAVE MUCH RESPONSE AFTER

2068
01:33:21,680 --> 01:33:25,280
FIRST DOSE, SOME CLONOTYPES DID

2069
01:33:25,280 --> 01:33:27,800
GO UP, NICE RESPONSE AFTER THE

2070
01:33:27,800 --> 01:33:29,760
SECOND DOSE, OVERALL IF YOU LOOK

2071
01:33:29,760 --> 01:33:31,080
ACROSS THE WHOLE RESPONSE MOST

2072
01:33:31,080 --> 01:33:32,600
OF THE RESPONSES SEEM TO COME

2073
01:33:32,600 --> 01:33:36,200
OUT OF A NAIVE POOL BECAUSE VERY

2074
01:33:36,200 --> 01:33:38,520
FEW WERE PRESENT IN THE MEMORY

2075
01:33:38,520 --> 01:33:40,920
POOL AND TOOK TWO SHOTS TO BRING

2076
01:33:40,920 --> 01:33:42,760
THESE OUT.

2077
01:33:42,760 --> 01:33:44,520
SOME PEOPLE ARE NICE MEMORY

2078
01:33:44,520 --> 01:33:46,600
AFTER ONE, OTHER TOOK TWO DOSES

2079
01:33:46,600 --> 01:33:50,000
AND DIDN'T RECRUIT TOO WELL OUT

2080
01:33:50,000 --> 01:33:51,880
OF PREVIOUS MEMORY.

2081
01:33:51,880 --> 01:33:54,600
THERE'S ONE METHOD TO NOMINATE

2082
01:33:54,600 --> 01:33:55,520
TCRs.

2083
01:33:55,520 --> 01:33:57,320
LET'S LOOK AT ORTHOGONAL

2084
01:33:57,320 --> 01:34:00,640
DIFFERENT METHOD, GOING BACK TO

2085
01:34:00,640 --> 01:34:01,520
ACTIVATION INDUCED MARKER

2086
01:34:01,520 --> 01:34:02,480
SERVING, HOT TIME POINT, THREE

2087
01:34:02,480 --> 01:34:04,640
OR FOUR WEEKS AFTER THE SECOND

2088
01:34:04,640 --> 01:34:05,440
DOSE OF VACCINE.

2089
01:34:05,440 --> 01:34:10,840
AND IF I THROW IN SPIKE PEPTIDE

2090
01:34:10,840 --> 01:34:12,560
POOL, I DON'T GET MUCH WITH

2091
01:34:12,560 --> 01:34:13,680
ACTIVATION MARKERS.

2092
01:34:13,680 --> 01:34:16,080
IF I THROW IN -- PARDON ME.

2093
01:34:16,080 --> 01:34:18,800
IF I THROW IN SPIKE PEPTIDE POOL

2094
01:34:18,800 --> 01:34:23,280
I'VE GOT A HUGE RESPONSE AND WE

2095
01:34:23,280 --> 01:34:29,200
COULD PUT THESE CELLS INTO 10 X

2096
01:34:29,200 --> 01:34:31,480
PLATFORM FOR SEQUENCING, GOT

2097
01:34:31,480 --> 01:34:39,040
30,000 PAIRED T CELLS CANDIDATE,

2098
01:34:39,040 --> 01:34:40,800
THERE ARE PAIN POINTS OR

2099
01:34:40,800 --> 01:34:41,080
PROBLEMS.

2100
01:34:41,080 --> 01:34:43,280
WE DON'T KNOW WHETHER CHOOSING

2101
01:34:43,280 --> 01:34:45,720
69 AND 137 MISSED A BUNCH OF

2102
01:34:45,720 --> 01:34:49,240
TCRs, WE DON'T KNOW HOW

2103
01:34:49,240 --> 01:34:50,880
SPECIFIC THIS PLOT HERE IS

2104
01:34:50,880 --> 01:34:55,280
BECAUSE OF THE PHENOMENON OF

2105
01:34:55,280 --> 01:34:55,560
ACTIVATION.

2106
01:34:55,560 --> 01:34:56,560
THIS IS NICE.

2107
01:34:56,560 --> 01:34:58,120
WE NEED TO DO FURTHER

2108
01:34:58,120 --> 01:34:58,560
CONFIRMATION.

2109
01:34:58,560 --> 01:35:00,360
ONE OF THE THINGS WE COULD DO TO

2110
01:35:00,360 --> 01:35:03,880
DO THIS WAS TO LOOK AT THE

2111
01:35:03,880 --> 01:35:04,200
OVERLAY.

2112
01:35:04,200 --> 01:35:05,960
I'M SHOWING YOU A VERY BIG

2113
01:35:05,960 --> 01:35:06,360
OVERLAY.

2114
01:35:06,360 --> 01:35:07,920
HERE IS THE BEFORE DOSE.

2115
01:35:07,920 --> 01:35:08,920
THERE'S THE AFTER DOSE HERE.

2116
01:35:08,920 --> 01:35:11,240
ALL OF THE DOTS ON THE UPPER

2117
01:35:11,240 --> 01:35:12,080
LEFT ARE POTENTIALLY VACCINE

2118
01:35:12,080 --> 01:35:14,080
RESPONSE FROM THE FIRST METHOD I

2119
01:35:14,080 --> 01:35:14,840
SHOWED YOU.

2120
01:35:14,840 --> 01:35:20,160
WE  OVERLAID WHETHER WE FOUND

2121
01:35:20,160 --> 01:35:21,520
THEM USING SINGLE CELL TCR Seq

2122
01:35:21,520 --> 01:35:26,200
AND THE SIZE OF THE MARKER IS

2123
01:35:26,200 --> 01:35:28,760
NUMBER OF SISTER CELLS WE WERE

2124
01:35:28,760 --> 01:35:37,040
ABLE TO RECOVER, QUITE A NICE

2125
01:35:37,040 --> 01:35:38,440
CORRESPONDENCE HAVING

2126
01:35:38,440 --> 01:35:38,800
CONFIDENCE.

2127
01:35:38,800 --> 01:35:40,320
COULD LOOK AT TRAJECTORY, NOW WE

2128
01:35:40,320 --> 01:35:42,440
HAVE THIS BARCODE FROM THE

2129
01:35:42,440 --> 01:35:43,640
SINGLE CELL METHODOLOGY, YOU CAN

2130
01:35:43,640 --> 01:35:45,760
LOOK BACK OVER THIS TWO-YEAR

2131
01:35:45,760 --> 01:35:49,560
TIME FRAME OF THESE INDIVIDUALS,

2132
01:35:49,560 --> 01:35:54,320
ASK DO THESE  CLONOTYPES GO UP?

2133
01:35:54,320 --> 01:35:56,040
FOCUS ON THE RIGHT, AVERAGE

2134
01:35:56,040 --> 01:35:58,680
INCREASE OVER THE COURSE OF THE

2135
01:35:58,680 --> 01:35:59,400
VACCINATION, AND CORE FINDING

2136
01:35:59,400 --> 01:36:04,040
HERE IS WHEN WE GIVE THE mRNA

2137
01:36:04,040 --> 01:36:06,360
VACCINE, WE SEE NICE INCREASE IN

2138
01:36:06,360 --> 01:36:12,960
ABUNDANCE IN THE BLOOD BUT NOT

2139
01:36:12,960 --> 01:36:13,960
NEARLY AS IMPRESSIVE.

2140
01:36:13,960 --> 01:36:19,080
THIS IS FROM U PENN, TRYING TO

2141
01:36:19,080 --> 01:36:21,480
RESOLVE WHAT THE PLUSES AND

2142
01:36:21,480 --> 01:36:26,840
MINUSES MIGHT BE AND HOW TO SORT

2143
01:36:26,840 --> 01:36:27,640
THIS OUT.

2144
01:36:27,640 --> 01:36:31,320
WHEN WE GATHER SEQUENCES WE CAN

2145
01:36:31,320 --> 01:36:34,760
CLUSTER THEM IN BIOINFORMATIC

2146
01:36:34,760 --> 01:36:39,000
SEQUENCE SPACE, A 

2147
01:36:39,000 --> 01:36:39,360
REPRESENTATION.

2148
01:36:39,360 --> 01:36:41,440
THIS IS FROM 17 PEOPLE, EACH

2149
01:36:41,440 --> 01:36:42,520
SHOWN IN DIFFERENT COLOR.

2150
01:36:42,520 --> 01:36:44,480
IF THE SEQUENCES ARE CLOSE TO

2151
01:36:44,480 --> 01:36:47,080
EACH OTHER, THEY WILL BE JOINED

2152
01:36:47,080 --> 01:36:49,520
BY A LINE, JOINING INTO

2153
01:36:49,520 --> 01:36:51,840
CLUSTERS, AND WE CAN CALL THIS

2154
01:36:51,840 --> 01:36:54,680
LIKE A SANITY CHECK THAT THESE T

2155
01:36:54,680 --> 01:36:55,920
CELLS FROM DIFFERENT INDIVIDUALS

2156
01:36:55,920 --> 01:36:57,480
ARE IDENTICAL OR SIMILAR TO EACH

2157
01:36:57,480 --> 01:36:57,800
OTHER.

2158
01:36:57,800 --> 01:37:02,320
SOME OF THE SANITY CHECKS WE CAN

2159
01:37:02,320 --> 01:37:04,960
DO ARE THESE CLUSTERS CO-SORT

2160
01:37:04,960 --> 01:37:09,080
WITH H ALLELES OR PHENOTYPES AND

2161
01:37:09,080 --> 01:37:15,240
SOME RECAPITULATE WILL IT  --

2162
01:37:15,240 --> 01:37:16,800
LITERATURE.

2163
01:37:16,800 --> 01:37:19,400
THIS CLUSTERS, SEEING THIS HOT

2164
01:37:19,400 --> 01:37:20,400
A2 EPITOPE.

2165
01:37:20,400 --> 01:37:23,440
WE WANTED TO TEST OTHER

2166
01:37:23,440 --> 01:37:24,000
CLUSTERS.

2167
01:37:24,000 --> 01:37:25,760
WE CHOSE SOME OF THESE SHOWN

2168
01:37:25,760 --> 01:37:28,960
WITH THE ARROWS THAT WERE A-3

2169
01:37:28,960 --> 01:37:31,160
RESTRICTED, SHOWN ON THE RIGHT

2170
01:37:31,160 --> 01:37:32,240
THESE ARE INDIVIDUAL PATIENTS,

2171
01:37:32,240 --> 01:37:34,200
THE FREQUENCY OF CELLS IN

2172
01:37:34,200 --> 01:37:36,200
CLUSTERS DID GO UP OVER TIME

2173
01:37:36,200 --> 01:37:36,960
WITH VACCINATION.

2174
01:37:36,960 --> 01:37:38,400
SO HERE WE'RE GETTING TO ONE OF

2175
01:37:38,400 --> 01:37:39,600
THE NICE TECHNOLOGIES IN THIS

2176
01:37:39,600 --> 01:37:42,560
AREA BUT ALSO A PAIN POINT WHICH

2177
01:37:42,560 --> 01:37:44,520
IS TCR RECONSTRUCTION.

2178
01:37:44,520 --> 01:37:45,760
WE PICK SIX AND RECONSTRUCTED

2179
01:37:45,760 --> 01:37:48,880
THEM AND PUT THEM IN REPORTER

2180
01:37:48,880 --> 01:37:52,960
CELLS, BOTTOM LINE IN RED IS WE

2181
01:37:52,960 --> 01:37:54,160
PREDICTED THIS TCR WOULD BE

2182
01:37:54,160 --> 01:37:55,800
RESTRICTED BASED ON ASSOCIATION

2183
01:37:55,800 --> 01:38:02,360
WITH PEOPLE WHO WERE HLA 3, WHEN

2184
01:38:02,360 --> 01:38:05,320
WE TRANSFECT, BOTH HLA 3 AND 4

2185
01:38:05,320 --> 01:38:07,720
SPIKE, REPORTER CELL HAS A NEON

2186
01:38:07,720 --> 01:38:11,040
GREEN SIGNAL THAT GOES UP WHEN

2187
01:38:11,040 --> 01:38:13,120
THE CELL IS ACTIVATED THROUGH

2188
01:38:13,120 --> 01:38:14,520
T-CELL RECEPTOR.

2189
01:38:14,520 --> 01:38:17,240
WE USE T-CELL RECEPTORS, PUT IN

2190
01:38:17,240 --> 01:38:19,560
LENTIVIRUSES, FORCED INTO THESE

2191
01:38:19,560 --> 01:38:20,000
REPORTER CELLS.

2192
01:38:20,000 --> 01:38:24,720
AND WE WERE ABLE TO DO THIS WITH

2193
01:38:24,720 --> 01:38:27,360
SIX RECEPTORS, ONE THROUGH SIX,

2194
01:38:27,360 --> 01:38:31,440
EPITOPE IS HERE, THIS K THROUGH

2195
01:38:31,440 --> 01:38:34,520
L AMINO ACID EPITOPE, LOOKING AT

2196
01:38:34,520 --> 01:38:36,080
VARIANTS IN THE INTEREST OF

2197
01:38:36,080 --> 01:38:38,200
TIME, DIFFERENT TRUNCATIONS, YOU

2198
01:38:38,200 --> 01:38:40,520
CAN SEE SUBTLE DIFFERENCES HERE

2199
01:38:40,520 --> 01:38:43,480
IN REACTIVITY WITH 100% TOP

2200
01:38:43,480 --> 01:38:45,320
REACTIVITY WITH SUBTLE

2201
01:38:45,320 --> 01:38:50,160
DIFFERENCES IN THE T-CELL

2202
01:38:50,160 --> 01:38:52,240
RECEPTOR LENGTH AND IDENTITY.

2203
01:38:52,240 --> 01:38:53,000
WE CAN VALIDATE T-CELL RECEPTORS

2204
01:38:53,000 --> 01:38:57,440
OUT OF THE TENS OF THOUSANDS

2205
01:38:57,440 --> 01:38:57,960
WE'VE NOMINATED BY

2206
01:38:57,960 --> 01:38:58,680
RECONSTRUCTION BUT DIFFICULT TO

2207
01:38:58,680 --> 01:39:00,960
DO THEM ALL.

2208
01:39:00,960 --> 01:39:06,520
LET'S GET BACK TO TO THIS.

2209
01:39:06,520 --> 01:39:09,520
WE SWABBED NOSES, MADE DNA,

2210
01:39:09,520 --> 01:39:14,440
SEQUENCED, LOOK FOR OVERLAP BY

2211
01:39:14,440 --> 01:39:16,720
COMPARING THE NOSE SEQUENCES TO

2212
01:39:16,720 --> 01:39:20,640
LOOKUP TABLES I'LL MENTION NEXT

2213
01:39:20,640 --> 01:39:23,280
THAT TO -- TO COUNT SARS-COV-2

2214
01:39:23,280 --> 01:39:24,160
SPECIFIC T CELLS.

2215
01:39:24,160 --> 01:39:26,720
ONE INDIVIDUAL ON THE LEFT, HERE

2216
01:39:26,720 --> 01:39:29,000
IS T-CELL RECEPTOR SEQUENCE FROM

2217
01:39:29,000 --> 01:39:31,600
THE NOSE, THE MOST ABUNDANT, ONE

2218
01:39:31,600 --> 01:39:42,040
OUT OF 50, AND YOU CAN SEE

2219
01:39:42,040 --> 01:39:44,000
TCRs WE RECONSTRUCTED WERE

2220
01:39:44,000 --> 01:39:48,080
ALSO FOUND IN THE NOSE, EXACT

2221
01:39:48,080 --> 01:39:48,320
MATCHES.

2222
01:39:48,320 --> 01:39:50,680
WE CAN SEE HYBRID IMMUNITY, YES

2223
01:39:50,680 --> 01:39:54,520
LOCALIZING TO THE SITE YOU NEED

2224
01:39:54,520 --> 01:39:56,800
HOST DEFENSE AGAINST INCOMING

2225
01:39:56,800 --> 01:39:57,280
SARS-COV-2 INFECTION.

2226
01:39:57,280 --> 01:39:59,080
ON THE RIGHT THESE ARE EVERY

2227
01:39:59,080 --> 01:40:01,640
COLORED CIRCLE HERE, THE SAME

2228
01:40:01,640 --> 01:40:04,480
ABUNDANCE HISTOGRAM, EACH ONE OF

2229
01:40:04,480 --> 01:40:14,880
THE COLORED CIRCLES IS A

2230
01:40:15,960 --> 01:40:17,440
SARS-COV-2, MOSTLY CD8s, A FEW

2231
01:40:17,440 --> 01:40:20,360
CD4s FOUND IN THE NOSE.

2232
01:40:20,360 --> 01:40:24,960
IN A LOOKUP TABLE LOOK AT TCRs

2233
01:40:24,960 --> 01:40:25,880
MORE ABUNDANT.

2234
01:40:25,880 --> 01:40:28,480
THIS IS SEQUENCING ONLY.

2235
01:40:28,480 --> 01:40:31,200
HERE IS EXAMPLE WHERE THE D CELL

2236
01:40:31,200 --> 01:40:32,880
RECEPTORS IN RED WERE FOUND IN

2237
01:40:32,880 --> 01:40:36,480
THIS AFTER GREATER THAN BEFORE,

2238
01:40:36,480 --> 01:40:37,360
COMPARATIVE BIOINFORMATIC

2239
01:40:37,360 --> 01:40:37,760
ANALYSIS.

2240
01:40:37,760 --> 01:40:39,400
FINALLY IF ALL HAVE YOU IS A

2241
01:40:39,400 --> 01:40:40,840
SWAB, YOU DON'T HAVE BLOOD, WANT

2242
01:40:40,840 --> 01:40:44,800
TO DO LESS WORK, YOU CAN CONSULT

2243
01:40:44,800 --> 01:40:46,520
A LOOKUP TABLE, PUBLISHED BY ONE

2244
01:40:46,520 --> 01:40:48,720
OF THE FIVE TECHNOLOGY THE

2245
01:40:48,720 --> 01:40:49,080
COMPANIES.

2246
01:40:49,080 --> 01:40:52,080
THIS COMPANY PUBLISHED A LONG

2247
01:40:52,080 --> 01:40:52,960
LIST.

2248
01:40:52,960 --> 01:40:55,160
T-CELL RECEPTORS THEY THINK ARE

2249
01:40:55,160 --> 01:40:56,360
SARS-COV-2 SPECIFIC.

2250
01:40:56,360 --> 01:40:57,480
NASAL SWABS FOUR PEOPLE.

2251
01:40:57,480 --> 01:41:00,840
IF WE LOOK WE CAN SEE THERE ARE

2252
01:41:00,840 --> 01:41:03,280
HITS FROM NASAL SWAB, SEQUENCING

2253
01:41:03,280 --> 01:41:07,160
THE NASAL SWAB THAT APPEAR TO BE

2254
01:41:07,160 --> 01:41:07,800
SARS-COV-2-SPECIFIC.

2255
01:41:07,800 --> 01:41:10,200
THE PROBLEM IS THE DATA IN THE

2256
01:41:10,200 --> 01:41:11,520
LOOKUP AVAILABLE IS NOT SUPER

2257
01:41:11,520 --> 01:41:13,400
WELL VETTED AND CAN SOMETIMES

2258
01:41:13,400 --> 01:41:15,240
HAVE DIFFICULTIES OR QUESTIONS

2259
01:41:15,240 --> 01:41:19,560
AND NEEDS TO BE IMPROVED.

2260
01:41:19,560 --> 01:41:23,760
FROM THE COVID WORK PRE-VERSUS

2261
01:41:23,760 --> 01:41:26,840
POST VACCINATION, COULD NOMINATE

2262
01:41:26,840 --> 01:41:28,960
SOME TCRs, THE OVERLAP MAKES

2263
01:41:28,960 --> 01:41:29,160
SENSE.

2264
01:41:29,160 --> 01:41:31,000
WE CAN DO LIMITED FUNCTIONAL

2265
01:41:31,000 --> 01:41:33,080
CONFIRMATION BUT THIS IS A PAIN

2266
01:41:33,080 --> 01:41:34,360
POINT THAT COSTS MONEY, TAKES

2267
01:41:34,360 --> 01:41:34,560
TIME.

2268
01:41:34,560 --> 01:41:38,120
CAN USE THIS DATA TO GO BACK TO

2269
01:41:38,120 --> 01:41:41,800
NASAL SWABS TO CONFIRM TISSUE

2270
01:41:41,800 --> 01:41:45,520
RESIDENT MEMORY T CELLS, VIA

2271
01:41:45,520 --> 01:41:52,640
USING TCRs AS BARCODE CAN BE

2272
01:41:52,640 --> 01:42:00,200
FOUND IN THE NOSE.

2273
01:42:00,200 --> 01:42:04,000
THIS IS A VIRUS THAT CAUSES A

2274
01:42:04,000 --> 01:42:10,280
RARE CANCER, EXPRESSED IN CELLS,

2275
01:42:10,280 --> 01:42:13,560
CAN BE STAINED FOR HERE, POOR

2276
01:42:13,560 --> 01:42:15,200
PROGNOSIS CANCER, YOU CAN SEE

2277
01:42:15,200 --> 01:42:18,360
DEPENDING ON PRESENTING STAGE.

2278
01:42:18,360 --> 01:42:21,560
THERE'S 400 AMINO ACID PROTEIN

2279
01:42:21,560 --> 01:42:25,640
SPACE EXPRESSED, REQUIRED FOR

2280
01:42:25,640 --> 01:42:27,240
ONCOGENESIS IN THIS CANCER.

2281
01:42:27,240 --> 01:42:31,560
WE'VE BEEN ABLE TO DO T CELL

2282
01:42:31,560 --> 01:42:33,960
EPITOPE MAPPING IN THIS, IT'S

2283
01:42:33,960 --> 01:42:36,480
TWO ISOFORMS OF THE PROTEIN.

2284
01:42:36,480 --> 01:42:39,520
WE CAN COVER ABOUT 95% OF THE

2285
01:42:39,520 --> 01:42:45,440
POPULATION WITH KNOWN CD8 T CELL

2286
01:42:45,440 --> 01:42:49,800
EPITOPES IN THIS ONCOPROTEIN.

2287
01:42:49,800 --> 01:42:54,280
SO, USING THIS APPROACH WE CAN

2288
01:42:54,280 --> 01:42:56,480
SHOW THAT INDIVIDUALS WHO HAVE

2289
01:42:56,480 --> 01:43:01,640
TETRAMER POSITIVE CELLS IN THE

2290
01:43:01,640 --> 01:43:03,840
BLOOD HAVE BETTER OUTCOME WITH

2291
01:43:03,840 --> 01:43:05,800
CHECKPOINT THERAPY AND FORM

2292
01:43:05,800 --> 01:43:07,440
CLUSTERS IF WE CLUSTER BY

2293
01:43:07,440 --> 01:43:11,160
SEQUENCE SPACE.

2294
01:43:11,160 --> 01:43:13,560
AS OUTCOME OF THIS WORK, WE HAVE

2295
01:43:13,560 --> 01:43:16,520
A CLINICAL TRIAL UNDERGOING

2296
01:43:16,520 --> 01:43:18,800
USING A VACCINE AND WE'RE

2297
01:43:18,800 --> 01:43:21,440
PLANNING ON USING TCR SEQUENCING

2298
01:43:21,440 --> 01:43:23,760
AS BIOMARKER FOR THIS

2299
01:43:23,760 --> 01:43:24,040
INDICATION.

2300
01:43:24,040 --> 01:43:26,600
WAY AT THE OTHER END OF THE

2301
01:43:26,600 --> 01:43:31,200
SPECTRUM OF A SMALL PROTEIN

2302
01:43:31,200 --> 01:43:31,560
SPACE.

2303
01:43:31,560 --> 01:43:32,640
WE'RE RUNNING LATE, TIM.

2304
01:43:32,640 --> 01:43:39,240
I WANT TO SWITCH GEARS TO

2305
01:43:39,240 --> 01:43:42,720
CHICKEN POX.

2306
01:43:42,720 --> 01:43:44,600
IT CAN CAUSE CHICKEN POX AND

2307
01:43:44,600 --> 01:43:45,920
LATER ON SHINGLES.

2308
01:43:45,920 --> 01:43:47,680
WE'RE INTERESTED IN STUDY LOCAL

2309
01:43:47,680 --> 01:43:55,000
T-CELL RESPONSE IN THIS CASE,

2310
01:43:55,000 --> 01:43:56,760
AND SEE WHETHER THERE'S A

2311
01:43:56,760 --> 01:43:57,440
DURABLE IMMUNE RESPONSE AFTER

2312
01:43:57,440 --> 01:43:58,120
INFECTION.

2313
01:43:58,120 --> 01:43:59,520
WE HAVE A PROTOCOL THAT LASTED

2314
01:43:59,520 --> 01:44:03,840
FOR A YEAR WHERE WE DID BIOPSIES

2315
01:44:03,840 --> 01:44:05,960
OF SHINGLES SKIN, HEALED SKIN,

2316
01:44:05,960 --> 01:44:16,520
FOR UP TO A YEAR AFTER SHINGLES.

2317
01:44:17,040 --> 01:44:20,440
AND WE WOULD TEST THE T CELLS

2318
01:44:20,440 --> 01:44:24,480
WITH THE WHOLE PROTEOME AND

2319
01:44:24,480 --> 01:44:25,600
EPITOPES TETRAMERS, SEQUENCE,

2320
01:44:25,600 --> 01:44:29,040
AND GOING BACK TO STAIN THE SKIN

2321
01:44:29,040 --> 01:44:32,800
FOR ANTIGEN SPECIFIC T CELLS.

2322
01:44:32,800 --> 01:44:38,720
SO, IN THIS PARTICULAR CASE WE

2323
01:44:38,720 --> 01:44:41,320
WERE ABLE TO PERFORM WHOLE

2324
01:44:41,320 --> 01:44:43,880
PROTEOME SCREENS AND EXPRESSED

2325
01:44:43,880 --> 01:44:50,000
ALL OF THE FRAMES AND STUDIED

2326
01:44:50,000 --> 01:44:55,560
THE T CELLS IN SKIN BIOPSIES OF

2327
01:44:55,560 --> 01:44:56,680
HEALED SHINGLES SKIN, TESTING

2328
01:44:56,680 --> 01:44:57,440
FOR REACTIVITY WITH EVERY

2329
01:44:57,440 --> 01:44:59,360
INDIVIDUAL OR AS YOU CAN SEE THE

2330
01:44:59,360 --> 01:45:01,680
SUBJECT ON DAY 45 AFTER RECOVERY

2331
01:45:01,680 --> 01:45:06,840
FROM SHINGLES HAD A LOT OF T

2332
01:45:06,840 --> 01:45:10,440
CELL REACTIVITY AGAINST MANY

2333
01:45:10,440 --> 01:45:11,560
INDIVIDUAL PROTEINS.

2334
01:45:11,560 --> 01:45:14,080
TO SUMMARIZE AN INDIVIDUAL HERE

2335
01:45:14,080 --> 01:45:19,240
AT DAY 45, DAY 90 AND 60, THREE

2336
01:45:19,240 --> 01:45:21,840
HLA ALLELES, SOME REACTIVITY

2337
01:45:21,840 --> 01:45:26,320
AGAINST PROTEINS ON HEALED

2338
01:45:26,320 --> 01:45:35,200
SHINGLES SIDE, VERY LITTLE ON

2339
01:45:35,200 --> 01:45:35,840
CONTRALATERAL.

2340
01:45:35,840 --> 01:45:42,440
ON TOP ARE SHINGLES SKIN DAY 45,

2341
01:45:42,440 --> 01:45:44,960
DAY 90, DAY 360, ONE TO 500.

2342
01:45:44,960 --> 01:45:47,240
WE HAD DIFFERENT HITS, LOOKING

2343
01:45:47,240 --> 01:45:51,960
AT CONTROL SKIN WE HAVE VERY

2344
01:45:51,960 --> 01:45:53,920
MUCH LESS REACTIVITY OVER IN THE

2345
01:45:53,920 --> 01:45:57,680
CONTROL SKIN.

2346
01:45:57,680 --> 01:46:00,360
SO, WHAT WE ARE -- THIS IS A

2347
01:46:00,360 --> 01:46:06,600
SUMMARY OF OVERALL DATA, CLEAR

2348
01:46:06,600 --> 01:46:09,720
WINNER, ORF 9.

2349
01:46:09,720 --> 01:46:12,880
MY MAIN POINT HERE IS TO SAY

2350
01:46:12,880 --> 01:46:17,240
THAT WE NEED TO LOOK ACROSS THE

2351
01:46:17,240 --> 01:46:19,760
PROTEOME, THIS LARGE PATHOGEN,

2352
01:46:19,760 --> 01:46:21,640
HARDER THAN SARS-COV-2 WITH

2353
01:46:21,640 --> 01:46:23,920
ABOUT 24 PROTEINS, THIS VIRUS

2354
01:46:23,920 --> 01:46:27,320
HAS ABOUT 70 PROTEINS, BUT WE

2355
01:46:27,320 --> 01:46:29,720
TOOK THE PAINS TO DO THIS AND

2356
01:46:29,720 --> 01:46:31,800
FOUND A CLEAR WINNER HERE, IN

2357
01:46:31,800 --> 01:46:33,720
RED ON THE RASH SITE ONLY A LOT

2358
01:46:33,720 --> 01:46:35,400
MORE REACTIVITY OVER ON THE RASH

2359
01:46:35,400 --> 01:46:39,560
SIDE THAN ON THE CONTRALATERAL

2360
01:46:39,560 --> 01:46:39,920
SITE.

2361
01:46:39,920 --> 01:46:42,320
SO, THE CONCLUSION OF THIS IS

2362
01:46:42,320 --> 01:46:46,360
THAT THERE IS A SEATING OF SKIN,

2363
01:46:46,360 --> 01:46:47,240
IMMUNE MEMORY, LOCAL MEMORY AT

2364
01:46:47,240 --> 01:46:49,960
THE SITE OF HEALED INFECTION.

2365
01:46:49,960 --> 01:46:51,720
WE FOUND MANY, MANY INDIVIDUAL

2366
01:46:51,720 --> 01:46:54,680
EPITOPES AND CONTRIBUTED THIS TO

2367
01:46:54,680 --> 01:46:56,760
IMMUNE EPITOPE DATABASE, SOME

2368
01:46:56,760 --> 01:47:00,720
EPITOPES LISTED HERE WITH

2369
01:47:00,720 --> 01:47:01,480
VARIOUS HLA RESTRICTIONS.

2370
01:47:01,480 --> 01:47:11,960
AND WE WERE ABLE TO MAKE AT THE

2371
01:47:11,960 --> 01:47:15,920
TETRAMERS, YOU CAN SEE VERY HIGH

2372
01:47:15,920 --> 01:47:16,680
REACTIVITY WITH SOME INDIVIDUAL

2373
01:47:16,680 --> 01:47:18,000
TETRAMERS AND USING THEM WERE

2374
01:47:18,000 --> 01:47:20,840
ABLE TO GO BACK AND STAIN

2375
01:47:20,840 --> 01:47:22,160
BIOPSIES OF THE SKIN.

2376
01:47:22,160 --> 01:47:24,440
WE'RE PROVING, THIS WAS IN A DAY

2377
01:47:24,440 --> 01:47:26,720
45 AND DAY 90, THESE ANTIGEN

2378
01:47:26,720 --> 01:47:29,800
SPECIFIC T CELLS ARE RETAINED

2379
01:47:29,800 --> 01:47:31,560
LONG TERM IN THE SKIN AFTER

2380
01:47:31,560 --> 01:47:33,720
RECOVERY FROM THE VIRAL

2381
01:47:33,720 --> 01:47:34,360
INFECTION.

2382
01:47:34,360 --> 01:47:38,480
THIS IS AN ASPIRATIONAL GOAL OF

2383
01:47:38,480 --> 01:47:39,640
VACCINOLOGY, WOULD LOVE TO GIVE

2384
01:47:39,640 --> 01:47:41,840
A SHOT AT I.M. AND HAVE T CELLS

2385
01:47:41,840 --> 01:47:45,000
GO TO THE NOSE IN TERMS OF

2386
01:47:45,000 --> 01:47:47,120
SARS-COV-2, AND BE

2387
01:47:47,120 --> 01:47:53,880
PRE-POSITIONED TO FIGHT AGAINST

2388
01:47:53,880 --> 01:47:55,520
INITIAL INOCULATION, WE'RE NOT

2389
01:47:55,520 --> 01:48:00,960
THERE YET BUT USING NOTHING BUT

2390
01:48:00,960 --> 01:48:03,880
BUT ESPECIALLY WITH IN SITU,

2391
01:48:03,880 --> 01:48:04,960
DEMONSTRATE THEY ARE RETAINED AT

2392
01:48:04,960 --> 01:48:05,920
THE INITIAL SITE.

2393
01:48:05,920 --> 01:48:10,000
I'M GOING TO SKIP THIS A LITTLE

2394
01:48:10,000 --> 01:48:12,160
BIT. 

2395
01:48:12,160 --> 01:48:14,280
I WOULD MENTION THAT WE -- A

2396
01:48:14,280 --> 01:48:17,680
CURRENT HORIZON TO TO MOVE TO

2397
01:48:17,680 --> 01:48:18,560
CULTURE INDEPENDENT EPITOPE

2398
01:48:18,560 --> 01:48:21,400
DISCOVERY, THIS IS USING POWER

2399
01:48:21,400 --> 01:48:22,680
OF TCR RECONSTRUCTION, IN THIS

2400
01:48:22,680 --> 01:48:26,320
CASE WE DID A CERVICAL BIOPSY,

2401
01:48:26,320 --> 01:48:29,280
AND SORTED THESE ACTIVATED CELLS

2402
01:48:29,280 --> 01:48:33,760
USING CD137 AS ACTIVATION MARKER

2403
01:48:33,760 --> 01:48:40,520
AND DID SINGLE CELL TCR, FOUND A

2404
01:48:40,520 --> 01:48:42,120
LENTIVIRUS, A REPORTER CELL ABLE

2405
01:48:42,120 --> 01:48:43,240
TO RECOGNIZE WHOLE VIRUS AND

2406
01:48:43,240 --> 01:48:45,520
ALWAYS LIKE TO DO THIS TO SHOW

2407
01:48:45,520 --> 01:48:47,120
RECOGNITION OF WHOLE VIRUS.

2408
01:48:47,120 --> 01:48:52,120
ONCE WE HAVE THIS RECOMBINANT

2409
01:48:52,120 --> 01:48:55,000
TCR WE'RE ABLE TO SCREEN IT

2410
01:48:55,000 --> 01:48:57,800
AGAINST ALL FOUR OF THE PERSON'S

2411
01:48:57,800 --> 01:49:00,840
HLA ALLELES AND HERPES PROTEINS

2412
01:49:00,840 --> 01:49:02,560
AND FOUND WHICH PROTEIN THIS

2413
01:49:02,560 --> 01:49:03,000
REPRESENTED.

2414
01:49:03,000 --> 01:49:04,440
WHILE THE TECHNOLOGIES I SHOWED

2415
01:49:04,440 --> 01:49:06,240
PREVIOUSLY ARE KIND OF, YOU

2416
01:49:06,240 --> 01:49:10,360
KNOW, DEPENDENT ON HAVING OR

2417
01:49:10,360 --> 01:49:11,520
GROWING LIVING T CELLS WITH

2418
01:49:11,520 --> 01:49:16,680
ENOUGH PAIN CAN DO THIS PURELY

2419
01:49:16,680 --> 01:49:20,960
FROM TCR SEQUENCE. 

2420
01:49:20,960 --> 01:49:23,360
A FEW SLIDES FROM SYPHILIS, A

2421
01:49:23,360 --> 01:49:24,560
NEW INITIATIVE TO STUDY THIS

2422
01:49:24,560 --> 01:49:26,760
BACTERIAL DISEASE FOR WHICH

2423
01:49:26,760 --> 01:49:27,280
THERE'S NO VACCINE.

2424
01:49:27,280 --> 01:49:30,160
IN THE KALES OF SECONDARY

2425
01:49:30,160 --> 01:49:32,760
SYPHILIS, OCCURS ABOUT A MONTH

2426
01:49:32,760 --> 01:49:35,400
AFTER PRIMARY SYPHILIS, AND SKIN

2427
01:49:35,400 --> 01:49:38,800
IS TEAMING WITH BACTERIUM, AND T

2428
01:49:38,800 --> 01:49:40,880
CELLS, AND QUESTION IS ARE THERE

2429
01:49:40,880 --> 01:49:41,960
ANTIGEN SPECIFIC T CELLS IN

2430
01:49:41,960 --> 01:49:42,400
THERE?

2431
01:49:42,400 --> 01:49:47,040
THIS IS A BIOPSY OF SECONDARY

2432
01:49:47,040 --> 01:49:49,200
SKIN LESION, RED SQUIGGLES ARE

2433
01:49:49,200 --> 01:49:49,520
BACTERIA.

2434
01:49:49,520 --> 01:49:51,520
YOU CAN SEE THIS SAMPLE IS

2435
01:49:51,520 --> 01:49:57,400
RELATIVELY LOADED WITH BACTERIA

2436
01:49:57,400 --> 01:49:58,840
AND INFILTRATE CONTRIBUTING TO

2437
01:49:58,840 --> 01:49:59,440
INFLAMMATION.

2438
01:49:59,440 --> 01:50:01,000
IF WE STAIN THIS BIOPSY FOR

2439
01:50:01,000 --> 01:50:04,600
IMMUNE CELLS, WE CAN SEE A LOT

2440
01:50:04,600 --> 01:50:08,800
OF CD4 AND CD8 CELLS, INTERESTED

2441
01:50:08,800 --> 01:50:10,920
IN STUDYING IF THEY ARE ANTIGEN

2442
01:50:10,920 --> 01:50:11,200
SPECIFIC.

2443
01:50:11,200 --> 01:50:11,880
THESE ARE BACTERIA.

2444
01:50:11,880 --> 01:50:13,960
WHAT ARE THEY DOING HERE?

2445
01:50:13,960 --> 01:50:16,280
COULD BE ANTIGEN SPECIFIC OR

2446
01:50:16,280 --> 01:50:20,280
SEMI INNATE CELLS, INTERESTED IN

2447
01:50:20,280 --> 01:50:20,960
THAT.

2448
01:50:20,960 --> 01:50:22,160
THERE'S LOCAL UPREGULATION AT

2449
01:50:22,160 --> 01:50:23,640
HLA CLASS 2, MIGHT BE EXPECTED

2450
01:50:23,640 --> 01:50:27,640
FROM THE REDNESS OF THE RASH,

2451
01:50:27,640 --> 01:50:32,160
EFFECTOR CELLS IN SKIN THOUGHT

2452
01:50:32,160 --> 01:50:38,920
TO BE MACROPHAGES, AND

2453
01:50:38,920 --> 01:50:41,480
PHAGOCYTOSIS OF ANTIBODY-COATED

2454
01:50:41,480 --> 01:50:46,200
THOUGHT TO BE HOW THE HOST

2455
01:50:46,200 --> 01:50:47,480
CLEARS THE BACTERIA BECAUSE THE

2456
01:50:47,480 --> 01:50:53,600
RASH WILL GO AWAY, MAKING

2457
01:50:53,600 --> 01:50:55,040
NEUTRON GAMMA WE HYPOTHESIZE TO

2458
01:50:55,040 --> 01:50:57,240
LEAD TO CLEARANCE.

2459
01:50:57,240 --> 01:50:59,120
WE TAKE TRADITIONAL APPROACH OF

2460
01:50:59,120 --> 01:51:02,800
CLONING IN THIS CASE A THOUSAND

2461
01:51:02,800 --> 01:51:05,200
OPEN FRAMES, WE CAN'T CLONE THEM

2462
01:51:05,200 --> 01:51:08,400
ALL, WE CLONED 50 HERE IN THIS

2463
01:51:08,400 --> 01:51:09,040
EXAMPLE.

2464
01:51:09,040 --> 01:51:11,360
WE USED BLOOD TO ENRICH CELLS

2465
01:51:11,360 --> 01:51:13,640
OUT OF THE BLOOD REACTIVE WITH

2466
01:51:13,640 --> 01:51:16,920
WHOLE TP AND USING AIM, MARKERS,

2467
01:51:16,920 --> 01:51:18,800
SORTING AND EXPANDING CELLS WE

2468
01:51:18,800 --> 01:51:22,920
DO HAVE SOME HITS HERE,

2469
01:51:22,920 --> 01:51:26,440
DUPLICATE HAVE DECODED FOR THE

2470
01:51:26,440 --> 01:51:28,880
FIRST TIME IDENTITY OF CD4 T

2471
01:51:28,880 --> 01:51:29,720
CELL ANTIGENS, INCLUDING

2472
01:51:29,720 --> 01:51:34,200
ACTIVITY OF WHOLE ORGANISMS OVER

2473
01:51:34,200 --> 01:51:36,400
HERE, WHOLE MICROORGANISMS, WELL

2474
01:51:36,400 --> 01:51:40,760
BEHAVED, I WON'T GO INTO DETAILS

2475
01:51:40,760 --> 01:51:42,840
BUT DR RESTRICTED, PREDICTED TO

2476
01:51:42,840 --> 01:51:45,480
BE PREDICTED BY DR BETA 7, SO WE

2477
01:51:45,480 --> 01:51:50,200
CAN DRILL DOWN INTO INDIVIDUAL

2478
01:51:50,200 --> 01:51:51,280
EPITOPES AND SHOW TRADITIONAL

2479
01:51:51,280 --> 01:51:53,160
HLA RESTRICTION.

2480
01:51:53,160 --> 01:51:54,400
WHAT'S INTERESTING HERE WAS

2481
01:51:54,400 --> 01:51:56,320
TISSUE RESIDENT MEMORY T CELLS

2482
01:51:56,320 --> 01:51:59,600
ARE LEFT BEHIND AFTER PENICILLIN

2483
01:51:59,600 --> 01:52:00,240
TREATMENT FOR SECONDARY

2484
01:52:00,240 --> 01:52:02,120
SYPHILIS, SOME INDIVIDUAL CAME

2485
01:52:02,120 --> 01:52:05,080
IN, STUDY WITH BOTH BLOOD AND

2486
01:52:05,080 --> 01:52:08,160
SKIN BIOPSY, DAY ZERO, ALSO ON

2487
01:52:08,160 --> 01:52:10,560
DAY 30 AND DAY 180 AFTER

2488
01:52:10,560 --> 01:52:11,680
PENICILLIN THERAPY.

2489
01:52:11,680 --> 01:52:15,120
WITH SKIN WE DIDN'T NEED

2490
01:52:15,120 --> 01:52:17,320
ENRICHMENT, GREW CELLS OUT OF

2491
01:52:17,320 --> 01:52:20,840
THE SKIN, NO CHECK FOR

2492
01:52:20,840 --> 01:52:21,240
ENRICHMENT.

2493
01:52:21,240 --> 01:52:22,240
IN MICE CONSISTENCY OVER THE

2494
01:52:22,240 --> 01:52:24,640
TIME, BLOOD AND SKIN, FOR THE

2495
01:52:24,640 --> 01:52:28,080
SAME OPEN READING FRAMES TEND TO

2496
01:52:28,080 --> 01:52:29,480
BE DETECTED AT BOTH TISSUES.

2497
01:52:29,480 --> 01:52:34,360
IN THE BLOOD AND SKIN BIOPSY BUT

2498
01:52:34,360 --> 01:52:40,960
INTERESTINGLY HOW TODAY 180

2499
01:52:40,960 --> 01:52:42,600
AFTER RESOLUTION AND PENICILLIN

2500
01:52:42,600 --> 01:52:44,160
TREATMENT WE SEE FUNCTIONAL

2501
01:52:44,160 --> 01:52:47,320
EVIDENCE FOR THESE STILL BEING

2502
01:52:47,320 --> 01:52:47,520
HERE.

2503
01:52:47,520 --> 01:52:55,040
AND THIS IS THE WORK OF TARA

2504
01:52:55,040 --> 01:52:58,840
BRINKLEY, MD/PHD IN THE LAB,

2505
01:52:58,840 --> 01:53:00,600
NOMINATING UNNAMED -- A BLANK

2506
01:53:00,600 --> 01:53:04,880
SPACE FOR THE ANTIGENIC TARGETS,

2507
01:53:04,880 --> 01:53:08,400
DOUBLE MEMORY, INNER AND OUTER

2508
01:53:08,400 --> 01:53:09,600
MEMBRANE POSITIVE SPACE.

2509
01:53:09,600 --> 01:53:12,320
WE HAVE SEVERAL PROTEINS HERE,

2510
01:53:12,320 --> 01:53:15,600
SOME ARE VACCINE CANDIDATES, WE

2511
01:53:15,600 --> 01:53:19,200
HAVE SUPPORT FROM THE NIAID AND

2512
01:53:19,200 --> 01:53:20,560
U19 PROGRAM TO SUPPORT FURTHER

2513
01:53:20,560 --> 01:53:24,160
DEVELOPMENT OF SOME OF THESE AS

2514
01:53:24,160 --> 01:53:24,720
VACCINES.

2515
01:53:24,720 --> 01:53:30,400
SO JUST TO SUMMARIZE HERE, THIS

2516
01:53:30,400 --> 01:53:33,440
IS THE TRIAD, PAIN POINTS, WISH

2517
01:53:33,440 --> 01:53:33,880
LIST.

2518
01:53:33,880 --> 01:53:35,680
SINGLE CELL IS GREAT BUT

2519
01:53:35,680 --> 01:53:37,720
EXPENSIVE, TAKES A LOT OF

2520
01:53:37,720 --> 01:53:42,440
HANDS-ON TIME. 

2521
01:53:42,440 --> 01:53:46,920
VALIDATION IS EXTENSIVE AND

2522
01:53:46,920 --> 01:53:48,560
SLOW.

2523
01:53:48,560 --> 01:53:51,640
PEOPLE ARE USING CRISPR/CAS9,

2524
01:53:51,640 --> 01:53:54,400
LENTIVIRUS, WE NEED BETTER

2525
01:53:54,400 --> 01:53:55,160
TECHNOLOGY.

2526
01:53:55,160 --> 01:53:57,000
DATABASES OF ANTIGEN SPECIFIC

2527
01:53:57,000 --> 01:54:01,280
TCRS ARE A MESS.

2528
01:54:01,280 --> 01:54:02,880
THERE'S REDUNDANCY, FALSE

2529
01:54:02,880 --> 01:54:05,120
POSITIVES, METADATA IN THERE IS

2530
01:54:05,120 --> 01:54:06,640
VARIABLE AND SOMETIMES POOR.

2531
01:54:06,640 --> 01:54:10,680
THERE ARE MANY POORLY DOCUMENTED

2532
01:54:10,680 --> 01:54:13,520
OR DISTRACTING TCRs IN THESE

2533
01:54:13,520 --> 01:54:14,200
DATABASES.

2534
01:54:14,200 --> 01:54:15,880
FINALLY ANOTHER PAIN POINT, I

2535
01:54:15,880 --> 01:54:21,200
THINK, THAT THERE'S A LOT OF

2536
01:54:21,200 --> 01:54:23,040
KNOWLEDGE WITH INDUSTRY, YOU

2537
01:54:23,040 --> 01:54:25,680
HAVE A TCR, WHAT DOES IT SEE,

2538
01:54:25,680 --> 01:54:28,000
THAT IS NOT MAYBE PUBLICLY

2539
01:54:28,000 --> 01:54:28,840
AVAILABLE.

2540
01:54:28,840 --> 01:54:30,400
FOR SUMMARY, I'M SORRY FOR GOING

2541
01:54:30,400 --> 01:54:33,320
SO LONG, WHAT WE'VE TRIED TO

2542
01:54:33,320 --> 01:54:35,280
INCORPORATE IS BIOLOGICALLY

2543
01:54:35,280 --> 01:54:37,240
INFORMATIVE STUDY DESIGNS,

2544
01:54:37,240 --> 01:54:37,760
LOOKING WITHIN SUBJECT,

2545
01:54:37,760 --> 01:54:40,320
LONGITUDINALLY PRE AND POST

2546
01:54:40,320 --> 01:54:44,920
VACCINE, AS IN COVID, AND THEN

2547
01:54:44,920 --> 01:54:45,680
CROSS-SECTION, BLOOD VERSUS

2548
01:54:45,680 --> 01:54:48,760
SKIN, LOOK FOR PUBLIC AND

2549
01:54:48,760 --> 01:54:53,560
SIMILAR TCRs, I SHOWED THE

2550
01:54:53,560 --> 01:54:54,440
CLUSTERING, USING TCR SEQUENCE,

2551
01:54:54,440 --> 01:54:56,960
WE'D LIKE TO MATCH TO PEPTIDE

2552
01:54:56,960 --> 01:54:59,360
HLA LIGANDS ON THE RIGHT, THE

2553
01:54:59,360 --> 01:55:03,400
HOLY GRAIL TO MATCH UP TRIADS,

2554
01:55:03,400 --> 01:55:06,040
TCR SEQUENCING AT SINGLE CELL OR

2555
01:55:06,040 --> 01:55:08,800
BULK LEVEL, FUZZY MATCHING DOES

2556
01:55:08,800 --> 01:55:09,440
SEEM TO HELP.

2557
01:55:09,440 --> 01:55:11,280
AND IT'S NICE TO HAVE METADATA

2558
01:55:11,280 --> 01:55:19,880
THAT GOES WITH EACH ONE OF THOSE

2559
01:55:19,880 --> 01:55:22,040
CELLS, AND LASTLY THE WET LAB

2560
01:55:22,040 --> 01:55:23,680
TOOLS FOR FIGURING OUT IF YOU

2561
01:55:23,680 --> 01:55:25,680
HAVE T CELLS, FIGURING OUT

2562
01:55:25,680 --> 01:55:28,160
PEPTIDE AND HLA, THAT'S HEREN MY

2563
01:55:28,160 --> 01:55:28,400
OPINION.

2564
01:55:28,400 --> 01:55:30,680
THANKS TO ALEX AND OTHERS,

2565
01:55:30,680 --> 01:55:34,400
SOFTWARE TOOLS, YOU CAN KNOW HLA

2566
01:55:34,400 --> 01:55:37,120
AND OPEN READING FRAME, FOR

2567
01:55:37,120 --> 01:55:38,360
PICKING EPITOPES, THESE ARE

2568
01:55:38,360 --> 01:55:41,960
LARGELY HERE.

2569
01:55:41,960 --> 01:55:43,080
BUT LOOKUP TABLES, IF YOU WANT

2570
01:55:43,080 --> 01:55:44,640
TO KNOW HAS ANYBODY SEEN IT

2571
01:55:44,640 --> 01:55:46,120
BEFORE OR WHAT DOES IT SEE,

2572
01:55:46,120 --> 01:55:48,680
THOSE ARE A MESS AND BETTER

2573
01:55:48,680 --> 01:55:54,120
LOOKUP TABLES ARE NEEDED. 

2574
01:55:54,120 --> 01:55:56,520
FINALLY ASPIRATIONALLY WE'VE GOT

2575
01:55:56,520 --> 01:55:57,840
HUNDREDS OF THOUSANDS OF TCR

2576
01:55:57,840 --> 01:55:58,920
SEQUENCES, CAN WE FOLD AND

2577
01:55:58,920 --> 01:56:01,920
FIGURE OUT, LET'S SAY WE KNOW

2578
01:56:01,920 --> 01:56:03,560
PATHOGEN, WHAT PEPTIDE DOES IT

2579
01:56:03,560 --> 01:56:03,960
SEE?

2580
01:56:03,960 --> 01:56:06,600
THAT'S REALLY A FUTURE HORIZON

2581
01:56:06,600 --> 01:56:07,920
THAT SOME COMPUTATIONAL BIOLOGY

2582
01:56:07,920 --> 01:56:09,200
COLLEAGUES ARE WORKING ON, BUT

2583
01:56:09,200 --> 01:56:10,560
MAYBE WE'LL GET THERE AND WE'LL

2584
01:56:10,560 --> 01:56:18,000
BE ABLE TO FIGURE OUT A TCR SEES

2585
01:56:18,000 --> 01:56:20,400
ARE VARIABLE LOOPS, TO PREDICT

2586
01:56:20,400 --> 01:56:26,920
GREEN AND BLUE LIGAND DOWN HERE.

2587
01:56:26,920 --> 01:56:29,120
THAT IS ALL I WANTED TO SAY.

2588
01:56:29,120 --> 01:56:29,800
THANK YOU, TIM.

2589
01:56:29,800 --> 01:56:31,800
>>THANKS, DAVID.

2590
01:56:31,800 --> 01:56:32,480
THAT WAS GREAT.

2591
01:56:32,480 --> 01:56:41,680
I'D LIKE TO OPEN THIS UP TO

2592
01:56:41,680 --> 01:56:48,360
EVERYONE FOR QUESTIONS PLEASE.

2593
01:56:48,360 --> 01:56:52,400
SO, DAVID, ONE OF THE THINGS

2594
01:56:52,400 --> 01:56:55,880
THAT WAS INTERESTED IN T

2595
01:56:55,880 --> 01:56:58,880
PALLIDUM STUDIES, YOU WERE ABLE

2596
01:56:58,880 --> 01:57:01,040
TO SEE THE RESPONSES IN SKIN, I

2597
01:57:01,040 --> 01:57:05,640
GUESS EVEN UP TO WHAT WAS IT

2598
01:57:05,640 --> 01:57:05,800
120?

2599
01:57:05,800 --> 01:57:11,400
>>DAYS, YEAH.

2600
01:57:11,400 --> 01:57:13,160
>>WHICH IS FASCINATING.

2601
01:57:13,160 --> 01:57:14,600
IS THERE RESIDUAL ANTIGEN?

2602
01:57:14,600 --> 01:57:16,000
WHAT IS DRIVING THAT.

2603
01:57:16,000 --> 01:57:17,000
>>THE TISSUE RESIDENT

2604
01:57:17,000 --> 01:57:19,200
PHENOMENON HAS COME OUT OVER THE

2605
01:57:19,200 --> 01:57:25,440
LAST 10 OR 15 YEARS, IN OUR

2606
01:57:25,440 --> 01:57:27,200
SHINGLES STUDIES DID SURFACE

2607
01:57:27,200 --> 01:57:30,560
SWABS UP TO A YEAR.

2608
01:57:30,560 --> 01:57:33,840
BY DAY 360 WE COULDN'T DETECT

2609
01:57:33,840 --> 01:57:35,840
DNA ANYMORE BUT PRESENCE OF

2610
01:57:35,840 --> 01:57:45,240
ANTIGEN OR PEPTIDE CAN'T BE

2611
01:57:45,240 --> 01:57:46,440
RULED OUT.

2612
01:57:46,440 --> 01:57:49,640
WHERE THEY ARE LACKING MOBILITY

2613
01:57:49,640 --> 01:57:50,280
RECEPTORS, MOBILITY RECEPTORS

2614
01:57:50,280 --> 01:57:57,840
SEEM TO BE TAKEN UP BY CD69,

2615
01:57:57,840 --> 01:58:01,600
BINDING, ALSO LACKING A LOT

2616
01:58:01,600 --> 01:58:02,480
OF -- ALSO EXPRESSING CD103

2617
01:58:02,480 --> 01:58:08,760
WHICH TENDS TO LOCK THEM INTO

2618
01:58:08,760 --> 01:58:10,320
THE SKIN BY BINDING REALLY MAKES

2619
01:58:10,320 --> 01:58:14,440
IT SUCH THAT PROBABLY CONTINUING

2620
01:58:14,440 --> 01:58:15,680
ANTIGEN ISN'T REQUIRED ANYMORE.

2621
01:58:15,680 --> 01:58:18,840
IT'S KNOWN THOSE TISSUE RESIDENT

2622
01:58:18,840 --> 01:58:21,600
MEMORY T CELLS PATROL LOCALLY BY

2623
01:58:21,600 --> 01:58:23,560
LIVE-CELL IMAGING BUT TEND NOT

2624
01:58:23,560 --> 01:58:32,120
TO EXIT VERY WELL TO THE BLOOD.

2625
01:58:32,120 --> 01:58:32,440
>>EXCELLENT.

2626
01:58:32,440 --> 01:58:38,480
>>DO YOU HAVE ANY
EVIDENCE OF

2627
01:58:38,480 --> 01:58:40,720
ENRICHMENT OF SPECIFIC TISSUE

2628
01:58:40,720 --> 01:58:51,160
SEQUENCES FOR SKIN OR FOR

2629
01:58:54,280 --> 01:58:55,080
SPECIFIC TISSUES?

2630
01:58:55,080 --> 01:58:56,480
>>WE OBTAINED SPECIFIC
TCRs

2631
01:58:56,480 --> 01:58:58,840
FROM THE BLOOD AND LOOKED AT

2632
01:58:58,840 --> 01:59:00,640
COMPARATIVE ABUNDANCE IN THE

2633
01:59:00,640 --> 01:59:03,400
SKIN, USING THE SKIN AS SITE OF

2634
01:59:03,400 --> 01:59:03,920
ENRICHMENT, COMPARED TO

2635
01:59:03,920 --> 01:59:06,560
ABUNDANCE IN THE SKIN TO BLOOD,

2636
01:59:06,560 --> 01:59:07,840
MUCH, MUCH MORE ABUNDANT IN THE

2637
01:59:07,840 --> 01:59:12,880
SKIN THAN BLOOD, BY A FACTOR OF

2638
01:59:12,880 --> 01:59:21,840
100 OR DID  1,000 FOLD, PUBLISHN

2639
01:59:21,840 --> 01:59:24,560
NATURE COMMUNICATION.

2640
01:59:24,560 --> 01:59:31,560
WE'VE SHOWN FOR ACUTE GENITAL

2641
01:59:31,560 --> 01:59:34,960
HERPES CELLS ARE MORE ABUNDANT

2642
01:59:34,960 --> 01:59:37,920
IF YOU BELIEVE TCR Seq COUNTS.

2643
01:59:37,920 --> 01:59:39,800
WITH NATION ALCOVED SITUATION,

2644
01:59:39,800 --> 01:59:41,440
HYBRID IMMUNITY VERSUS PEOPLE

2645
01:59:41,440 --> 01:59:44,440
INFECTED AND HAD THE SHOT, THE

2646
01:59:44,440 --> 01:59:46,880
DOUBLE BOOST, IF YOU LOOK AT

2647
01:59:46,880 --> 01:59:48,640
NASAL SWABS VERSUS ABUNDANCE IN

2648
01:59:48,640 --> 01:59:50,560
BLOOD THEY ARE MORE ABUNDANT IN

2649
01:59:50,560 --> 01:59:51,920
NASAL SWABS THAN IN THE BLOOD.

2650
01:59:51,920 --> 01:59:55,320
>>BUT IS IT DRIVEN
BECAUSE OF

2651
01:59:55,320 --> 01:59:57,800
VIRUSES THERE OR WHAT I'M SAYING

2652
01:59:57,800 --> 02:00:07,960
IS THAT IS THERE EVIDENCE OF --

2653
02:00:07,960 --> 02:00:12,440
WITHOUT ANTIGEN LOAD TO BE

2654
02:00:12,440 --> 02:00:13,600
DRIVEN TO SPECIFIC TISSUE?

2655
02:00:13,600 --> 02:00:15,520
>>THAT'S A TOUGH
QUESTION.

2656
02:00:15,520 --> 02:00:20,120
>>THERE'S SOME EVIDENCE
IN THE

2657
02:00:20,120 --> 02:00:22,000
GUT, MORE IN THE GUT THAN

2658
02:00:22,000 --> 02:00:23,160
SOMEWHERE ELSE.

2659
02:00:23,160 --> 02:00:24,400
>>IN WHICH TISSUE?

2660
02:00:24,400 --> 02:00:24,840
>>IN THE GUT.

2661
02:00:24,840 --> 02:00:32,320
>>OH, IN THE GUT. 

2662
02:00:32,320 --> 02:00:37,840
DR. NO CHEMOKINE RECEPTORS

2663
02:00:37,840 --> 02:00:44,960
ASSOCIATED WITH LAMINA, BUT YOU

2664
02:00:44,960 --> 02:00:46,080
CAN GUIDE RESPONSE, WHETHER THEY

2665
02:00:46,080 --> 02:00:48,480
KNOW THEY ARE SUPPOSED TO GO TO

2666
02:00:48,480 --> 02:00:51,000
GUT OR SKIN, THAT'S ASPIRATIONAL

2667
02:00:51,000 --> 02:00:52,640
AND I HAVEN'T SEEN EVIDENCE FOR

2668
02:00:52,640 --> 02:00:54,640
THAT, YOU KNOW, IN THE ABSENCE

2669
02:00:54,640 --> 02:00:57,160
OF CHEMOKINE SIGNAL OR ABSENCE

2670
02:00:57,160 --> 02:01:00,440
OF LOCAL INFLAMMATION OR CERTAIN

2671
02:01:00,440 --> 02:01:10,720
TCRs PRONE TO CERTAIN TISSUES.

2672
02:01:10,720 --> 02:01:11,800
>>THANK YOU.

2673
02:01:11,800 --> 02:01:13,240
>>DR. AUGUSTINE?

2674
02:01:13,240 --> 02:01:16,640
>>DO WE HAVE TIME?

2675
02:01:16,640 --> 02:01:17,840
THANK YOU FOR THAT PRESENTATION.

2676
02:01:17,840 --> 02:01:26,040
I THOUGHT I HEARD YOU SAY THAT

2677
02:01:26,040 --> 02:01:30,400
YOU DON'T THINK VACCINATION IS

2678
02:01:30,400 --> 02:01:32,600
GOING TO INDUCE -- RIGHT NOW WE

2679
02:01:32,600 --> 02:01:36,560
CAN'T USE VACCINE TO TRIGGER

2680
02:01:36,560 --> 02:01:37,800
TISSUE SPECIFIC T-CELL RESPONSES

2681
02:01:37,800 --> 02:01:39,840
BUT WITH YOUR SARS-COV-2 STUDIES

2682
02:01:39,840 --> 02:01:40,960
THOSE PEOPLE WERE INFECT AND

2683
02:01:40,960 --> 02:01:43,400
THEN YOU WERE ABLE TO GET T

2684
02:01:43,400 --> 02:01:44,800
CELLS FROM THE NOSE BUT THEY

2685
02:01:44,800 --> 02:01:47,080
WERE ALSO VACCINATED.

2686
02:01:47,080 --> 02:01:49,720
DO YOU REALLY THINK THAT THE

2687
02:01:49,720 --> 02:01:55,080
VIRUS INFECTION WAS TRIGGERING

2688
02:01:55,080 --> 02:01:58,600
THAT MIGRATION TO THE NOSE OR

2689
02:01:58,600 --> 02:02:00,960
VACCINES HAD A ROLE TO PLAY AND

2690
02:02:00,960 --> 02:02:02,960
I DIDN'T CATCH HOW LONG T CELLS

2691
02:02:02,960 --> 02:02:07,000
RESPONSES REMAINED IN THE NOSE.

2692
02:02:07,000 --> 02:02:09,560
>>UNFORTUNATELY WE ONLY
ABLE TO

2693
02:02:09,560 --> 02:02:11,160
STUDY NASAL RESPONSES AT ONE

2694
02:02:11,160 --> 02:02:11,760
TIME POINT.

2695
02:02:11,760 --> 02:02:14,440
WE STUDIED THREE OR FOUR WEEKS

2696
02:02:14,440 --> 02:02:15,880
AFTER THE BOOST, THE CANONICAL

2697
02:02:15,880 --> 02:02:16,560
THIRD DOSE.

2698
02:02:16,560 --> 02:02:21,560
I CAN'T TELL YOU BECAUSE WE

2699
02:02:21,560 --> 02:02:23,240
DON'T HAVE A PARALLEL STUDY BUT

2700
02:02:23,240 --> 02:02:25,080
THERE ARE STUDIES IN SINGAPORE,

2701
02:02:25,080 --> 02:02:32,760
I THINK VACCINE-ONLY, IF I

2702
02:02:32,760 --> 02:02:34,640
RECALL CORRECTLY, THEY COULD

2703
02:02:34,640 --> 02:02:38,320
RECOVER USING ELISPOT OR ICS

2704
02:02:38,320 --> 02:02:39,760
COULD RECOVER T CELLS FROM THE

2705
02:02:39,760 --> 02:02:40,240
NOSE.

2706
02:02:40,240 --> 02:02:42,520
THEY DIDN'T HAVE A QUANTITATIVE

2707
02:02:42,520 --> 02:02:44,760
TCR Seq.

2708
02:02:44,760 --> 02:02:47,760
THE LYLE McKINNON GROUP FROM

2709
02:02:47,760 --> 02:02:48,520
CANADA DID FUNCTIONAL STUDIES

2710
02:02:48,520 --> 02:02:50,000
THAT MIGHT HAVE BEEN ON

2711
02:02:50,000 --> 02:02:51,160
INFECTION ONLY BUT I THINK

2712
02:02:51,160 --> 02:02:53,320
YOU'RE ASKING A BIGGER QUESTION,

2713
02:02:53,320 --> 02:02:54,760
FASCINATING, ONCE T CELLS ARE

2714
02:02:54,760 --> 02:02:57,600
PRIMED BY TISSUE SPECIFIC

2715
02:02:57,600 --> 02:02:59,360
INFECTION LET'S SAY RESPIRATORY

2716
02:02:59,360 --> 02:03:00,360
TRACT ARE LEFTOVER MEMORY CELLS

2717
02:03:00,360 --> 02:03:02,440
IN THE BLOOD OR CENTRAL MEMORY

2718
02:03:02,440 --> 02:03:03,720
CELLS SOMEHOW ADDRESSED TO GO

2719
02:03:03,720 --> 02:03:06,360
BACK TO THAT TISSUE OF

2720
02:03:06,360 --> 02:03:06,800
EDUCATION?

2721
02:03:06,800 --> 02:03:17,280
AND WE KNOW THAT'S TRUE WITH

2722
02:03:19,960 --> 02:03:22,360
GENITAL HERPES.

2723
02:03:22,360 --> 02:03:23,400
A SUGAR MODIFICATION IS ON SOME

2724
02:03:23,400 --> 02:03:24,400
T CELLS.

2725
02:03:24,400 --> 02:03:28,600
IF YOU SAMPLE MY BLOOD, 50 TO

2726
02:03:28,600 --> 02:03:31,560
70% OF THOSE TETRAMER POSITIVE

2727
02:03:31,560 --> 02:03:34,080
CELLS HAVE CLA ON THEM READY TO

2728
02:03:34,080 --> 02:03:35,840
GO BACK TO SKIN.

2729
02:03:35,840 --> 02:03:37,800
THE IDEA A TISSUE-SPECIFIC

2730
02:03:37,800 --> 02:03:40,640
INFECTION CAN FIRST PRIME CELLS

2731
02:03:40,640 --> 02:03:42,360
FOR HOMING, COULD THEN BE TAKEN

2732
02:03:42,360 --> 02:03:43,120
ADVANTAGE OF WITH VACCINE,

2733
02:03:43,120 --> 02:03:45,320
THERE'S SOME SORT OF STABLE

2734
02:03:45,320 --> 02:03:48,960
IMPRINTING THAT'S GOING ON AFTER

2735
02:03:48,960 --> 02:03:50,760
A GEOGRAPHICAL OR ANATOMIC

2736
02:03:50,760 --> 02:03:57,760
LIMITED INFECTION IN G.I. TRACT

2737
02:03:57,760 --> 02:04:00,960
OR RESPIRATORY TRACT, TRUE FOR

2738
02:04:00,960 --> 02:04:03,240
SKIN IN HERPES, ALSO MELANOMA.

2739
02:04:03,240 --> 02:04:10,080
>>THANK YOU VERY MUCH.

2740
02:04:10,080 --> 02:04:11,280
>>THAT WAS GREAT.

2741
02:04:11,280 --> 02:04:13,960
I WANT TO THANK DR. KOELLE FOR A

2742
02:04:13,960 --> 02:04:17,680
GREAT TALK AND THE OTHER

2743
02:04:17,680 --> 02:04:23,960
SPEAKERS, DOCTORS CROWE AND

2744
02:04:23,960 --> 02:04:25,480
SETTE FOR A WONDERFUL AFTERNOON

2745
02:04:25,480 --> 02:04:29,200
SESSION AND I'LL TURN IT OVER TO

2746
02:04:29,200 --> 02:04:29,640
DAN.

2747
02:04:29,640 --> 02:04:34,160
DAN, ARE YOU --

2748
02:04:34,160 --> 02:04:34,680
>>YES, I'M HERE.

2749
02:04:34,680 --> 02:04:36,120
>>THANK YOU.

2750
02:04:36,120 --> 02:04:39,440
MY THANKS ALSO TO ALL THREE

2751
02:04:39,440 --> 02:04:40,280
SPEAKERS FOR COVERING REALLY

2752
02:04:40,280 --> 02:04:44,480
INTERESTING DATA AND ALSO SOME

2753
02:04:44,480 --> 02:04:47,600
VERY PROVOCATIVE FORWARD-LOOKING

2754
02:04:47,600 --> 02:04:49,920
THOUGHTS. 

2755
02:04:49,920 --> 02:05:00,360
WE HAVE FOUR CONCEPTS FOR

2756
02:05:01,000 --> 02:05:03,600
CLEARANCE DISCUSSION BY COUNCIL.

2757
02:05:03,600 --> 02:05:06,600
WE'RE OVER ON TIME, WE'LL GO

2758
02:05:06,600 --> 02:05:11,840
OVER 3:30 ADJOURNMENT IF WE NEED

2759
02:05:11,840 --> 02:05:12,280
TO.

2760
02:05:12,280 --> 02:05:14,440
I HOPE STAFF CAN BE BRIEF AND WE

2761
02:05:14,440 --> 02:05:18,960
WON'T PUSH PEOPLE BEYOND THAT

2762
02:05:18,960 --> 02:05:19,280
TIME.

2763
02:05:19,280 --> 02:05:21,720
FIRST OF THESE IS CALLED

2764
02:05:21,720 --> 02:05:29,000
INNOVATIONS IN FUNCTIONAL B CELL

2765
02:05:29,000 --> 02:05:29,760
EPITOPE DISCOVERY.

2766
02:05:29,760 --> 02:05:32,320
AS WE'VE DONE IN THE PAST, I'M

2767
02:05:32,320 --> 02:05:35,000
GOING TO ASK FOR AN EN BLOC

2768
02:05:35,000 --> 02:05:36,800
RECOMMENDATION AFTER ALL OF

2769
02:05:36,800 --> 02:05:40,400
THESE ARE DISCUSSED, UNLESS THAT

2770
02:05:40,400 --> 02:05:42,920
CONVERSATION FOR ANY ONE OF THEM

2771
02:05:42,920 --> 02:05:44,120
SUGGESTS THERE MIGHT BE TOO MANY

2772
02:05:44,120 --> 02:05:49,760
CONCERNS TO GO WITH THAT.

2773
02:05:49,760 --> 02:05:52,000
JOE, PLEASE TAKE IT OVER FROM
HERE

2774
02:05:52,000 --> 02:05:54,200
SO, I'M JOE BREEN.

2775
02:05:54,200 --> 02:05:58,160
I'M GOING TO TALK ABOUT THE

2776
02:05:58,160 --> 02:06:00,640
RENEWAL OF WHAT'S CURRENTLY

2777
02:06:00,640 --> 02:06:02,960
CALLED B CELL EPITOPE DISCOVERY

2778
02:06:02,960 --> 02:06:04,040
MECHANISMS OF ANTIBODY

2779
02:06:04,040 --> 02:06:06,560
PROTECTION PROGRAM, AND I CAN

2780
02:06:06,560 --> 02:06:13,800
KEEP THIS BRIEF BECAUSE YOU

2781
02:06:13,800 --> 02:06:14,920
HEARD A VERY INTERESTING

2782
02:06:14,920 --> 02:06:17,400
INTRODUCTION BY DR. CROWE

2783
02:06:17,400 --> 02:06:17,640
EARLIER.

2784
02:06:17,640 --> 02:06:20,040
WANT TO MAKE SURE ALL ASPECTS

2785
02:06:20,040 --> 02:06:22,480
ARE CLEAR AS WE REQUEST RENEWAL

2786
02:06:22,480 --> 02:06:23,320
OF THIS FY 24 INITIATIVE.

2787
02:06:23,320 --> 02:06:25,120
CAN YOU GO TO THE NEXT SLIDE

2788
02:06:25,120 --> 02:06:27,720
PLEASE.

2789
02:06:27,720 --> 02:06:32,080
SO, THE PURPOSE OF THIS PROGRAM

2790
02:06:32,080 --> 02:06:34,640
IS TO IDENTIFY AND VALIDATE

2791
02:06:34,640 --> 02:06:37,560
HUMAN B CELL EPITOPES THAT

2792
02:06:37,560 --> 02:06:38,040
INDUCE PROTECTIVE OR

2793
02:06:38,040 --> 02:06:40,440
PATHOGENNICS RESPONSES IN SOME

2794
02:06:40,440 --> 02:06:42,920
CASES THROUGH INFECTIOUS

2795
02:06:42,920 --> 02:06:44,880
DISEASES BUT ALSO AUTOIMMUNITY,

2796
02:06:44,880 --> 02:06:47,080
ALLERGY MODELS, TRANSPLANT

2797
02:06:47,080 --> 02:06:48,640
REJECTION AS WELL.

2798
02:06:48,640 --> 02:06:51,280
THE PROGRAM HAS REALLY

2799
02:06:51,280 --> 02:06:52,560
EMPHASIZED IDENTIFYING

2800
02:06:52,560 --> 02:06:53,920
MECHANISMS OF ANTIBODY MEDIATED

2801
02:06:53,920 --> 02:06:57,120
PROTECTION AS WELL AS DISCOVERY

2802
02:06:57,120 --> 02:06:59,200
OF EPITOPES, AND THAT FOCUS ON

2803
02:06:59,200 --> 02:07:01,680
FUNCTION HAS REALLY INCREASED AS

2804
02:07:01,680 --> 02:07:04,000
THIS RATHER LONGSTANDING PROGRAM

2805
02:07:04,000 --> 02:07:04,440
HAS MATURED.

2806
02:07:04,440 --> 02:07:08,600
AND AS YOU HEARD FROM DR. CROWE

2807
02:07:08,600 --> 02:07:11,560
AND OTHER EXAMPLES AS WELL

2808
02:07:11,560 --> 02:07:13,880
PROGRAM'S BEEN VERY HELPFUL FOR

2809
02:07:13,880 --> 02:07:14,840
MONOCLONAL ANTIBODY DISCOVERY

2810
02:07:14,840 --> 02:07:18,080
AND DESIGN, AND WE HOPE WILL

2811
02:07:18,080 --> 02:07:20,000
CONTINUE TO INFORM VACCINE

2812
02:07:20,000 --> 02:07:23,240
DESIGN OVERALL AS WELL.

2813
02:07:23,240 --> 02:07:25,200
NEXT SLIDE PLEASE.

2814
02:07:25,200 --> 02:07:28,840
THE CURRENT AWARDEES, THESE ARE

2815
02:07:28,840 --> 02:07:30,360
CONTRACTORS, ARE DR. CROWE WHOSE

2816
02:07:30,360 --> 02:07:33,240
WORK YOU HEARD, WAS ORIGINALLY

2817
02:07:33,240 --> 02:07:34,760
SUPPORTED FOR INFLUENZA WORK BUT

2818
02:07:34,760 --> 02:07:41,440
AS TIM MENTIONED WE EXPANDED

2819
02:07:41,440 --> 02:07:44,920
WITH SARS-COV-2.

2820
02:07:44,920 --> 02:07:55,360
ALSO, THERE'S BEN  DORANZ.

2821
02:07:57,080 --> 02:07:58,760
THE FIRST THREE, DAVID FREMONT

2822
02:07:58,760 --> 02:07:59,960
AT WASHINGTON UNIVERSITY IS ALSO

2823
02:07:59,960 --> 02:08:02,160
IN THIS PROGRAM.

2824
02:08:02,160 --> 02:08:04,200
THOSE THREE ACTUALLY COLLABORATE

2825
02:08:04,200 --> 02:08:08,240
CLOSELY TO UTILIZE STRENGTHS AND

2826
02:08:08,240 --> 02:08:09,800
STRUCTURAL AREAS, BIOLOGY, SOME

2827
02:08:09,800 --> 02:08:10,800
HIGH-THROUGHPUT ANALYSIS THAT

2828
02:08:10,800 --> 02:08:15,040
DR. CROWE TALKED ABOUT.

2829
02:08:15,040 --> 02:08:19,960
THE FOURTH AWARDEE IS OUR

2830
02:08:19,960 --> 02:08:24,120
BACTERIAL PROJECT, DR. NICK

2831
02:08:24,120 --> 02:08:34,280
MANTIS TRYING TO IDENTIFY

2832
02:08:34,280 --> 02:08:34,880
BORELLIA BURGDOFERI, LYME

2833
02:08:34,880 --> 02:08:39,440
DISEASE, DIAGNOSE  DIAGNOSTICS A

2834
02:08:39,440 --> 02:08:40,800
CHALLENGE, NO HUMAN DISEASE

2835
02:08:40,800 --> 02:08:42,600
CURRENTLY AVAILABLE.

2836
02:08:42,600 --> 02:08:46,240
NEXT SLIDE PLEASE.

2837
02:08:46,240 --> 02:08:48,240
SO THE PROGRAM'S BEEN VERY

2838
02:08:48,240 --> 02:08:48,840
PRODUCTIVE.

2839
02:08:48,840 --> 02:08:50,840
TIM MENTIONED THIS IN BOTH THE

2840
02:08:50,840 --> 02:08:51,840
T- AND B-CELL PROGRAM.

2841
02:08:51,840 --> 02:08:53,680
B CELL PROGRAM WE'VE HAD JUST IN

2842
02:08:53,680 --> 02:08:58,160
THE LAST 3 1/2 YEARS ABOUT 70

2843
02:08:58,160 --> 02:09:02,440
PUBLICATIONS, YOU HEARD ABOUT

2844
02:09:02,440 --> 02:09:11,840
EVUSHELD, NO LONGER AVAILABLE

2845
02:09:11,840 --> 02:09:12,600
UNDER EUA.

2846
02:09:12,600 --> 02:09:17,560
IN TICK BIOLOGY TRYING TO

2847
02:09:17,560 --> 02:09:27,160
DEVELOP AND UNDERSTAND BORELLIA

2848
02:09:27,160 --> 02:09:31,120
BURGDOFERI IMMUNITY.

2849
02:09:31,120 --> 02:09:32,360
STILL WORKING ON INFLUENZA

2850
02:09:32,360 --> 02:09:34,320
PROJECTS AND OTHER PREVIOUS

2851
02:09:34,320 --> 02:09:34,520
SLIDES.

2852
02:09:34,520 --> 02:09:36,080
NEXT SLIDE PLEASE.

2853
02:09:36,080 --> 02:09:39,360
THIS IS A PROPOSED FY 24

2854
02:09:39,360 --> 02:09:40,880
INITIATIVE, CONCEPT FOR COUNCIL

2855
02:09:40,880 --> 02:09:46,800
APPROVAL, THE SCOPE WIFF  -- OF

2856
02:09:46,800 --> 02:09:50,480
WHICH WAS A SMALL ENHANCEMENT.

2857
02:09:50,480 --> 02:09:52,840
WE REFER TO DISCOVERY AND

2858
02:09:52,840 --> 02:09:54,800
VALIDATION IN HUMANS, STILL WANT

2859
02:09:54,800 --> 02:09:56,280
THE MECHANISMS OF ANTIBODY

2860
02:09:56,280 --> 02:09:59,680
FUNCTION BECAUSE IT'S SO

2861
02:09:59,680 --> 02:10:01,240
IMPORTANT, AND CONTINUE TO

2862
02:10:01,240 --> 02:10:03,960
PUBLICLY SHARE THE EPITOPE DATA

2863
02:10:03,960 --> 02:10:05,720
ANTIBODY AND STRUCTURAL DATA

2864
02:10:05,720 --> 02:10:09,120
SUBMISSION THROUGH THE IEDB AND

2865
02:10:09,120 --> 02:10:11,400
OTHER PUBLICLY RELEVANT

2866
02:10:11,400 --> 02:10:11,960
DATABASES.

2867
02:10:11,960 --> 02:10:13,760
AND PROPOSE THE CONTRACTORS CAN

2868
02:10:13,760 --> 02:10:16,760
ALSO DEVELOP PREDICTION TOOLS

2869
02:10:16,760 --> 02:10:17,840
ALTHOUGH MANY ARE ALREADY

2870
02:10:17,840 --> 02:10:19,720
AVAILABLE ON THE IDB SO IT'S NOT

2871
02:10:19,720 --> 02:10:23,200
A REQUIREMENT, IT'S AN OPTION.

2872
02:10:23,200 --> 02:10:26,800
IN THIS FY 24 WE'VE ADDED

2873
02:10:26,800 --> 02:10:30,840
POTENTIAL AND HIGHLIGHTED

2874
02:10:30,840 --> 02:10:32,840
PATHOGENS OF PANDEMIC POTENTIAL

2875
02:10:32,840 --> 02:10:34,800
PUBLISHED BY NIAID RECENTLY, IN

2876
02:10:34,800 --> 02:10:36,240
EIGHT FAMILIES ALEX MENTIONED

2877
02:10:36,240 --> 02:10:38,280
EARLIER, THAT COULD BE

2878
02:10:38,280 --> 02:10:39,920
CONSIDERED AS WELL AS THE

2879
02:10:39,920 --> 02:10:42,120
PATHOGENS IN THE OTHER AREAS

2880
02:10:42,120 --> 02:10:43,720
THAT ARE IN NIAID'S INTEREST

2881
02:10:43,720 --> 02:10:45,640
THAT WERE ON PREVIOUS SLIDES.

2882
02:10:45,640 --> 02:10:47,480
WE DON'T SUPPORT CLINICAL TRIALS

2883
02:10:47,480 --> 02:10:48,920
FOR THIS.

2884
02:10:48,920 --> 02:10:50,880
WE OF COURSE UTILIZE CURRENTLY

2885
02:10:50,880 --> 02:10:53,960
AVAILABLE CLINICAL TRIALS OR

2886
02:10:53,960 --> 02:10:55,560
HUMAN SAMPLES ALREADY AVAILABLE

2887
02:10:55,560 --> 02:10:57,000
ARE PREFERABLE.

2888
02:10:57,000 --> 02:10:58,880
IN PARTICULAR, WE'D LIKE TO

2889
02:10:58,880 --> 02:11:01,280
EXPAND THE USE OF TECHNOLOGIES

2890
02:11:01,280 --> 02:11:01,840
INCLUDING HIGH-THROUGHPUT

2891
02:11:01,840 --> 02:11:05,760
APPROACHES TO MAKE IT MORE

2892
02:11:05,760 --> 02:11:07,720
SCALABLE EPITOPE DISCOVERY AND

2893
02:11:07,720 --> 02:11:09,280
CHARACTERIZATION AND LOWER COST

2894
02:11:09,280 --> 02:11:10,800
AND EFFICIENT, VERY MUCH ALONG

2895
02:11:10,800 --> 02:11:13,760
THE LINES OF WHAT DR. CROWE

2896
02:11:13,760 --> 02:11:15,400
DESCRIBED, BUT THERE ARE OTHER

2897
02:11:15,400 --> 02:11:16,720
APPROACHES AS WELL.

2898
02:11:16,720 --> 02:11:21,080
HE DESCRIBED HIS BUT THERE ARE

2899
02:11:21,080 --> 02:11:22,400
OTHERS IN PLACE, CURRENT

2900
02:11:22,400 --> 02:11:24,160
CONTRACT POOL, WE WOULD ASSUME

2901
02:11:24,160 --> 02:11:28,000
THAT OTHERS WOULD APPLY AS WELL.

2902
02:11:28,000 --> 02:11:34,880
THE MECHANISM IS BROAD AGENCY

2903
02:11:34,880 --> 02:11:35,840
ANNOUNCEMENT FOR FIVE-YEAR TERM,

2904
02:11:35,840 --> 02:11:36,920
WORKED WELL, PRODUCTIVE AND

2905
02:11:36,920 --> 02:11:39,280
FLEXIBLE FOR US OVER THE PAST --

2906
02:11:39,280 --> 02:11:40,360
SINCE THE EVOLUTION OF THIS

2907
02:11:40,360 --> 02:11:42,760
PROGRAM AND WE PREFER TO KEEP

2908
02:11:42,760 --> 02:11:43,560
THAT THIS WAY.

2909
02:11:43,560 --> 02:11:45,280
I'LL STOP AND BE HAPPY TO TAKE

2910
02:11:45,280 --> 02:11:45,800
QUESTIONS.

2911
02:11:45,800 --> 02:11:46,560
THANK YOU.

2912
02:11:46,560 --> 02:11:49,640
AGAIN, SORRY FOR THE AV

2913
02:11:49,640 --> 02:11:49,960
PROBLEMS.

2914
02:11:49,960 --> 02:11:53,680
OVER.

2915
02:11:53,680 --> 02:11:59,680
 

2916
02:11:59,680 --> 02:12:05,400
 

2917
02:12:05,400 --> 02:12:07,880
>>IF THERE ARE NO
QUESTIONS

2918
02:12:07,880 --> 02:12:10,440
WE'LL MOVE TO TIM, YOU HAVE THE

2919
02:12:10,440 --> 02:12:13,280
NEXT CONCEPT CLEARANCE.

2920
02:12:13,280 --> 02:12:15,680
 

2921
02:12:15,680 --> 02:12:16,520
>>EXCELLENT.

2922
02:12:16,520 --> 02:12:18,080
THANK YOU VERY MUCH, DAN.

2923
02:12:18,080 --> 02:12:19,920
SO, THE CONCEPT I'M GOING TO

2924
02:12:19,920 --> 02:12:24,080
PRESENT IS T CELL IMMUNE EPITOPE

2925
02:12:24,080 --> 02:12:26,080
DISCOVERY AND MECHANISMS OF T

2926
02:12:26,080 --> 02:12:27,160
CELL PROTECTION PROGRAM.

2927
02:12:27,160 --> 02:12:30,360
THIS IS A RENEWAL OF THE

2928
02:12:30,360 --> 02:12:33,000
EXISTING PROGRAM, BUT EXPANDS IT

2929
02:12:33,000 --> 02:12:35,600
AND I'LL EXPLAIN HOW THAT WORKS

2930
02:12:35,600 --> 02:12:38,840
AS WE GO ON.

2931
02:12:38,840 --> 02:12:40,000
BUT PRIMARY OBJECTIVES OF THE T

2932
02:12:40,000 --> 02:12:43,640
CELL PROGRAM ARE TO IDENTIFY AND

2933
02:12:43,640 --> 02:12:45,120
VALIDATE HUMAN IMMUNE EPITOPES.

2934
02:12:45,120 --> 02:12:47,320
THIS IS, YOU KNOW, OF COURSE

2935
02:12:47,320 --> 02:12:50,720
INCREDIBLY IMPORTANT IN THE

2936
02:12:50,720 --> 02:12:54,920
PROTECTION FROM INFECTIOUS

2937
02:12:54,920 --> 02:12:56,960
DISEASE, AUTOIMMUNE DISEASE,

2938
02:12:56,960 --> 02:12:59,040
UNDERSTANDING VACCINE RESPONSE

2939
02:12:59,040 --> 02:13:02,760
AND UNDERSTANDING REJECTION OF

2940
02:13:02,760 --> 02:13:04,080
TRANSPLANTED CELLS AND TISSUES.

2941
02:13:04,080 --> 02:13:06,160
WE HELP TO BE ABLE TO CONTRIBUTE

2942
02:13:06,160 --> 02:13:10,400
TO A BETTER UNDERSTANDING OF

2943
02:13:10,400 --> 02:13:12,640
IMMUNE MEDIATED PATHOGENESIS,

2944
02:13:12,640 --> 02:13:15,040
TRIGGERED BY INFECTION,

2945
02:13:15,040 --> 02:13:16,000
AUTOIMMUNE PROCESS, MICROBIOME

2946
02:13:16,000 --> 02:13:18,560
OR TRANSPLANTATION.

2947
02:13:18,560 --> 02:13:23,000
WE FOUND THAT WE'VE BEEN ABLE TO

2948
02:13:23,000 --> 02:13:24,760
REALLY UNDERSTAND VIRAL

2949
02:13:24,760 --> 02:13:25,720
EVOLUTION AND STABILITY OF

2950
02:13:25,720 --> 02:13:28,280
T-CELL RESPONSES WITH THIS

2951
02:13:28,280 --> 02:13:33,040
PROGRAM, EVEN WITH RAPID VIRAL

2952
02:13:33,040 --> 02:13:34,360
EVOLUTION, AND GET A GOOD SCOPE

2953
02:13:34,360 --> 02:13:37,360
OF THE BREADTH OF HUMAN T-CELL

2954
02:13:37,360 --> 02:13:41,400
RESPONSES TO A VACCINE OR

2955
02:13:41,400 --> 02:13:41,640
PATHOGEN.

2956
02:13:41,640 --> 02:13:44,320
WE'VE BEEN ABLE TO LOOK AT

2957
02:13:44,320 --> 02:13:46,440
FAMILIES OF RELATED PATHOGENS

2958
02:13:46,440 --> 02:13:51,560
AND SEE HOW THERE MIGHT BE

2959
02:13:51,560 --> 02:13:52,680
CROSS-REACTIVITY BETWEEN VARIOUS

2960
02:13:52,680 --> 02:13:53,960
EPITOPES FROM THESE PATHOGENS

2961
02:13:53,960 --> 02:13:56,800
WITH THE IDEA THAT IF YOU SEE

2962
02:13:56,800 --> 02:13:58,640
CROSS-REACTIVITY ACROSS FAMILIES

2963
02:13:58,640 --> 02:14:02,280
OF PATHOGENS, YOU CAN ESTABLISH

2964
02:14:02,280 --> 02:14:08,760
A RATIONAL UNIVERSAL VACCINE FOR

2965
02:14:08,760 --> 02:14:10,280
THAT PATHOGEN.

2966
02:14:10,280 --> 02:14:12,440
WE'VE LOOKED AT THIS IN TARGETS

2967
02:14:12,440 --> 02:14:15,720
OF THERAPEUTIC INTERVENTIONS. 

2968
02:14:15,720 --> 02:14:18,800
THIS IS A LONGSTANDING PROGRAM

2969
02:14:18,800 --> 02:14:21,440
INITIATED IN 2004 AND IN 2004

2970
02:14:21,440 --> 02:14:25,800
WERE ABLE TO AWARD 11 CONTRACTS,

2971
02:14:25,800 --> 02:14:28,080
ACROSS BOTH T- AND B-CELL

2972
02:14:28,080 --> 02:14:30,720
EPITOPES AND THEY ALSO INCLUDED

2973
02:14:30,720 --> 02:14:36,080
TWO CONTRACTS FOR EPITOPE

2974
02:14:36,080 --> 02:14:37,120
PREDICTION TOOLS.

2975
02:14:37,120 --> 02:14:40,280
IN 2009 THE CELLS SEPARATED TO

2976
02:14:40,280 --> 02:14:42,240
GET MORE CONTRACTS THAT ARE

2977
02:14:42,240 --> 02:14:44,960
INTERESTED IN THE B CELL

2978
02:14:44,960 --> 02:14:46,360
MECHANISMS OF PROTECTION, SO

2979
02:14:46,360 --> 02:14:52,480
THIS ONE REQUIRED ONLY T CELL

2980
02:14:52,480 --> 02:14:54,240
EPITOPE DISCOVERY PLUS EPITOPE

2981
02:14:54,240 --> 02:14:54,840
VALIDATION.

2982
02:14:54,840 --> 02:14:56,840
IN 2014 A REQUIREMENT THIS BE

2983
02:14:56,840 --> 02:15:04,480
VALIDATED IN HUMANS.

2984
02:15:04,480 --> 02:15:05,720
IN 2019 INCREASED SCOPE FOR

2985
02:15:05,720 --> 02:15:11,640
INFECTIOUS DISEASE AND VACCINE

2986
02:15:11,640 --> 02:15:12,240
RESPONSE, AUTOIMMUNE DISEASE,

2987
02:15:12,240 --> 02:15:16,040
INCLUDE 

2988
02:15:16,040 --> 02:15:20,960
INCLUDE IDENTIFICATION OF

2989
02:15:20,960 --> 02:15:23,600
PATHOGEN EPITOPES, AND INCREASE

2990
02:15:23,600 --> 02:15:28,040
SOLICITATION SCOPE. 

2991
02:15:28,040 --> 02:15:33,440
AWARDED SIX CONTRACTS, BOTH

2992
02:15:33,440 --> 02:15:35,840
VIRAL AND BACTERIA, BECAUSE OF

2993
02:15:35,840 --> 02:15:37,800
THE FLEXIBILITY OF THE PROGRAM

2994
02:15:37,800 --> 02:15:45,000
WERE ABLE TO ADD SARS-COV-2 WHEN

2995
02:15:45,000 --> 02:15:49,040
THAT BECAME EMERGING PATHOGENS

2996
02:15:49,040 --> 02:15:50,040
AND FUNGAL PATHOGENS,

2997
02:15:50,040 --> 02:15:52,000
UNDERSTUDIED, AND ABLE TO AWARD

2998
02:15:52,000 --> 02:15:54,800
A CONTRACT TO STUDY AUTOIMMUNE

2999
02:15:54,800 --> 02:15:57,840
DISEASES, AND IN THIS CASE

3000
02:15:57,840 --> 02:15:59,240
RHEUMATOID ARTHRITIS.

3001
02:15:59,240 --> 02:16:05,480
IT'S BEEN A SUCCESSFUL PROGRAM.

3002
02:16:05,480 --> 02:16:06,840
WE'VE IDENTIFIED THOUSANDS OF

3003
02:16:06,840 --> 02:16:12,640
EPITOPES OVER THE YEARS AND JUST

3004
02:16:12,640 --> 02:16:16,920
RECENTLY GREAT SUCCESS WITH

3005
02:16:16,920 --> 02:16:18,520
SARS-COV-2, PERTUSSIS, HSV-1 AND

3006
02:16:18,520 --> 02:16:21,480
2, EVEN WITH OUR AUTOIMMUNE

3007
02:16:21,480 --> 02:16:23,920
PROGRAM WITH ARTHRITIS, ALL

3008
02:16:23,920 --> 02:16:29,280
BEING DEPOSITED INTO THE IEDB

3009
02:16:29,280 --> 02:16:30,680
AND BECOME PUBLICLY ACCESSIBLE,

3010
02:16:30,680 --> 02:16:35,200
ACROSS CD 4 AND CD8 T CELLS

3011
02:16:35,200 --> 02:16:36,600
WE'RE DISCOVERING THEM.

3012
02:16:36,600 --> 02:16:39,000
WE MENTIONED PUBLICATIONS

3013
02:16:39,000 --> 02:16:40,520
EARLIER AND MENTIONED MEGAPOOL

3014
02:16:40,520 --> 02:16:41,880
DISTRIBUTION EARLIER BUT, AGAIN,

3015
02:16:41,880 --> 02:16:45,000
THIS IS SOMETHING THAT WAS

3016
02:16:45,000 --> 02:16:50,040
ENABLED BY THIS BEING IN THE

3017
02:16:50,040 --> 02:16:51,040
CONTRACT MECHANISM.

3018
02:16:51,040 --> 02:16:53,520
AND FINALLY, THE FY 24 PROPOSED

3019
02:16:53,520 --> 02:16:54,960
INITIATIVE, IT MUST ADDRESS ONE

3020
02:16:54,960 --> 02:16:57,520
OF THE THREE RESEARCH AREAS,

3021
02:16:57,520 --> 02:17:00,360
EITHER INFECTIOUS DISEASE OR

3022
02:17:00,360 --> 02:17:04,800
VACCINE RESPONSES, AUTOIMMUNE

3023
02:17:04,800 --> 02:17:06,920
DISEASE OR TRANSPLANTATION

3024
02:17:06,920 --> 02:17:09,440
ANTIGENS, ALOE OR AUTOANTIGENS

3025
02:17:09,440 --> 02:17:12,520
COULD BE INCLUDED. 

3026
02:17:12,520 --> 02:17:14,280
SCOPE EXPANSION FOR FISCAL 24

3027
02:17:14,280 --> 02:17:15,200
REQUIRES FUNCTIONAL

3028
02:17:15,200 --> 02:17:17,200
CHARACTERIZATION OF THE T CELL

3029
02:17:17,200 --> 02:17:19,400
SUBSETS AND MECHANISMS OF T CELL

3030
02:17:19,400 --> 02:17:21,040
PROTECTION AND PATHOGENS.

3031
02:17:21,040 --> 02:17:23,120
THIS IS SOMETHING THAT

3032
02:17:23,120 --> 02:17:24,040
INVESTIGATORS HAD PROPOSED

3033
02:17:24,040 --> 02:17:28,040
BEFORE BUT NOW WILL BE REQUIRED

3034
02:17:28,040 --> 02:17:31,960
COMPONENT OF THIS SOLICITATION.

3035
02:17:31,960 --> 02:17:35,600
AS OPTIONAL COMPONENTS, WE ARE

3036
02:17:35,600 --> 02:17:38,320
ALLOWING INVESTIGATORS AND

3037
02:17:38,320 --> 02:17:40,560
ENCOURAGING IN SOME WAYS TCR

3038
02:17:40,560 --> 02:17:42,480
REPERTOIRE ANALYSIS TO BE

3039
02:17:42,480 --> 02:17:43,360
INCLUDED, NOVEL EPITOPE

3040
02:17:43,360 --> 02:17:44,240
PREDICTION TOOLS HAVE ALWAYS

3041
02:17:44,240 --> 02:17:48,640
BEEN AN OPTION FOR THIS, IT'S

3042
02:17:48,640 --> 02:17:50,040
STILL INCLUDED, AND WE'RE ALSO

3043
02:17:50,040 --> 02:17:53,520
INCLUDING AS AN OPTION LOOKING

3044
02:17:53,520 --> 02:17:55,320
AT PANDEMIC PROTOTYPE PATHOGENS

3045
02:17:55,320 --> 02:17:56,520
AS WAS MENTIONED BEFORE.

3046
02:17:56,520 --> 02:17:59,000
MUCH LIKE THE B CELL WE'RE NOT

3047
02:17:59,000 --> 02:18:01,080
ALLOWING CLINICAL TRIALS FOR

3048
02:18:01,080 --> 02:18:02,800
THIS.

3049
02:18:02,800 --> 02:18:05,800
BUT WE ENCOURAGE INDIVIDUALS

3050
02:18:05,800 --> 02:18:08,200
TO -- INDIVIDUAL INVESTIGATORS

3051
02:18:08,200 --> 02:18:09,280
TO FORM COLLABORATIONS WITH

3052
02:18:09,280 --> 02:18:12,160
OTHER CLINICAL TRIAL GROUPS SO

3053
02:18:12,160 --> 02:18:13,800
THAT THEY CAN UTILIZE THOSE

3054
02:18:13,800 --> 02:18:14,840
SAMPLES.

3055
02:18:14,840 --> 02:18:21,000
WE'RE GOING TO USE THE CONTRACT

3056
02:18:21,000 --> 02:18:26,560
BROAD AGENCY ANNOUNCEMENT

3057
02:18:26,560 --> 02:18:29,200
MECHANISM, A FIVE YEAR DURATION.

3058
02:18:29,200 --> 02:18:31,320
WITH THAT, I'M HAPPY TO TAKE ANY

3059
02:18:31,320 --> 02:18:35,760
QUESTIONS. 

3060
02:18:35,760 --> 02:18:38,960
>>TIM, THIS IS JIM.

3061
02:18:38,960 --> 02:18:40,680
ONE CLARIFICATION.

3062
02:18:40,680 --> 02:18:42,880
SO THE CORRELATES OF PROTECTION,

3063
02:18:42,880 --> 02:18:45,840
IS THAT LARGELY ACCOMPLISHED

3064
02:18:45,840 --> 02:18:47,760
THEN THROUGH COLLABORATIONS

3065
02:18:47,760 --> 02:18:49,880
SINCE THERE AREN'T CLINICAL

3066
02:18:49,880 --> 02:18:53,080
TRIALS THAT ARE INVOLVED OR DOES

3067
02:18:53,080 --> 02:18:54,280
THIS ALLOW SOME OBSERVATIONAL

3068
02:18:54,280 --> 02:18:59,720
STUDIES TO BE ABLE TO DO THAT?

3069
02:18:59,720 --> 02:19:01,480
>>SO, REALLY IT'S

3070
02:19:01,480 --> 02:19:02,360
UNDERSTANDING -- SO

3071
02:19:02,360 --> 02:19:04,760
UNDERSTANDING WHICH T CELLS ARE

3072
02:19:04,760 --> 02:19:05,880
INVOLVED, YOU CAN GET CLINICAL

3073
02:19:05,880 --> 02:19:07,160
SAMPLES, SO OF COURSE THERE'S

3074
02:19:07,160 --> 02:19:11,840
GOING TO BE LOADS OF CLINICAL

3075
02:19:11,840 --> 02:19:15,400
SAMPLES AVAILABLE, MOST OF THE

3076
02:19:15,400 --> 02:19:16,480
INSTITUTIONS HAVE EITHER

3077
02:19:16,480 --> 02:19:17,240
CLINICAL CENTERS ASSOCIATED WITH

3078
02:19:17,240 --> 02:19:27,360
THEM.

3079
02:20:00,000 --> 02:20:01,160
... (TECHNICAL DIFFICULTIES,

3080
02:20:01,160 --> 02:20:11,440
PLEASE STAND BY)

3081
02:20:25,880 --> 02:20:36,320
>>MACAQUE BREEDING
COLONIES. 

3082
02:20:43,280 --> 02:20:49,200
 

3083
02:20:49,200 --> 02:20:54,240
 

3084
02:20:54,240 --> 02:20:57,000
>>WE CAN SEE YOUR SLIDES
BUT

3085
02:20:57,000 --> 02:20:57,840
CAN'T HEAR YOU.

3086
02:20:57,840 --> 02:20:58,640
>>THAT LOOKS ALL RIGHT?

3087
02:20:58,640 --> 02:20:59,040
>>YES.

3088
02:20:59,040 --> 02:21:04,440
NOW WE CAN HEAR YOU, GREAT.

3089
02:21:04,440 --> 02:21:06,440
>>I WAS GOING TO ASK YOU
TO PUT

3090
02:21:06,440 --> 02:21:08,360
IT IN PRESENTER VIEW.

3091
02:21:08,360 --> 02:21:10,120
SORRY ABOUT THAT.

3092
02:21:10,120 --> 02:21:10,480
>>IT'S NOT?

3093
02:21:10,480 --> 02:21:12,320
>>NOT FROM OUR END.

3094
02:21:12,320 --> 02:21:15,280
IF YOU WANT TO GO FORWARD WITH

3095
02:21:15,280 --> 02:21:17,080
THIS VIEW, YOU CAN.

3096
02:21:17,080 --> 02:21:20,360
IT'S NO NON-PRESENTER VIEW.

3097
02:21:20,360 --> 02:21:21,760
>>I SHOULD CHANGE THE
DISPLAY?

3098
02:21:21,760 --> 02:21:22,840
>>NO.

3099
02:21:22,840 --> 02:21:24,600
ON THE ACTUAL POWERPOINT ITSELF,

3100
02:21:24,600 --> 02:21:25,840
LOWER RIGHT-HAND CORNER THERE'S

3101
02:21:25,840 --> 02:21:27,040
A PRESENTER VIEW BUTTON. 

3102
02:21:27,040 --> 02:21:29,760
THERE YOU GO, YEAH.

3103
02:21:29,760 --> 02:21:36,360
>>I CLICKED BUT IT SHOWS
UP ON

3104
02:21:36,360 --> 02:21:37,120
A DIFFERENT SCREEN.

3105
02:21:37,120 --> 02:21:39,080
>>WE CAN PROCEED WITH
THIS

3106
02:21:39,080 --> 02:21:39,280
VIEW.

3107
02:21:39,280 --> 02:21:40,880
WE'RE PRESSED FOR TIME.

3108
02:21:40,880 --> 02:21:45,920
I JUST WANTED TO CLARIFY.

3109
02:21:45,920 --> 02:21:46,760
>>SORRY ABOUT THAT.

3110
02:21:46,760 --> 02:21:52,120
I'M NOT SURE HOW TO FIX THIS.

3111
02:21:52,120 --> 02:21:54,120
 

3112
02:21:54,120 --> 02:22:02,360
GOOD AFTERNOON, I'LL JULIA SHAW,

3113
02:22:02,360 --> 02:22:03,640
TRANSPLANTATION BRANCH

3114
02:22:03,640 --> 02:22:05,560
PRESENTING NIAID SPF MACAQUE

3115
02:22:05,560 --> 02:22:08,040
BREEDING COLONIES FOR CONCEPT

3116
02:22:08,040 --> 02:22:08,320
CLEARANCE.

3117
02:22:08,320 --> 02:22:16,040
OKAY. 

3118
02:22:16,040 --> 02:22:16,680
>>STAND BY.

3119
02:22:16,680 --> 02:22:27,240
I'LL SHARE THE SLIDES FOR YOU. 

3120
02:22:31,320 --> 02:22:34,800
>>SORRY. 

3121
02:22:34,800 --> 02:22:35,400
OKAY.

3122
02:22:35,400 --> 02:22:43,960
NEXT SLIDE. 

3123
02:22:43,960 --> 02:22:48,000
ALL RIGHT. 

3124
02:22:48,000 --> 02:22:50,000
THE TRANSPLANTATION BRANCH

3125
02:22:50,000 --> 02:22:51,920
SUPPORTS ROBUST AND INTERACTIVE

3126
02:22:51,920 --> 02:22:55,320
NON-HUMAN PRIMATE PROGRAM THAT

3127
02:22:55,320 --> 02:22:58,520
INCLUDES TWO RESEARCH CONSORTIA,

3128
02:22:58,520 --> 02:23:05,640
ONE ON PIGS AND NON-HUMAN

3129
02:23:05,640 --> 02:23:08,600
PRIMATE TRANSPLANTATION, OTHER

3130
02:23:08,600 --> 02:23:10,560
ALLOGENICS, AND SUPPORT ALLELE

3131
02:23:10,560 --> 02:23:16,360
DISCOVERY AND TYPING

3132
02:23:16,360 --> 02:23:21,680
TECHNOLOGIES CONTRACT AND NIAID

3133
02:23:21,680 --> 02:23:23,560
MACAQUE BREEDING COLONY, FOR

3134
02:23:23,560 --> 02:23:25,080
COOPERATIVE STUDY GROUP

3135
02:23:25,080 --> 02:23:26,120
PROJECTS.

3136
02:23:26,120 --> 02:23:28,640
IT WAS ESTABLISHED IN 1999, TO

3137
02:23:28,640 --> 02:23:30,920
EVALUATE SAFETY AND EFFICACY OF

3138
02:23:30,920 --> 02:23:33,560
FDA-APPROVED AGENTS AND NOVEL

3139
02:23:33,560 --> 02:23:34,640
TREATMENTS IN CLINICALLY

3140
02:23:34,640 --> 02:23:35,960
RELEVANT TRANSPLANT MODEL.

3141
02:23:35,960 --> 02:23:39,120
THIS SUPPORTS THE MAJORITY OF

3142
02:23:39,120 --> 02:23:40,000
TRANSPLANT TOLERANCE RESEARCH

3143
02:23:40,000 --> 02:23:41,520
CONDUCTED IN NON-HUMAN PRIMATE

3144
02:23:41,520 --> 02:23:44,600
MODELS AND INCLUDES WORK IN

3145
02:23:44,600 --> 02:23:48,960
KIDNEY, HEART, ISLET, AND LUNG

3146
02:23:48,960 --> 02:23:50,640
TRANSPLANTATION.

3147
02:23:50,640 --> 02:23:51,640
FINDINGS HELPED TRANSITION NINE

3148
02:23:51,640 --> 02:23:53,800
REAGENTS TO CLINICAL TRIALS AND

3149
02:23:53,800 --> 02:23:54,760
TRANSPLANTATION AND RENEWAL

3150
02:23:54,760 --> 02:23:56,840
AWARDS FOR THIS INITIATIVE ARE

3151
02:23:56,840 --> 02:24:02,440
EXPECTED EARLY THIS YEAR.

3152
02:24:02,440 --> 02:24:06,680
HOWEVER, AT INCEPTION IT FACED

3153
02:24:06,680 --> 02:24:07,280
CONSIDER CHALLENGES OBTAINING

3154
02:24:07,280 --> 02:24:11,520
NON-HUMAN PRIMATE DUE TO LOW

3155
02:24:11,520 --> 02:24:13,240
AVAILABILITY AND HIGH COST,

3156
02:24:13,240 --> 02:24:16,480
DRIVEN BY HIGH DEMAND FOR

3157
02:24:16,480 --> 02:24:22,840
MACAQUES FOR HIV/AIDS RESEARCH.

3158
02:24:22,840 --> 02:24:24,280
NEXT SLIDE.

3159
02:24:24,280 --> 02:24:30,840
STARTING IN 2000 NIAID

3160
02:24:30,840 --> 02:24:34,360
ESTABLISHED BREEDING COLONIES

3161
02:24:34,360 --> 02:24:40,160
FOR PATHOGENS RHESUS MACAQUES

3162
02:24:40,160 --> 02:24:41,240
AND CYNMOLGUS MACAQUES, SEVERAL

3163
02:24:41,240 --> 02:24:43,360
YEARS LATER THE AWARD WAS

3164
02:24:43,360 --> 02:24:44,880
CONVERTED TO CONTRACT MECHANISM

3165
02:24:44,880 --> 02:24:46,960
TO ALLOW FOR ENHANCED NIAID

3166
02:24:46,960 --> 02:24:48,600
OVERSIGHT AND DIRECTION.

3167
02:24:48,600 --> 02:24:50,560
MORE RECENTLY SUPPORT FOR

3168
02:24:50,560 --> 02:24:52,400
COLONIES ONGOING CARE AND

3169
02:24:52,400 --> 02:24:54,920
BREEDING HAS BEEN SUPPORTED

3170
02:24:54,920 --> 02:24:56,360
THROUGH SEVEN-YEAR COMPETITIVE

3171
02:24:56,360 --> 02:24:57,640
CONTRACTS SOLICITATION WITH

3172
02:24:57,640 --> 02:25:01,280
AWARDS ISSUED IN 2010 AND AGAIN

3173
02:25:01,280 --> 02:25:04,880
IN 2017.

3174
02:25:04,880 --> 02:25:07,520
NEXT SLIDE.

3175
02:25:07,520 --> 02:25:09,840
THE OVERARCHING GOAL REMAINS THE

3176
02:25:09,840 --> 02:25:17,480
PROVISION OF HIGH QUALITY

3177
02:25:17,480 --> 02:25:19,240
PEDIGREED MACAQUES.

3178
02:25:19,240 --> 02:25:20,560
REQUIREMENT FOR SPF ANIMALS

3179
02:25:20,560 --> 02:25:29,520
REDUCES RISK OF OPPORTUNISTIC

3180
02:25:29,520 --> 02:25:33,480
INFECTION TO PREVENT ALLOGRAFT

3181
02:25:33,480 --> 02:25:33,880
REJECTION.

3182
02:25:33,880 --> 02:25:39,280
PEDIGREE ENABLES KNOWLEDGE OF

3183
02:25:39,280 --> 02:25:41,240
DEGREE OF DONOR-RECIPIENT

3184
02:25:41,240 --> 02:25:44,640
RELATEDNESS, PROMOTING RIGOROUS

3185
02:25:44,640 --> 02:25:47,800
DESIGN AND DATA INTERPRETATION,

3186
02:25:47,800 --> 02:25:49,120
BETTER APPROXIMATES CLINICAL

3187
02:25:49,120 --> 02:25:55,160
PRACTICE AND COLONY MANAGEMENT

3188
02:25:55,160 --> 02:25:57,240
PERSPECTIVE INFORMS BREEDING

3189
02:25:57,240 --> 02:25:58,200
STRATEGIES.

3190
02:25:58,200 --> 02:26:01,640
THE GOAL IS TO ENHANCE RIGOR AND

3191
02:26:01,640 --> 02:26:03,800
REPRODUCIBILITY FOR TRANSPLANT

3192
02:26:03,800 --> 02:26:04,480
EXPERIMENTS WHILE REDUCING

3193
02:26:04,480 --> 02:26:06,560
NON-HUMAN PRIMATE LOSS THROUGH

3194
02:26:06,560 --> 02:26:09,080
OPPORTUNISTIC INFECTIONS AND USE

3195
02:26:09,080 --> 02:26:13,120
RELATED TO SUBOPTIMAL STUDY

3196
02:26:13,120 --> 02:26:13,520
DESIGN.

3197
02:26:13,520 --> 02:26:15,240
NEXT SLIDE.

3198
02:26:15,240 --> 02:26:24,520
IN ADDITION TO ACHIEVING AND

3199
02:26:24,520 --> 02:26:26,760
MAINTAINING SPF STATUS,

3200
02:26:26,760 --> 02:26:29,040
CONSISTENTLY STRONG WITH CASE

3201
02:26:29,040 --> 02:26:31,080
RESOLUTION OVER 90%.

3202
02:26:31,080 --> 02:26:33,080
SHIPMENTS FALL SHARPLY IN 2019

3203
02:26:33,080 --> 02:26:38,440
CONTRACT YEAR DUE TO COVID-19

3204
02:26:38,440 --> 02:26:41,520
RELATED RESEARCH RESTRICTIONS

3205
02:26:41,520 --> 02:26:43,280
SHIPMENTS HAVE RECOVERED,

3206
02:26:43,280 --> 02:26:45,280
MATURED AND ABLE TO MEET

3207
02:26:45,280 --> 02:26:48,400
RESEARCH NEEDS.

3208
02:26:48,400 --> 02:26:49,280
NEXT SLIDE.

3209
02:26:49,280 --> 02:26:51,960
YOU MAY APPRECIATE CHANGES IN

3210
02:26:51,960 --> 02:26:54,160
NON-HUMAN PRIMATE DEMAND CAN

3211
02:26:54,160 --> 02:26:54,760
OCCUR UNPREDICTABLY, THE

3212
02:26:54,760 --> 02:26:55,760
SITUATION TODAY IS NOT SO

3213
02:26:55,760 --> 02:26:58,760
DIFFERENT FROM WHAT IT WAS WHEN

3214
02:26:58,760 --> 02:27:00,520
COLONIES WERE FIRST ESTABLISHED.

3215
02:27:00,520 --> 02:27:08,280
IN THIS CASE HIGH DEMAND IS

3216
02:27:08,280 --> 02:27:10,840
BEING DRIVEN BY THE COVID-19

3217
02:27:10,840 --> 02:27:15,640
PUBLIC HEALTH CRISIS AND THE

3218
02:27:15,640 --> 02:27:16,720
DECISION TO CEASE EXPORTING,

3219
02:27:16,720 --> 02:27:18,040
EXPANSION REQUIRES LONG LEAD

3220
02:27:18,040 --> 02:27:21,120
TIMES, 3 TO 6 YEARS BEFORE

3221
02:27:21,120 --> 02:27:23,120
ADDITIONAL RESEARCH AGED ANIMALS

3222
02:27:23,120 --> 02:27:24,720
BECOME AVAILABLE.

3223
02:27:24,720 --> 02:27:28,600
THIS HIGH DEMAND AND LOW

3224
02:27:28,600 --> 02:27:29,440
AVAILABILITY IS FUELING

3225
02:27:29,440 --> 02:27:32,840
COMPETITION FOR A LIMITED POOL

3226
02:27:32,840 --> 02:27:33,600
OF NON-HUMAN PRIMATES, RESULTING

3227
02:27:33,600 --> 02:27:37,880
IN SUBSTANTIAL INCREASE IN COST

3228
02:27:37,880 --> 02:27:41,680
FOR MOST IN DEMAND SPECIES.

3229
02:27:41,680 --> 02:27:45,120
UNFORTUNATELY THIS CAN ALSO FEED

3230
02:27:45,120 --> 02:27:46,680
UNSUSTAINABLE ILLEGAL TRADE IN

3231
02:27:46,680 --> 02:27:47,960
THESE ANIMALS.

3232
02:27:47,960 --> 02:27:48,640
NEXT SLIDE.

3233
02:27:48,640 --> 02:27:51,560
FOR THESE REASONS WE SUPPORT THE

3234
02:27:51,560 --> 02:27:54,400
RENEWAL OF THE NIAID SPF MACAQUE

3235
02:27:54,400 --> 02:27:56,920
BREEDING COLONIES TO ENSURE A

3236
02:27:56,920 --> 02:28:01,440
RELIABLE DOMESTIC SUPPLY OF HIGH

3237
02:28:01,440 --> 02:28:03,280
QUALITY PRIMATES.

3238
02:28:03,280 --> 02:28:05,160
THIS SOLICITATION TYPE MECHANISM

3239
02:28:05,160 --> 02:28:07,360
AND DURATION REMAIN UNCHANGED

3240
02:28:07,360 --> 02:28:08,640
FROM THE PREVIOUS RENEWAL.

3241
02:28:08,640 --> 02:28:10,800
THANK YOU FOR YOUR ATTENTION, BE

3242
02:28:10,800 --> 02:28:15,040
HAPPY TO TAKE QUESTIONS AT THIS

3243
02:28:15,040 --> 02:28:17,720
TIME.

3244
02:28:17,720 --> 02:28:18,040
 

3245
02:28:18,040 --> 02:28:20,480
>>THANKS FOR THE
PRESENTATION.

3246
02:28:20,480 --> 02:28:22,880
ARE THROWS COLONIES OWNED BY NIH

3247
02:28:22,880 --> 02:28:24,920
OR OWNED BY THEIR CONTRACTOR?

3248
02:28:24,920 --> 02:28:27,120
>>THE ANIMALS ARE OWNED
BY

3249
02:28:27,120 --> 02:28:28,440
NIAID, AND WE, YEAH, HAVE A

3250
02:28:28,440 --> 02:28:30,600
CONTRACT FOR THEIR CARE AND

3251
02:28:30,600 --> 02:28:30,880
BREEDING.

3252
02:28:30,880 --> 02:28:33,040
>>GREAT.

3253
02:28:33,040 --> 02:28:43,240
THANK YOU. 

3254
02:28:48,760 --> 02:28:49,760
>>INTERESTING QUESTION,

3255
02:28:49,760 --> 02:28:51,080
DIFFICULT TO MOVE THESE ANIMALS

3256
02:28:51,080 --> 02:28:57,320
BUT WE HAVE THAT CAPABILITY IF A

3257
02:28:57,320 --> 02:29:04,680
NEW CONTRACTOR IS CHOSEN THROUGH

3258
02:29:04,680 --> 02:29:05,320
COMPETITOR PROCESS.

3259
02:29:05,320 --> 02:29:08,160
AND IT'S BEEN AN EXTRAORDINARILY

3260
02:29:08,160 --> 02:29:09,040
VALUABLE RESOURCE FOR US

3261
02:29:09,040 --> 02:29:10,760
CONSIDERING WHAT WE COULDN'T

3262
02:29:10,760 --> 02:29:13,080
POSSIBLY HAVE ANTICIPATED ABOUT

3263
02:29:13,080 --> 02:29:16,160
THE COST OF ANIMALS AND QUALITY

3264
02:29:16,160 --> 02:29:21,320
AND ASSURANCES WE HAVE THROUGH

3265
02:29:21,320 --> 02:29:21,960
OWNING THIS COLONY.

3266
02:29:21,960 --> 02:29:23,840
>>TOTALLY UNDERSTAND.

3267
02:29:23,840 --> 02:29:25,880
IT'S AWESOME YOU'RE EXPANDING

3268
02:29:25,880 --> 02:29:26,680
COLONIES.

3269
02:29:26,680 --> 02:29:27,120
SOUND GREAT.

3270
02:29:27,120 --> 02:29:28,400
>>I'M CURIOUS, MAYBE THIS
IS AN

3271
02:29:28,400 --> 02:29:30,680
ASIDE, BUT DO YOU HAVE TO GET

3272
02:29:30,680 --> 02:29:34,440
INVOLVED IN MONITORING THE

3273
02:29:34,440 --> 02:29:36,920
ILLEGAL TRADE AND MAYBE EVEN

3274
02:29:36,920 --> 02:29:42,760
STEMMING IT SINCE IT'S SOMETHING

3275
02:29:42,760 --> 02:29:43,080
YOU MENTIONED?

3276
02:29:43,080 --> 02:29:44,400
>>I DON'T THINK SO
BECAUSE WE

3277
02:29:44,400 --> 02:29:47,400
HAVE OUR OWN SUPPLY HERE BUT IT

3278
02:29:47,400 --> 02:29:50,320
IS VERY DIFFICULT FOR PEOPLE WHO

3279
02:29:50,320 --> 02:29:59,640
ARE TRYING TO PURCHASE THEM

3280
02:29:59,640 --> 02:30:01,040
COMMERCIALLY, SOMETIMES TO KNOW.

3281
02:30:01,040 --> 02:30:06,640
>>WHAT WOULD HAPPEN IF A

3282
02:30:06,640 --> 02:30:08,280
RESEARCHER MAKES AN INNOCENT

3283
02:30:08,280 --> 02:30:10,280
MISTAKE PURCHASING AN ILLEGAL

3284
02:30:10,280 --> 02:30:10,520
ANIMAL?

3285
02:30:10,520 --> 02:30:11,040
>>I DON'T KNOW.

3286
02:30:11,040 --> 02:30:13,200
THAT'S A GOOD QUESTION.

3287
02:30:13,200 --> 02:30:15,360
I THINK THERE HAVE BEEN SOME

3288
02:30:15,360 --> 02:30:17,480
THAT HAVE BEEN HELD AT CERTAIN

3289
02:30:17,480 --> 02:30:19,880
FACILITY 

3290
02:30:19,880 --> 02:30:21,000
FACILITIES FOR A WHILE BECAUSE

3291
02:30:21,000 --> 02:30:26,600
THEY WERE SUSPECTED TO HAVE BEEN

3292
02:30:26,600 --> 02:30:27,040
ILLEGALLY ACQUIRED.

3293
02:30:27,040 --> 02:30:27,560
>>YEAH.

3294
02:30:27,560 --> 02:30:29,840
>>WE DON'T ACTUALLY
RECEIVE

3295
02:30:29,840 --> 02:30:30,640
THOSE ANIMALS.

3296
02:30:30,640 --> 02:30:31,840
>>THE SITUATION WE'VE

3297
02:30:31,840 --> 02:30:32,960
THANKFULLY AVOIDED BY HAVING

3298
02:30:32,960 --> 02:30:38,720
THIS COLONY AND BEING ABLE TO

3299
02:30:38,720 --> 02:30:42,360
MEET THE NEEDS WITH THE ANIMALS

3300
02:30:42,360 --> 02:30:48,040
READY FOR RESEARCH. 

3301
02:30:48,040 --> 02:30:49,760
>>ANY OTHER COMMENTS OR

3302
02:30:49,760 --> 02:30:53,640
QUESTIONS ABOUT THIS OR ANY OF

3303
02:30:53,640 --> 02:30:56,560
THE INITIATIVES JUST PRESENTED?

3304
02:30:56,560 --> 02:31:02,600
 

3305
02:31:02,600 --> 02:31:08,480
 

3306
02:31:08,480 --> 02:31:10,040
>>OKAY, MERCY, LET'S GO
ON.

3307
02:31:10,040 --> 02:31:12,280
YOU HAVE THE FINAL ONE.

3308
02:31:12,280 --> 02:31:16,480
>>YES, I WILL NOT TAKE
LONG.

3309
02:31:16,480 --> 02:31:16,920
THANKS, BRIAN.

3310
02:31:16,920 --> 02:31:19,520
I'M MERCY, AND I'M PROGRAM

3311
02:31:19,520 --> 02:31:22,160
OFFICER AT THE BASIC IMMUNOLOGY

3312
02:31:22,160 --> 02:31:22,360
BRANCH.

3313
02:31:22,360 --> 02:31:23,040
NEXT SLIDE PLEASE.

3314
02:31:23,040 --> 02:31:26,120
I'LL BE TALKING TO YOU ABOUT THE

3315
02:31:26,120 --> 02:31:28,720
RENEWAL OF THE PROGRAM ON

3316
02:31:28,720 --> 02:31:31,600
MATERNAL FETAL IMMUNITY, AND THE

3317
02:31:31,600 --> 02:31:33,440
MAIN OBJECTIVES ARE TO DETERMINE

3318
02:31:33,440 --> 02:31:35,560
THE ROLES AND INTERACTIONS OF

3319
02:31:35,560 --> 02:31:38,160
HUMAN IMMUNE CELLS AT THE

3320
02:31:38,160 --> 02:31:44,920
MATERNAL FETAL INTERFACE AND TO

3321
02:31:44,920 --> 02:31:47,120
ELUCIDATE EFFECTS OF VACCINATION

3322
02:31:47,120 --> 02:31:48,960
IN PREGNANCY ON INTERFACE CELLS

3323
02:31:48,960 --> 02:31:51,280
AND DEVELOPING FETAL IMMUNE

3324
02:31:51,280 --> 02:31:54,880
SYSTEM, INITIATED IN FISCAL YEAR

3325
02:31:54,880 --> 02:31:59,360
2019, AND CURRENTLY 11 AWARDS, 9

3326
02:31:59,360 --> 02:32:04,400
FROM DAIT, 2 DMID, AROUND 53

3327
02:32:04,400 --> 02:32:05,280
PUBLICATIONS.

3328
02:32:05,280 --> 02:32:07,800
NEXT SLIDE PLEASE.

3329
02:32:07,800 --> 02:32:12,840
SO, THE MATERNAL-FETAL INTERFACE

3330
02:32:12,840 --> 02:32:14,040
UNDERGOES DYNAMIC IMMUNOLOGIC

3331
02:32:14,040 --> 02:32:17,680
MODELING AND CHANGES DURING

3332
02:32:17,680 --> 02:32:18,080
PREGNANCY.

3333
02:32:18,080 --> 02:32:20,280
AND SO THREE IMMUNE EVENTS ARE

3334
02:32:20,280 --> 02:32:22,920
CRUCIAL TO SUCCESSFUL PREGNANCY

3335
02:32:22,920 --> 02:32:26,520
OUTCOMES, AND FIRST IT'S THE

3336
02:32:26,520 --> 02:32:27,280
EMBRYO IMPLANTATION, EARLY

3337
02:32:27,280 --> 02:32:29,800
TRANSPLANTATION THAT ARE

3338
02:32:29,800 --> 02:32:32,840
IMPORTANT, EARLY EVENTS ARE

3339
02:32:32,840 --> 02:32:34,200
COUNTER-BALANCED BY STATE OF

3340
02:32:34,200 --> 02:32:38,000
TOLERANCE INDUCED BY VARIOUS

3341
02:32:38,000 --> 02:32:39,760
FACTORS WHICH INCLUDE

3342
02:32:39,760 --> 02:32:41,480
RECRUITMENT AND PROLIFERATION OF

3343
02:32:41,480 --> 02:32:43,440
DIFFERENT REGULATORY CELLS AND

3344
02:32:43,440 --> 02:32:45,440
EXPRESSION OF VARIOUS REGULATORY

3345
02:32:45,440 --> 02:32:52,440
MOLECULES. 

3346
02:32:52,440 --> 02:32:58,680
A SECOND PHASE LASTS UNTIL

3347
02:32:58,680 --> 02:33:02,040
PARTURITION IS INDUCED,

3348
02:33:02,040 --> 02:33:08,560
INCREASED PRODUCTION OF

3349
02:33:08,560 --> 02:33:10,000
PRO-INFLAMMATORY CYTOKINES.

3350
02:33:10,000 --> 02:33:11,040
SOME IMPORTANT INSIGHTS WERE

3351
02:33:11,040 --> 02:33:12,600
DISCOVERED BY INVESTIGATORS IN

3352
02:33:12,600 --> 02:33:15,600
THE PROGRAM.

3353
02:33:15,600 --> 02:33:16,440
SEVERAL QUESTIONS REMAIN AND WE

3354
02:33:16,440 --> 02:33:22,480
WOULD LIKE TO BUILD ON THE

3355
02:33:22,480 --> 02:33:24,560
FOUNDATION ESTABLISHED UNDER

3356
02:33:24,560 --> 02:33:26,200
FIRST INITIATIVE INCLUDING

3357
02:33:26,200 --> 02:33:28,080
LOOKING AT HEALTHY UTERINE

3358
02:33:28,080 --> 02:33:31,000
IMMUNOLOGIC CHANGES AT INTERFACE

3359
02:33:31,000 --> 02:33:32,720
CONTRIBUTING TO RECURRENT

3360
02:33:32,720 --> 02:33:33,440
IMPLANTATION FAILURE AND

3361
02:33:33,440 --> 02:33:34,960
RECURRENT PREGNANCY LOSS.

3362
02:33:34,960 --> 02:33:39,760
THERE'S A NEED FOR TOOLS THAT

3363
02:33:39,760 --> 02:33:41,960
REFLECT THE MATERNAL-FETAL

3364
02:33:41,960 --> 02:33:45,200
INTERFACE, AND MODELS THAT

3365
02:33:45,200 --> 02:33:46,640
APROXIMATE THE INTRAUTERINE

3366
02:33:46,640 --> 02:33:47,640
ENVIRONMENT DURING PREGNANCY,

3367
02:33:47,640 --> 02:33:49,040
EARLY PREGNANCY, AND THERE'S A

3368
02:33:49,040 --> 02:33:55,840
LACK OF REAL HUMAN  MODELS,

3369
02:33:55,840 --> 02:33:58,360
RELIANCE ON MICE INHIBITS

3370
02:33:58,360 --> 02:34:00,440
ABILITY TO MAKE PROGRESS,

3371
02:34:00,440 --> 02:34:04,720
LOOKING FOR PRIMARY CELL

3372
02:34:04,720 --> 02:34:05,360
ISOLATION, ORGANIZED

3373
02:34:05,360 --> 02:34:06,000
MICROPHYSIOLOGIC SYSTEMS AND THE

3374
02:34:06,000 --> 02:34:11,560
LIKE AND WANT TO BE ABLE TO

3375
02:34:11,560 --> 02:34:13,560
INVESTIGATE THE VARIOUS CHANGES

3376
02:34:13,560 --> 02:34:15,520
THAT WILL ALLOW CONSTRUCTION OF

3377
02:34:15,520 --> 02:34:17,040
IMMUNE LANDSCAPE DURING

3378
02:34:17,040 --> 02:34:17,720
PREGNANCY AND COVID-19 ALSO HAS

3379
02:34:17,720 --> 02:34:21,880
BEEN SHOWN TO BE MORE SEVERE IN

3380
02:34:21,880 --> 02:34:24,240
PREGNANT WOMEN, AND HIGHLIGHTS

3381
02:34:24,240 --> 02:34:26,440
THE NEED FOR ATTENTION TO UNIQUE

3382
02:34:26,440 --> 02:34:31,200
STATE OF

3383
02:34:31,200 --> 02:34:32,600
NEXT SLIDE PLEASE.

3384
02:34:32,600 --> 02:34:38,840
I'D LIKE TO HIGHLIGHT A FEW

3385
02:34:38,840 --> 02:34:39,360
ACCOMPLISHMENTS.

3386
02:34:39,360 --> 02:34:41,680
FIRST ONE IS FROM JUDY

3387
02:34:41,680 --> 02:34:45,960
LIEBERMAN'S LAB AT BOSTON

3388
02:34:45,960 --> 02:34:52,200
CHILDREN'S HOSPITAL, HERE SHE'S

3389
02:34:52,200 --> 02:34:58,880
SHOWN HUMAN DECIDUAL NK CELLS

3390
02:34:58,880 --> 02:35:03,240
EXPRESS PEPTIDE, TRANSFERRED VIA

3391
02:35:03,240 --> 02:35:05,960
NANOTUBES TO KILL EXTRACELLULAR

3392
02:35:05,960 --> 02:35:08,120
LISTERIA WITHOUT KILLING THE

3393
02:35:08,120 --> 02:35:09,920
TROPHOBLASTS, AND THESE

3394
02:35:09,920 --> 02:35:12,880
NANOTUBES ORIGINATE FROM THE NK

3395
02:35:12,880 --> 02:35:16,920
CELL AND TRANSFER IN AN

3396
02:35:16,920 --> 02:35:21,920
ACTIN-DEPENDENT MANNER.

3397
02:35:21,920 --> 02:35:27,040
CAROLINE COIN'S GROUP SHOWED

3398
02:35:27,040 --> 02:35:32,800
MID-GESTATION PERIOD INDUCES

3399
02:35:32,800 --> 02:35:36,640
INFLAMMASOME SIGNALING, SHE

3400
02:35:36,640 --> 02:35:40,040
SHOWED THAT THESE TROPHOBLASTS

3401
02:35:40,040 --> 02:35:41,000
SECRETE INFLAMMASOME-ASSOCIATED

3402
02:35:41,000 --> 02:35:46,120
CYTOKINES LIKE IL-1 BETA, AND

3403
02:35:46,120 --> 02:35:48,720
THEN SHOW THIS -- IDENTIFY

3404
02:35:48,720 --> 02:35:50,240
INFLAMMASOME AS IMPORTANT

3405
02:35:50,240 --> 02:35:53,080
MECHANISM BY WHICH HUMAN

3406
02:35:53,080 --> 02:35:55,240
PLACENTA REGULATES SYSTEMIC AND

3407
02:35:55,240 --> 02:35:57,000
LOCAL IMMUNITY DURING PREGNANCY

3408
02:35:57,000 --> 02:36:01,040
TO DEFEND AGAINST INFECTION.

3409
02:36:01,040 --> 02:36:03,160
NEXT SLIDE PLEASE.

3410
02:36:03,160 --> 02:36:13,000
AND THEN NEXT STUDY, WHILE

3411
02:36:13,000 --> 02:36:16,080
SEVERE CORONAVIRUS DISEASE IS

3412
02:36:16,080 --> 02:36:18,840
ASSOCIATED WITH IMMUNE

3413
02:36:18,840 --> 02:36:20,160
ACTIVATION OF MATERNAL-FETAL

3414
02:36:20,160 --> 02:36:24,040
INTERFACE, RESPONSES TO

3415
02:36:24,040 --> 02:36:27,120
ASYMPTOMATIC OR MILD INFECTION

3416
02:36:27,120 --> 02:36:31,480
DURING PREGNANCIES REMAIN

3417
02:36:31,480 --> 02:36:31,800
UNKNOWN.

3418
02:36:31,800 --> 02:36:36,000
THE LAB LOOKED AT RESPONSES TO

3419
02:36:36,000 --> 02:36:39,240
ASYMPTOMATIC OR MILD COVID-19

3420
02:36:39,240 --> 02:36:41,880
DURING PREGNANCY, AND REPORT

3421
02:36:41,880 --> 02:36:44,040
ATTENUATION OF ANTIGEN

3422
02:36:44,040 --> 02:36:46,280
PRESENTATION AND TYPE I

3423
02:36:46,280 --> 02:36:48,120
INTERFERON SIGNALING AND THEN

3424
02:36:48,120 --> 02:36:51,320
ALSO REMODELING OF LANDSCAPE OF

3425
02:36:51,320 --> 02:36:53,720
THE INTERFACE, AND WHICH HAS A

3426
02:36:53,720 --> 02:36:56,360
POTENTIAL FOR LONG-TERM ADVERSE

3427
02:36:56,360 --> 02:37:01,800
OUTCOMES FOR THE OFFSPRING.

3428
02:37:01,800 --> 02:37:11,880
AND THEN LASTLY, A LAB IN

3429
02:37:11,880 --> 02:37:17,040
CINCINNATI SHOWED PREGNANCY --

3430
02:37:17,040 --> 02:37:18,560
DURING PRESS NANCY THERE'S

3431
02:37:18,560 --> 02:37:21,400
DEACETYLATION WHICH EXPANDS

3432
02:37:21,400 --> 02:37:22,520
PROTECTION TO EXTRACELLULAR

3433
02:37:22,520 --> 02:37:24,520
PATHOGENS, HERE THEY DESCRIBE

3434
02:37:24,520 --> 02:37:25,560
PREGNANCY SPECIFIC MODIFICATION

3435
02:37:25,560 --> 02:37:27,560
OF MATERNAL ANTIBODIES WHICH

3436
02:37:27,560 --> 02:37:32,160
THEN ENHANCE PROTECTION AGAINST

3437
02:37:32,160 --> 02:37:34,640
LISTERIA INFECTION AND SUGGESTS

3438
02:37:34,640 --> 02:37:37,080
THE DEACETYLATION THEN ENABLES

3439
02:37:37,080 --> 02:37:38,200
CD22 BINDING AND INHIBITION OF

3440
02:37:38,200 --> 02:37:43,520
SUPPRESS IVE B CELL SUBSET.

3441
02:37:43,520 --> 02:37:47,600
NEXT SLIDE PLEASE.

3442
02:37:47,600 --> 02:37:51,680
SO, THE SCOPE OF THE PROPOSED

3443
02:37:51,680 --> 02:37:57,040
PROGRAM, THE RENEWAL, IS TO

3444
02:37:57,040 --> 02:38:00,200
INCLUDE MECHANISMS OF INDUCTION,

3445
02:38:00,200 --> 02:38:01,760
ACTIVATION OF VARIOUS LEUKOCYTE

3446
02:38:01,760 --> 02:38:06,560
RESPONSES AND MAINTENANCE OF

3447
02:38:06,560 --> 02:38:08,000
HOMEOSTASIS AT MATERNAL FETAL

3448
02:38:08,000 --> 02:38:11,240
INTERFACE AND WILL LOOK AT THE

3449
02:38:11,240 --> 02:38:14,560
EFFECT OF PERTURBATION, WHETHER

3450
02:38:14,560 --> 02:38:16,520
INFECTIOUS OR NON-INFECTIOUS ON

3451
02:38:16,520 --> 02:38:17,800
IMMUNE REGULATORY MECHANISMS AND

3452
02:38:17,800 --> 02:38:21,760
ARCHITECTURE AND FUNCTION AT THE

3453
02:38:21,760 --> 02:38:24,920
INTERFACE, AND WILL ALSO

3454
02:38:24,920 --> 02:38:26,160
DETERMINE IMMUNE CONTRIBUTIONS

3455
02:38:26,160 --> 02:38:32,720
TO KEY OBSTETRICAL DISEASES IN

3456
02:38:32,720 --> 02:38:33,600
PREGNANCY AND DEFINE REPERTOIRE

3457
02:38:33,600 --> 02:38:41,040
OF IMMUNE CELLS AND PROTEINS

3458
02:38:41,040 --> 02:38:42,840
DURING GESTATION, ALSO TO

3459
02:38:42,840 --> 02:38:45,080
ENCOURAGE DEVELOPMENT OF EX VIVO

3460
02:38:45,080 --> 02:38:50,440
SYSTEMS THAT WE CAPITULATE THE

3461
02:38:50,440 --> 02:38:52,200
INTERFACE.

3462
02:38:52,200 --> 02:38:54,280
SO, POTENTIAL PARTNERS NIEHS,

3463
02:38:54,280 --> 02:38:56,680
NICHD, NIDA, AND WE WANT TO

3464
02:38:56,680 --> 02:39:00,200
CONTINUE WITH R01 MECHANISM.

3465
02:39:00,200 --> 02:39:02,160
AND WITH THAT WE'LL END THE

3466
02:39:02,160 --> 02:39:02,920
PRESENTATION AND I'M HAPPY TO

3467
02:39:02,920 --> 02:39:04,560
TAKE ANY QUESTIONS.

3468
02:39:04,560 --> 02:39:06,200
>>LOOKS LIKE CREATIVE
RESEARCH

3469
02:39:06,200 --> 02:39:07,920
AND FINDINGS THERE, VERY

3470
02:39:07,920 --> 02:39:08,200
EXCITING.

3471
02:39:08,200 --> 02:39:10,080
>>YES, A LOT OF NEW
THINGS THAT

3472
02:39:10,080 --> 02:39:12,520
HAVE COME UP OUT OF THE PROGRAM.

3473
02:39:12,520 --> 02:39:24,200
IT'S GRATIFYING.

3474
02:39:24,200 --> 02:39:24,520
>>OKAY.

3475
02:39:24,520 --> 02:39:27,520
IF WE HAVE NO OTHER QUESTIONS OR

3476
02:39:27,520 --> 02:39:31,760
COMMENTS, ON THIS OR ANY OF THE

3477
02:39:31,760 --> 02:39:34,600
OTHER CONCEPT CLEARANCES

3478
02:39:34,600 --> 02:39:36,600
PRESENTED, WE SHOULD MOVE TO EN

3479
02:39:36,600 --> 02:39:40,240
BLOC MOTION TO PROCEED AND A

3480
02:39:40,240 --> 02:39:40,480
SECOND.

3481
02:39:40,480 --> 02:39:42,960
>>THESE ARE IMPRESSIVE

3482
02:39:42,960 --> 02:39:43,400
PRESENTATIONS.

3483
02:39:43,400 --> 02:39:46,360
ACCOMPLISHMENTS ARE AWESOME.

3484
02:39:46,360 --> 02:39:49,760
I MOVE FOR A VOTE,

3485
02:39:49,760 --> 02:39:53,560
RECOMMENDATION FOR ALL FOUR.

3486
02:39:53,560 --> 02:39:56,120
>>I SECOND.

3487
02:39:56,120 --> 02:39:58,960
>>GREAT, THANK YOU.

3488
02:39:58,960 --> 02:40:01,360
REMINDER THAT THE CONCEPT

3489
02:40:01,360 --> 02:40:02,160
CLEARANCES WE DIDN'T DISCUSS,

3490
02:40:02,160 --> 02:40:06,760
THOSE THAT I MENTIONED BRIEFLY

3491
02:40:06,760 --> 02:40:09,920
FOR THE SMALL BUSINESS CONTRACTS

3492
02:40:09,920 --> 02:40:15,480
AND THE ODD SET INFORMATICS

3493
02:40:15,480 --> 02:40:16,800
PROPOSALS ARE IN THE ELECTRONIC

3494
02:40:16,800 --> 02:40:19,000
COUNCIL BOOK AND WE NEED YOUR

3495
02:40:19,000 --> 02:40:20,280
APPROVAL TO GO THROUGH WITH

3496
02:40:20,280 --> 02:40:25,040
THOSE, NO NEED FOR DISCUSSION.

3497
02:40:25,040 --> 02:40:26,440
YVETTE, HAVE WE COVERED

3498
02:40:26,440 --> 02:40:27,880
EVERYTHING BEFORE WE ADJOURN?

3499
02:40:27,880 --> 02:40:28,840
>>WE HAVE.

3500
02:40:28,840 --> 02:40:31,800
I WANT TO REMIND COUNCIL MEMBERS

3501
02:40:31,800 --> 02:40:34,520
TO VOTE ON THE FOUR CONCEPT

3502
02:40:34,520 --> 02:40:36,560
CLEARANCES THEY HEARD AND FOUR

3503
02:40:36,560 --> 02:40:39,000
DATE FYIS AND TWO ODD SETS,

3504
02:40:39,000 --> 02:40:44,120
EVERYTHING IS IN ECB TO APPROVE 

3505
02:40:44,120 --> 02:40:45,120
I WOULD APPRECIATE THAT.

3506
02:40:45,120 --> 02:40:45,400
>>TERRIFIC.

3507
02:40:45,400 --> 02:40:49,440
THANK YOU TO THE SPEAKERS TODAY

3508
02:40:49,440 --> 02:40:52,240
AND EVERYBODY ELSE WHO JOINED US

3509
02:40:52,240 --> 02:40:54,120
AND COUNCIL MEMBERS, WE HOPE

3510
02:40:54,120 --> 02:40:55,800
THAT COME JUNE WE'LL SEE YOU ALL

3511
02:40:55,800 --> 02:40:58,400
IN PERSON.

3512
02:40:58,400 --> 02:41:01,120
>>OKAY.

3513
02:41:01,120 --> 02:41:01,400
VERY GOOD.

3514
02:41:01,400 --> 02:41:02,560
>>WE ANTICIPATE THAT I
WILL

3515
02:41:02,560 --> 02:41:06,040
NEED TO BE AVAILABLE IN JUNE OR

3516
02:41:06,040 --> 02:41:06,520
PROBABLY NOT, RIGHT?

3517
02:41:06,520 --> 02:41:09,440
>>THIS SHOULD BE YOUR
LAST

3518
02:41:09,440 --> 02:41:11,560
COUNCIL ROUND.

3519
02:41:11,560 --> 02:41:16,600
I THINK THEY EXTENDED YOU, AND

3520
02:41:16,600 --> 02:41:17,320
LET ME SEE.

3521
02:41:17,320 --> 02:41:20,800
I BELIEVE THIS IS YOUR LAST

3522
02:41:20,800 --> 02:41:21,000
ROUND.

3523
02:41:21,000 --> 02:41:22,200
>>ALL RIGHT.

3524
02:41:22,200 --> 02:41:23,840
>>APPRECIATE IT THOUGH.

3525
02:41:23,840 --> 02:41:26,560
>>OH, WELL, THEN A
SPECIAL

3526
02:41:26,560 --> 02:41:29,840
THANKS TO BOTH OF YOU FOR YEARS

3527
02:41:29,840 --> 02:41:32,800
OF SERVICE AND FOR THE

3528
02:41:32,800 --> 02:41:33,320
EXTENSION.

3529
02:41:33,320 --> 02:41:35,120
WE'VE REALLY ENJOYED HAVING BOTH

3530
02:41:35,120 --> 02:41:37,720
OF YOU ON THE COUNCIL

3531
02:41:37,720 --> 02:41:38,720
SUBCOMMITTEE AND YOUR COMMITMENT

3532
02:41:38,720 --> 02:41:42,120
AND CONTRIBUTIONS HAVE BEEN

3533
02:41:42,120 --> 02:41:42,680
TERRIFIC.

3534
02:41:42,680 --> 02:41:43,560
ORDINARILY I THINK IF IT WOULD

3535
02:41:43,560 --> 02:41:44,320
HAVE BEEN IN PERSON IT WOULD

3536
02:41:44,320 --> 02:41:48,000
HAVE BEEN A PHOTO WITH DR. FAUCI

3537
02:41:48,000 --> 02:41:49,720
OR IN THIS CASE YOU.

3538
02:41:49,720 --> 02:41:52,400
>>I THINK AT THE LAST ONE
OUR

3539
02:41:52,400 --> 02:41:53,160
FINAL ONE, RIGHT?

3540
02:41:53,160 --> 02:41:55,000
THAT'S WHY I WAS ASKING ABOUT

3541
02:41:55,000 --> 02:41:56,560
THE EXTENSION BECAUSE I DON'T

3542
02:41:56,560 --> 02:41:59,400
THINK THEY WERE SO OBVIOUS.

3543
02:41:59,400 --> 02:42:03,000
BUT ANYWAY, IT'S BEEN FUN, MOST

3544
02:42:03,000 --> 02:42:03,680
HAS BEEN.

3545
02:42:03,680 --> 02:42:03,880
>>YEAH.

3546
02:42:03,880 --> 02:42:04,240
>>A PLEASURE.

3547
02:42:04,240 --> 02:42:04,760
THANK YOU SO MUCH.

3548
02:42:04,760 --> 02:42:06,400
THANKS TO ALL THE PEOPLE IN THE

3549
02:42:06,400 --> 02:42:07,680
OFFICE THERE.

3550
02:42:07,680 --> 02:42:10,240
ALL THE FOLKS THAT PRESENTED

3551
02:42:10,240 --> 02:42:11,240
THIS AMAZING INFORMATION.

3552
02:42:11,240 --> 02:42:11,560
>>GREAT.

3553
02:42:11,560 --> 02:42:15,720
WELL, THANK YOU AGAIN.

3554
02:42:15,720 --> 02:42:18,200
AND WE'LL ADJOURN HERE AND LOOK

3555
02:42:18,200 --> 02:42:20,160
FORWARD TO SEEING PEOPLE IN

3556
02:42:20,160 --> 02:42:20,760
JUNE.

3557
02:42:20,760 --> 02:42:21,920
>>THANK YOU.

3558
02:42:21,920 --> 02:42:25,120
BYE-BYE NOW.

3559
02:42:25,120 --> 02:42:31,120
 

3560
02:42:31,120 --> 02:42:41,160
 

3561
02:47:17,720 --> 02:47:28,160
 CAPTION TEST, CAPTION TEST. 

3562
02:47:59,200 --> 02:48:08,120
 

3563
02:48:08,120 --> 02:48:18,160
 

3564
02:48:18,480 --> 02:48:23,920
IS NOT A GOOD TARGET FOR T CELLS

3565
02:48:23,920 --> 02:48:32,000
HERE, SPIKE IS A GOOD TARGET

3566
02:48:32,000 --> 02:48:35,480
VACCINE MADE OF SPIKE ONLY,

3567
02:48:35,480 --> 02:48:36,280
WHICH WAS ORIGINALLY BEING

3568
02:48:36,280 --> 02:48:36,600
DEVELOPED.

3569
02:48:36,600 --> 02:48:42,040
AT THE SAME TIME WE SAW T-CELL

3570
02:48:42,040 --> 02:48:44,480
RESPONSES CD4 AND CD8 RESPONSE

3571
02:48:44,480 --> 02:48:47,840
AGAINST A NUMBER OF SARS-COV-2

3572
02:48:47,840 --> 02:48:49,080
ANTIGENS, RAISING THE PROSPECT

3573
02:48:49,080 --> 02:48:49,600
IF A BROADER SPECTRUM OF T