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IT'S TIME TO GET

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GOING AND I'M JUST THRILLED TO

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BE HERE, EVERYONE, ON THIS

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BEAUTIFUL AFTERNOON.

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NICE COZY AFTERNOON TO BE IN

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HERE LISTENING TO AMAZING

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SCIENCE IT IS MY PLEASURE TO

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INTRODUCE OUR SPEAKER FOR

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TODAY'S ROLLA E. DYER LECTURE

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DR. JASON Mc LELLAN, AND I

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UNDERSTAND THIS IS A WELCOME

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BACK WHICH IS WONDERFUL, HE IS

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AT THE DOCTOR OF BIOSCIENCES AT

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THE UNIVERSITY OF TEXAS AT

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AUSTIN.

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BEFORE I TELL YOU ABOUT HIS

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BACKGROUND, I SHOULD TELL YOU

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THIS STUFF, IF YOU ARE ATTENDING

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THIS CODE FOR CME, THE CODE IS

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50666.

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IF YOU ARE WATCHING ONLINE

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PLEASE CLICK ON THE SEND LIVE

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FEEDBACK BUTTON AND YOUR

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QUESTION WILL BE RELAYED TO THE

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SPEAKER AT THE END OF THE

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PICTURE.

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YOU CAN SUBMIT QUESTIONS AT ANY

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TIME DURING THE LECTURE.

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SO NOW THE IMPORTANT THINGS.

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WE ARE DELIGHTED TO HAVE

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DR. Mc LCERTAINLY--CERTAINLY

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LLAN HERE TODAY, WE IS A

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STRUCTURAL BIOLOGIST

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SPECIALIZING IN VIROLOGY AND

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VACCINES.

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AS A POST DOC IN THE

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LABORATORIES OF PETER KD--SALLY

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MEN AND WOMEN ASK BARNY GRAHAM,

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FROM 2000-2013 HE WAS

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RESPONSIBLE FOR A PRAIK THROUGH

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TOWARD DEVELOPING AN RSV

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VACCINE.

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HE DETERMINED THE STRUCTURE OF

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THE RSV-F PROTEIN AND ENGINEERED

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A PREFUSION STABILIZED ANTIGEN

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WHICH ELICITED VERY HIGH TITERS

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IN ANTIBODIES AND THEN IN

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HUMANS, THE MULTIPLE APPROVE

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WILL OF VACCINES LAST YEAR AND

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THIS YEAR ENDED A 50 YEAR QUEST

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TO DEVELOP AN EFFECTIVE VACCINE

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AGAINST RESPIRATORY STITTIAL

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VIRUS.

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THIS HAS BEEN A GREAT BURDEN TO

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SOCIETY OVER THE YEARS

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ESPECIALLY TO VULNERABLE

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POPULATIONS NEOINATES FOR

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ESPECIALLY FOR WHOM IT'S BEEN

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THE LEADING CAUSE OF

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HOSPITALIZATION.

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BUILDING ON HIS PIONEERING RSV

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STUDIES, DR. Mc LELLAN'S

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COLLAB HELPED DETERMINE THE

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STRUCTURE OF THE HUMAN COONA

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VIRUS, THEY RESEARCHED

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S-PROTEINS INCORPORATED INTO THE

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COVID VACCINES IN DEVELOPING

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COUNTRIES.

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WITH 150 PUBLICATIONS, PULT PEL

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PATENTS AND STILL IN HIS EARLY

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40S DR. Mc LELLAN IS REGARDED

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AS THE LEADING SCIENTIST IN THE

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FIELD OF STRUCTURE BASED VACCINE

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DEVELOPMENT.

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CAN'T WAIT TO SEE WHAT YOU DO

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NEXT.

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AMONG OTHER HONORS HE RECEIVED A

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NATIONAL ACADEMY OF SCIENCES

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AWARD IN MOLECULAR BIOLOGY IN

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THE UT AUSTIN PRESIDENT'S

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RESEARCH IMPACT AWARD BOTH LAST

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YEAR AND A TRIPLE AAS GOLDEN

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GOOSE AWARD IN 2020.

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THOSE ARE GREAT.

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YEAH, THOSE ARE GREAT.

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HE EARNED A BACHELOR OF SCIENCE

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IN CHEMISTRY FROM UNIVERSITY OF

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DETROIT, AND Ph.D. IN

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CHEMISTRY FROM JOHNS HOPKINS

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SCHOOL OF MEDICINE.

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PLEASE YOIN ME IN WELCOME BEING

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DR. Mc LELLAN.

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[ APPLAUSE ]

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>> ALL RIGHT, WELL THANK
YOU

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VERY MUCH FOR THAT GENEROUS

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INTRODUCTION, I THOUGHT I WOULD

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TALK ABOUT THE ROLE THAT NIERK H

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AND NIH FUNDING HAS PLAYED IN

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THE DEVELOPMENT OF INFECTIOUS

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DISEASE, GOING THROUGH AND

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HITTING SOME OF THE HIGHLIGHTS

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ABOUT RSV AND CORONA VIRUS AND

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ENDING ON SOME OF OUR RECENT

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WORK ON CONGO FEVER VIRUS, I DO

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HAVE CONFLICTS OF INTEREST WHICH

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WERE ALREADY SHOWN ABOUT I AM AN

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INVENTOR TO PATENT AND RECEIVE

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PATENT ROYALTIES RELATED TO WHAT

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I WILL SPEAK ABOUT.

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SO FOR STRUCTURE BASED ANTIGEN

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DESIGN, IT'S 1 COMPONENT OF THIS

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REVERSE VACSINNOLOGY APPROACH TO

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VACCINE DESIGN AND WE SAY

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REVERSE BECAUSE HISTORICALLY YOU

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WOULD START WITH THE PATHOIEN

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AND ISOLATE THE PATHOIEN IS

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WEAKEN IT OR ENACTIVATE IT AND

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IMMUNIZE WITH IT AND HOPE IT

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PROVIDED A ROBUST IMMUNE

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RESPONSE AND YOU WOULD

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EFFECTIVELY WEAKEN IT SO IT

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DIDN'T CAUSE DISEASE AND IT

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WORKED WELL FOR A NUMBER OF

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PATHOIENS AND NOW WHAT WE'RE

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DOING IS THE REVERSE IS STARTING

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WITH PEOPLE, PEOPLE WHO HAVE

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MAYBE SURVIVES THE INFECTIONS

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THAT WE'RE INTERESTED IN AND

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THEY SURVIVED IT IN PART BECAUSE

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THEY MOUNTED A ROBUST IMMUNE

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RESPONSE.

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PARTICULARLY WHAT WE'RE

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INTERESTED IN IS PROTECTIVE

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ANTIBODIES AND THEN WE LEVERAGED

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MAJOR ADVANCES IN ANTIBODY

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ISOLATION, SO WE CAN NOW SORT

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THESE CELLS AND COME UP WITH

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OTHER WAYS FROM ISOLATING

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ANTIBODIES FROM PATIENTS AND

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FUNCTIONALLY CHARACTERIZE THEM,

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IDENTIFY THOSE THAT ARE

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NEUTRALIZING, BROADLY

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PROTECTIVE, WE CAN DOWN SELECT

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AND IDENT WHAT WE CONSIDERED TO

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BE THE TOP 5, 10, 20, BEST

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ANTIBODIES THAT HUMANS CAN MAKE

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AGAINST THAT PATHOGEN.

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HOPEFULLY THESE ANTIBODIES ARE

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ALSO PROTECTIVE AND THEN THE

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GOAL OF THE VACCINE DEVELOPMENT

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IS TO CREATE IMMUNOGENS AND

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IMMUNIZATION REGIMENS THAT WILL

153
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REENLIST THESE ANTIBODIES IN THE

154
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VACCINE RECIPIENTS.

155
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SO WE COME IN HERE WITH THE

156
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STRUCTURAL BIOLOGY, AND TRY TO

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DETERMINE THE HIGH RESOLUTION

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STRUCKURES OF THE ANTIBODIES IN

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COMPLEX WITH THE ANTIIEN THAT

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PRORIDES INSIGHT INTO THE

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MECHANISM OF ANTIBODY MEDIATED

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NEUTRALIZATION AND IT CAN ALSO

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PROVIDE INSIGHT INTO THE ROLE

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THE VIRAL GLYCOPROTEINS THAT

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IT'S BINDING, TOO, AND

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IMPORTANTLY PROVIDES ACCESS TO

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THE CHEMISTRY AT THE IRPT FACE

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AND THIS ALLOWS FOR STRUCTURE

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BASED AND COMPUTATIONAL

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APPROACHES TO ANTIGEN DESIGN, SO

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HERE WE CAN SEE MAYBE THIS

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PARLIAMENT OF THE ANTIBODY IS

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BINDING THIS RED PORTION OF THE

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ANTIGEN, NOT THE PURPLE PORTION,

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MAYBE THE PERIPHERAL PORTION IS

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IMMUNO DOMINANT UNLESS IT'S

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NONNEUTRALLIZING ANTIBODIES SO

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YOU COULD DO THINGS LIKE

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SCAFFOLDING AND TRANSPLANT THAT

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RED REGION INTO A

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SELF-ASSEMBLING NANO PARTICLE

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AND TRY TO FOCUS AN IMMUNE

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RESPONSE TO THAT PART.

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SO A LOT OF THIS IS BASED ON

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IMMUNO FOCUS XG ILLICITTING BEST

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IN CLASS ANTIBODIES THAT WERE

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PREVIOUSLY ISOLATED.

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WITH THE STRUCTURAL INFORMATION,

189
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THERE'S SEVERAL DIFFERENT TYPES

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OF COMPUTATIONAL DESIGN

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APPROACHES AND YOU CAN DID

192
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SEQUENCE BASED DESIGN WHERE

193
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MAYBE YOU'RE TRYING TO PROVIDE

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BREDTH AGAINST MANY DIFFERENT

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ISOLATES SO WE HAVE DIFFERENT

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ISOLATES, SEQUENCES 1-5.

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YOU COULD COME UP WITH IDEAS OF

198
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USING LIKE CONSENSUS SEQUENCES

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00:06:28,713 --> 00:06:31,116
TO DESIGN YOUR ANTIGEN OR COMMON

200
00:06:31,116 --> 00:06:32,083
ANCESTORS THAT WOULD SHARE

201
00:06:32,083 --> 00:06:35,320
RESIDUES FROM BOTH OF THOSE

202
00:06:35,320 --> 00:06:37,289
ISOLATS, YOU DO CONFIRMATIONAL

203
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STABILIZATION WHICH WILL BE THE

204
00:06:38,490 --> 00:06:42,360
FOCUS OF MY TALK, SOME OF THESE

205
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VIRAL GLYCOPROTEINS EXIST IN

206
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MULTIPLE CONFRONTATIONS

207
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PREFUSION AND POST FUSION.

208
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ONE OF THESE IS LIKELY TO BE A

209
00:06:48,800 --> 00:06:50,302
BETTER'MUNE O GEN AND WE

210
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DETERMINE HOW TO STABILIZE THEM

211
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AND IMMUNIZE WITH THE CORRECT

212
00:06:54,105 --> 00:06:55,440
CONFIRMATION AND THEN OTHER

213
00:06:55,440 --> 00:06:56,474
STRUCTURED BASE DESIGN

214
00:06:56,474 --> 00:06:58,543
APPROACHES AS MENTIONED THE

215
00:06:58,543 --> 00:06:59,811
EPITELOMERE SCAFFOLDING WHERE WE

216
00:06:59,811 --> 00:07:02,914
CAN TAKE AN ANTIBODY BINDING

217
00:07:02,914 --> 00:07:04,883
SITE LIKE THIS HELIX FROM THIS

218
00:07:04,883 --> 00:07:06,851
PROTEIN GRAFFED ON TO A SCAFFOLD

219
00:07:06,851 --> 00:07:08,520
AND IMMUNIZE WITH THAT TO FOCUS

220
00:07:08,520 --> 00:07:10,121
THE IMMUNE RESPONSE ON TO JUST 1

221
00:07:10,121 --> 00:07:11,823
PORTION OF THAT PARTICULAR

222
00:07:11,823 --> 00:07:12,357
ANTIGEN.

223
00:07:12,357 --> 00:07:13,491
AND THEN SUBSEQUENTLY THESE CAN

224
00:07:13,491 --> 00:07:15,026
BE DELIVERED IN DIFFERENT WAYS

225
00:07:15,026 --> 00:07:20,432
AND EVEN PRESENTED ON

226
00:07:20,432 --> 00:07:23,001
SELF-ABLING NANO PARTING --

227
00:07:23,001 --> 00:07:23,635
SELF-ASSEMBLING NANO PARTICLES.

228
00:07:23,635 --> 00:07:26,304
WE WILL TALK ABOUT CLASS 1 VIRAL

229
00:07:26,304 --> 00:07:26,671
PROTEINS.

230
00:07:26,671 --> 00:07:29,808
THESE ARE ALL SYNTHESIZED AS

231
00:07:29,808 --> 00:07:30,775
SINGLE CHAIN INACTIVE

232
00:07:30,775 --> 00:07:32,811
PRECURSORS, YOU SEE THE MOST

233
00:07:32,811 --> 00:07:35,280
COMMON 1S, HIV ENVELOPE AND

234
00:07:35,280 --> 00:07:36,314
INFLUENZA HEMATBLIEWTIN AND THEN

235
00:07:36,314 --> 00:07:39,484
THE F PROTEINS FROM PARAMIX O

236
00:07:39,484 --> 00:07:40,185
VIRUSES AND PNEUMOVIRUSES.

237
00:07:40,185 --> 00:07:42,020
THESE ARE GENERALLY EVOLVE

238
00:07:42,020 --> 00:07:44,689
FRIDAY 1 OR 2 ORIGINAL COMMON

239
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ANCESTORS.

240
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THEY NEED TO BE PROTEIN COMPLEX

241
00:07:48,593 --> 00:07:50,195
LYTICALLY ACTIVATED AT A

242
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CONSERVED SITE AND YOU SEE THIS

243
00:07:51,596 --> 00:07:53,865
HAS THE 2 COMPONENTS, THERE'S

244
00:07:53,865 --> 00:07:55,567
MEMBRANE FUSION COMPONENT AND A

245
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FUSION SUPPRESSIVE CAP AND THE

246
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MEMBRANE FUSION MACHINERY,

247
00:07:59,971 --> 00:08:01,873
THAT'S BEEN CONSERVED, AND

248
00:08:01,873 --> 00:08:04,109
EVOLVE FROM A COMMON ANCESTOR,

249
00:08:04,109 --> 00:08:06,077
IT HAS THE 4 ELEMENTS NEEDED TO

250
00:08:06,077 --> 00:08:07,946
PROMOTE MEMBRANE FUSION WHICH IS

251
00:08:07,946 --> 00:08:08,780
A TRANSMEMBRANE DOMAIN, THE

252
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ANCHORS AND THE VIRAL MEMBRANE,

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A FUSION PEPTIDE THAT

254
00:08:13,084 --> 00:08:15,153
GERONTOLOGYSTSS RELEASED AFTER

255
00:08:15,153 --> 00:08:18,223
THE PROTEOLYTIC ACTIVATION THAT

256
00:08:18,223 --> 00:08:18,990
GENERATES LITTLE HYDROPHOBIC

257
00:08:18,990 --> 00:08:20,325
STRETCH OF ACIDS THAT WILL

258
00:08:20,325 --> 00:08:23,662
HARPOON INTO THE TARGET CELL

259
00:08:23,662 --> 00:08:25,463
MEMBRANE AND THEN 2 HAVE TO HAVE

260
00:08:25,463 --> 00:08:29,334
REPEATS SO 7 STRETCHES OF IMMUNO

261
00:08:29,334 --> 00:08:30,702
ACIDS, THEY HAVE HYDROPHOBIC

262
00:08:30,702 --> 00:08:32,270
POSITIONS AT WOB AND 4, THEY

263
00:08:32,270 --> 00:08:34,339
WILL INTERACT WITH EACH AND FORM

264
00:08:34,339 --> 00:08:36,775
A HIGHLY STABLED COIL-COIL AND

265
00:08:36,775 --> 00:08:38,043
LATER A 6 HELIX BUNDLE AND THEN

266
00:08:38,043 --> 00:08:40,045
YOU HAVE SOME OF THESE FUSION

267
00:08:40,045 --> 00:08:41,780
SUPPRESSIVE CAPS SO WE LIKE TO

268
00:08:41,780 --> 00:08:43,982
THINK OF THESE AS BEING SPRING

269
00:08:43,982 --> 00:08:46,551
LOADED, THEY WANT TO UPDATER GO

270
00:08:46,551 --> 00:08:47,919
A CONFIRMATIONAL CHANGE FROM

271
00:08:47,919 --> 00:08:50,422
PRETO POSE, AND LIKE A MUSHROOM,

272
00:08:50,422 --> 00:08:52,557
SITS ON TOP AND PREVENTS EARLY

273
00:08:52,557 --> 00:08:53,758
ACTIVATION AND GENERALLY YOU

274
00:08:53,758 --> 00:08:54,726
COUPLE LIKE RECEPTOR BINDING IN

275
00:08:54,726 --> 00:08:56,528
THE CASE OF CORONA VIRUS,

276
00:08:56,528 --> 00:08:59,564
RECEPTOR BINDING TO THE S1

277
00:08:59,564 --> 00:09:01,633
SUBUNIT AND RBD, DESTABILIZES IT

278
00:09:01,633 --> 00:09:04,102
AND CAUSES SHEDDING AND YOU GET

279
00:09:04,102 --> 00:09:04,536
REFOLDING OF S2.

280
00:09:04,536 --> 00:09:07,505
SO THIS IS WHAT WE LIKE TO THINK

281
00:09:07,505 --> 00:09:10,175
FOR HOW THESE WOULD SIT IN THE

282
00:09:10,175 --> 00:09:11,342
MEMBRANE, THEY INITIALLY FOLD

283
00:09:11,342 --> 00:09:12,510
INTO THE METASTABLE STATE, SO

284
00:09:12,510 --> 00:09:15,513
IT'S NOT THE LOWEST ENERGY

285
00:09:15,513 --> 00:09:16,781
STATE, THAT'S THE POST FUSION

286
00:09:16,781 --> 00:09:19,184
ESTATE BUT THEY START OFF IN

287
00:09:19,184 --> 00:09:20,018
THIS METASTABLE PREFUSION

288
00:09:20,018 --> 00:09:21,786
ESTATE, THERE'S SOME ACTIVATION

289
00:09:21,786 --> 00:09:23,188
ENERGY, A TRIGGERING EVENT THAT

290
00:09:23,188 --> 00:09:25,390
CAUSES IT TO REFOLD, YOU THEN

291
00:09:25,390 --> 00:09:28,159
HAVE THE HARPOONING OF THE

292
00:09:28,159 --> 00:09:29,728
HYDROPHOBIC FUSION PEPTIDE INTO

293
00:09:29,728 --> 00:09:31,963
THE HOST CELL MEMBRANE AND AT

294
00:09:31,963 --> 00:09:34,099
THIS POINT IT ADOPTED WHAT WE

295
00:09:34,099 --> 00:09:35,333
CALL AN INTERMEDIATE WHERE THE

296
00:09:35,333 --> 00:09:36,968
PROTEIN IS SPANNING THE BOTH THE

297
00:09:36,968 --> 00:09:40,872
VIRAL MEMBRANE AND THE HOST CELL

298
00:09:40,872 --> 00:09:42,307
MEMBRANE, THIS COLLAPSES IN HALF

299
00:09:42,307 --> 00:09:44,175
AS THE COILED COILS WALK TOWARD

300
00:09:44,175 --> 00:09:46,578
EACH OTHER, THIS BRINGS THE

301
00:09:46,578 --> 00:09:48,179
HOST-CELL MEMBRANE AND VIRAL

302
00:09:48,179 --> 00:09:49,948
MEMBRANE TOGETHER.

303
00:09:49,948 --> 00:09:52,150
EVENTUALLY THE PROTEIN ADOPS THE

304
00:09:52,150 --> 00:09:52,951
POST FUSION CONFIRMATION AND

305
00:09:52,951 --> 00:09:55,286
THEN THE HOST MEMBRANE AND VIRAL

306
00:09:55,286 --> 00:09:56,788
MEMBRANE'S FUSE, YOU NOW HAVE A

307
00:09:56,788 --> 00:09:58,523
FUSION FOR, SO THE GENOME OF THE

308
00:09:58,523 --> 00:10:01,693
VIRUS CAN ENTER THE CELL AND AT

309
00:10:01,693 --> 00:10:02,961
THAT POINT THE CELL IS INFECTED

310
00:10:02,961 --> 00:10:08,767
AND WHAT WE WANT TO DO IS

311
00:10:08,767 --> 00:10:10,068
GENERATE ANTIBODIES AND MAYBE

312
00:10:10,068 --> 00:10:11,669
SMALL MOLL KIEWMS THAT COMBINE

313
00:10:11,669 --> 00:10:14,873
TO THE FUSION STATE AND PREVENT

314
00:10:14,873 --> 00:10:15,840
THE CONFIRMATIONAL CHANGE FROM

315
00:10:15,840 --> 00:10:18,710
OCCURRING, SO IF WE CAN PURIFY

316
00:10:18,710 --> 00:10:20,979
AND ISOLATE ANTIBODIES AND PASS

317
00:10:20,979 --> 00:10:22,046
PERIPHERAL AXIS OR GENERATE

318
00:10:22,046 --> 00:10:24,282
THESE TYPES OF ANTIBODIES

319
00:10:24,282 --> 00:10:25,550
THROUGH VACCINATION, THEY

320
00:10:25,550 --> 00:10:27,752
COMBINED AND PREVENT THE

321
00:10:27,752 --> 00:10:28,987
CONFIRMATIONAL GYMNASTICS AND

322
00:10:28,987 --> 00:10:30,555
THEN THE VIRUS COOPERATE ENTER

323
00:10:30,555 --> 00:10:32,190
AND THAT PROVIDES PROTECTION, A

324
00:10:32,190 --> 00:10:35,093
PROBLEM IS THAT THE PRE-FUSION

325
00:10:35,093 --> 00:10:36,094
STATE AND METASTABLE AND SO

326
00:10:36,094 --> 00:10:38,296
THERE'S A NICE PAPER FROM DAVID

327
00:10:38,296 --> 00:10:45,103
BAKER AND DAVID AGARD DESCRIBING

328
00:10:45,103 --> 00:10:46,938
THIS, SOING IT'S UNSTABLE BUT

329
00:10:46,938 --> 00:10:47,405
NOT TRAPPED.

330
00:10:47,405 --> 00:10:50,775
SO IT'S NOT THE LOWEST FREE

331
00:10:50,775 --> 00:10:53,411
ENERGY STATE, IT'S HIGHER BUT

332
00:10:53,411 --> 00:10:54,612
IT'S KINETICALLY TRAPPED UNTIL

333
00:10:54,612 --> 00:10:56,281
THERE'S AN EVENT THAT GETS IT

334
00:10:56,281 --> 00:10:57,282
OVER THE HILL.

335
00:10:57,282 --> 00:10:59,284
>> SO 1 PROBLEM IS WHEN
YOU TRY

336
00:10:59,284 --> 00:11:00,585
TO PURIFY THESE AND LOOK AT

337
00:11:00,585 --> 00:11:01,753
THEM, THEY JUST QUICKLY

338
00:11:01,753 --> 00:11:03,321
TRANSITION TO THE POST FUSION

339
00:11:03,321 --> 00:11:05,456
STATE AND SO MANY TIMES YOU'RE

340
00:11:05,456 --> 00:11:07,091
IMMUNIZING OR WORKING WITH THE

341
00:11:07,091 --> 00:11:08,593
POST FUSION STATE, WHEN THE IDLE

342
00:11:08,593 --> 00:11:10,695
ANTIGEN MAY BE THE PREFUSION

343
00:11:10,695 --> 00:11:11,529
CONFIRMATION, AND SO WE DID A

344
00:11:11,529 --> 00:11:13,264
LOT OF WORK ON THIS BACK WHEN I

345
00:11:13,264 --> 00:11:15,233
WAS A POST DOC HERE AT THE

346
00:11:15,233 --> 00:11:17,869
VACCINE RESEARCH CENTER IN PETER

347
00:11:17,869 --> 00:11:19,571
QUAWNG'S LAB AND WORKING WITH

348
00:11:19,571 --> 00:11:20,839
BARNY GRAHAM TO DETERMINE

349
00:11:20,839 --> 00:11:23,908
STRUCTURES OF THE POST FUSION

350
00:11:23,908 --> 00:11:26,344
AND PREFUSION CONFIRMATIONS OF

351
00:11:26,344 --> 00:11:27,178
THE RESPIRATORY INTERSTITIAL

352
00:11:27,178 --> 00:11:29,280
VIRUS F PROTEIN, THESE ARE TRI

353
00:11:29,280 --> 00:11:31,683
MERRIC SO THERE'S 3 COPIES OF

354
00:11:31,683 --> 00:11:32,584
F-PROTEIN.

355
00:11:32,584 --> 00:11:35,053
AND YOU CAN SEE THAT 1 PROTEIN

356
00:11:35,053 --> 00:11:38,356
COMPLEX MERIS IN RIBBONS, 1

357
00:11:38,356 --> 00:11:41,125
PROTOMERIS IN SURFACE AND 1

358
00:11:41,125 --> 00:11:41,759
PROTOMER IS IN WHITE.

359
00:11:41,759 --> 00:11:44,929
SO WE LOOK AT 1 INDIVIDUAL

360
00:11:44,929 --> 00:11:47,332
PROTOMER THE 1 IN RIBBONS AND WE

361
00:11:47,332 --> 00:11:48,499
CAN APPRECIATE THE CONFIRMATION

362
00:11:48,499 --> 00:11:50,201
WILLA CHANGES THAT OCCUR IN THE

363
00:11:50,201 --> 00:11:50,869
PREAND POST FUSIONITATE.

364
00:11:50,869 --> 00:11:51,502
SO YOU SLEEP APNEA AND OBESITYY

365
00:11:51,502 --> 00:11:53,838
ABOUT HALF THE MOLECULE THAT'S

366
00:11:53,838 --> 00:11:56,541
IN WHITE DOES NOT GO UNDERGO A

367
00:11:56,541 --> 00:11:57,575
CONFIRMATIONAL CHANGE.

368
00:11:57,575 --> 00:11:59,811
SO THESE AMINO ACIDS ARE WITHIN

369
00:11:59,811 --> 00:12:05,016
ABOUT 5 

370
00:12:05,016 --> 00:12:06,517
ABOUT 5-ANGSTROM, THERE'S A

371
00:12:06,517 --> 00:12:08,052
LARGE BETA SHEET THAT'S MOSTLY

372
00:12:08,052 --> 00:12:08,519
THE SAME.

373
00:12:08,519 --> 00:12:12,290
BUT THEN THE N-AND C TERMINUS OF

374
00:12:12,290 --> 00:12:14,592
THE F-1 SUBUNIT UNDERGO

375
00:12:14,592 --> 00:12:15,693
REFOLDING AND CONFIRMATIONAL

376
00:12:15,693 --> 00:12:16,261
REARRANGEMENT.

377
00:12:16,261 --> 00:12:19,197
SO THE C-TERMINUS OF F1 PIVOTS

378
00:12:19,197 --> 00:12:20,265
AROUND THIS AMINO ACID HERE AND

379
00:12:20,265 --> 00:12:22,133
THIS FLIPS ALL THE WAY AROUND TO

380
00:12:22,133 --> 00:12:25,737
FORM THE OUTER HELIX OF THIS

381
00:12:25,737 --> 00:12:27,171
HIGHLY STABLE 6 HELIX BUNDLE AND

382
00:12:27,171 --> 00:12:29,374
THEN THE END TERMINUS OF F1

383
00:12:29,374 --> 00:12:30,475
COMPLETELY REFOLDS.

384
00:12:30,475 --> 00:12:32,844
YOU HAVE THE HYDROPHOBIC FUSION

385
00:12:32,844 --> 00:12:33,912
PEPTIDE WHICH IS SEQUESTERED

386
00:12:33,912 --> 00:12:34,979
INSIDE THE CENTER OF THE

387
00:12:34,979 --> 00:12:37,815
PROTEIN, YOU THEN HAVE A HELIX

388
00:12:37,815 --> 00:12:39,450
TURN HELIX, BETA HAIR PIN IN

389
00:12:39,450 --> 00:12:42,353
YELLOW AND GREEN, AND THEN THE

390
00:12:42,353 --> 00:12:44,088
FINAL ALPHA HELIX 4 IN BLUE, ALL

391
00:12:44,088 --> 00:12:46,658
OF THIS FLIPS AROUND AND

392
00:12:46,658 --> 00:12:47,425
POLYMERIZES THE CENTRAL HELIX

393
00:12:47,425 --> 00:12:49,694
AND FORM THIS IS HIGHLY

394
00:12:49,694 --> 00:12:51,095
ELONGATED ALPHA HELIX IN THE

395
00:12:51,095 --> 00:12:51,629
POST FUSION STATE.

396
00:12:51,629 --> 00:12:53,531
SO CAN YOU HAVE THESE ELEMENTS

397
00:12:53,531 --> 00:12:55,733
LIKE THE BETA HAIR PIN IN YELLOW

398
00:12:55,733 --> 00:12:57,502
AND GREEN, ARE REFOLDING AND

399
00:12:57,502 --> 00:12:59,103
TRANSITIONING INTO AN ALPHA

400
00:12:59,103 --> 00:13:01,606
HELIX, SO IT'S A REALLY

401
00:13:01,606 --> 00:13:03,007
SUBSTANTIAL REFOLDING AND

402
00:13:03,007 --> 00:13:03,708
CONFIRMATIONAL CHANGE.

403
00:13:03,708 --> 00:13:06,411
SO WITH THIS INFORMATION, WE'RE

404
00:13:06,411 --> 00:13:12,083
THEN ABLE TO IDENTIFY STABLE

405
00:13:12,083 --> 00:13:13,685
AMINO ACID SUBSTITUTIONS THAT

406
00:13:13,685 --> 00:13:16,554
WOULD LOCK THE PROTEIN IN A

407
00:13:16,554 --> 00:13:17,956
PREPROTEIN STATE SO WE COULD USE

408
00:13:17,956 --> 00:13:18,790
IT AS AN ANTIGEN.

409
00:13:18,790 --> 00:13:21,125
SO TO DO THIS WE IDENTIFY

410
00:13:21,125 --> 00:13:24,796
SEVERAL CLASSES OF STABILIZING

411
00:13:24,796 --> 00:13:25,596
SUBSTITUTIONS, DISULPHIDE BONDS

412
00:13:25,596 --> 00:13:27,131
ARE ALWAYS IDEAL WHEN WE FIND

413
00:13:27,131 --> 00:13:27,332
THEM.

414
00:13:27,332 --> 00:13:28,299
PARTICULARLY IF WEB CONNECTED

415
00:13:28,299 --> 00:13:30,134
CAN GET 1 CYSTINE IN THE

416
00:13:30,134 --> 00:13:30,768
REASONNION THAT MOVES AND

417
00:13:30,768 --> 00:13:32,403
ANOTHER CYSTINE IN A REGION THAT

418
00:13:32,403 --> 00:13:34,706
DOESN'T MOVE, SO THEN THEY COULD

419
00:13:34,706 --> 00:13:37,542
FORM A COVALENT DISULPHIDE BOND,

420
00:13:37,542 --> 00:13:38,876
STAPPLE THOSE 2 REGIONS TOGETHER

421
00:13:38,876 --> 00:13:41,980
AND PREVENT THE CONFIRMATIONAL

422
00:13:41,980 --> 00:13:43,014
CHANGE FROM OCCURRING.

423
00:13:43,014 --> 00:13:44,882
WE CAN ALSO IDENTIFY CAVITY

424
00:13:44,882 --> 00:13:46,050
SUBSTITUTIONS, MANY TIMES IN

425
00:13:46,050 --> 00:13:47,585
THESE PROTEINS THESE EVOLVE TO

426
00:13:47,585 --> 00:13:49,554
BE SOMEWHAT UNSTABLE, SO THERE'S

427
00:13:49,554 --> 00:13:53,057
LITTLE POCKETS AND CAVITIES THAT

428
00:13:53,057 --> 00:13:54,592
THE EVOLUTION THAT IS CREATED

429
00:13:54,592 --> 00:13:56,227
INSTABILITY SO WE CAN FIND THOSE

430
00:13:56,227 --> 00:13:58,229
AND FILL THEM, SO IN THIS CASE,

431
00:13:58,229 --> 00:14:03,201
THERE'S NORMALLY A SMALLER

432
00:14:03,201 --> 00:14:04,335
IMMUNO ACID SIRRINE POINTING TO

433
00:14:04,335 --> 00:14:06,004
THIS CAVITY, AND WE REPLACE IT

434
00:14:06,004 --> 00:14:09,440
WITH A LARGER [INDISCERNIBLE],

435
00:14:09,440 --> 00:14:12,844
AND STABILIZES THE PROTEIN AND

436
00:14:12,844 --> 00:14:17,248
MAKES IT GIFUL TO PULL IT OUT

437
00:14:17,248 --> 00:14:18,483
AND STARVE IT.

438
00:14:18,483 --> 00:14:20,018
THERE'S 6 NEGATIVELY CHARGED

439
00:14:20,018 --> 00:14:22,887
IMMUNO ARK SIDS, CAN YOU MUTATE

440
00:14:22,887 --> 00:14:26,124
THESE TO SPARRAGING OR GLUTAMINE

441
00:14:26,124 --> 00:14:28,993
TO REDUCE THE CHARGE OR

442
00:14:28,993 --> 00:14:29,794
PROPULSION, SOMETIMES WE

443
00:14:29,794 --> 00:14:31,095
ENGINEER IN SALT BRIDGES,

444
00:14:31,095 --> 00:14:32,730
NORMALLY THIS IS AN

445
00:14:32,730 --> 00:14:38,603
R-GENERATEDDINE NEXT TO A

446
00:14:38,603 --> 00:14:39,370
POSITIVELY CHARGED TBLIEWTA MATE

447
00:14:39,370 --> 00:14:43,041
AND NOW YOU GET A

448
00:14:43,041 --> 00:14:44,642
POSITIVE-NEGATIVE CELL BRIDGE TO

449
00:14:44,642 --> 00:14:46,811
HELP STABILIZE IT AND FINALLY

450
00:14:46,811 --> 00:14:49,747
PROLEANS WHICH HAY LOVE AND THEY

451
00:14:49,747 --> 00:14:50,782
WORK REALLY WELL AND THEY'VE

452
00:14:50,782 --> 00:14:54,619
BEEN SHOWN FOR HIV, RSV, AND

453
00:14:54,619 --> 00:14:57,255
LATER FOR COONA VIRUSES, AND

454
00:14:57,255 --> 00:14:58,890
PROTEINS THAT CAP HELIXES OR

455
00:14:58,890 --> 00:15:01,125
THESE RANGES THAT NEED TO

456
00:15:01,125 --> 00:15:03,161
UNDERGO A COIL TO HELIX

457
00:15:03,161 --> 00:15:05,463
TRANSITION, PUTTING IT IN THERE,

458
00:15:05,463 --> 00:15:06,764
RELATIVELY FLEXIBLE AND HELP THE

459
00:15:06,764 --> 00:15:07,465
CHANGE FROM OCCURRING.

460
00:15:07,465 --> 00:15:09,467
WE USED TO DO THIS JUST BY EYE,

461
00:15:09,467 --> 00:15:13,037
NOW THERE'S A LOT OF SERVERS,

462
00:15:13,037 --> 00:15:14,105
TOOLS, AI-ML MODELS TO ASSIST

463
00:15:14,105 --> 00:15:15,773
WITH THIS SO IT'S AN EXCITING

464
00:15:15,773 --> 00:15:18,743
TIME FOR DOING THIS TYPE OF

465
00:15:18,743 --> 00:15:21,179
DESIGN, ULTIMATELY, BACK IN 213,

466
00:15:21,179 --> 00:15:23,281
WE SETTLED ON A SINGLE

467
00:15:23,281 --> 00:15:24,782
DISULPHIDE BONDS THAT LINK THIS

468
00:15:24,782 --> 00:15:27,085
MOVING REGION IN BLUE TO THIS

469
00:15:27,085 --> 00:15:28,619
MOVING REGION IN GRAY AND SO

470
00:15:28,619 --> 00:15:30,922
THAT FORMED THE COVALENT LINKAGE

471
00:15:30,922 --> 00:15:32,790
AND THEN ADDED IN THESE CAVITY

472
00:15:32,790 --> 00:15:33,458
FILLING SUBSIDIARY CONSTITUTIONS

473
00:15:33,458 --> 00:15:35,259
AT THE APEX AND THAT WAS

474
00:15:35,259 --> 00:15:36,794
SUFFICIENT TO KEEP THE MOLECULE

475
00:15:36,794 --> 00:15:39,063
IN THE PREFUSION STATE AND THEN

476
00:15:39,063 --> 00:15:41,499
WHEN BARNY AND COLLEAGUES AT THE

477
00:15:41,499 --> 00:15:43,835
BRC IMMUNIZE MICE AND RECESS MA

478
00:15:43,835 --> 00:15:45,002
CABBINGS WITH A PRIME BOOST AND

479
00:15:45,002 --> 00:15:48,239
LOOK AT THE RSV NEUTRALIZING

480
00:15:48,239 --> 00:15:49,240
ANTIBODY TITERS, WE CAN SEE THAT

481
00:15:49,240 --> 00:15:50,274
HIGHER IS BETTER WITH THE POST

482
00:15:50,274 --> 00:15:52,076
FUSION FORM OF THE FPROTEIN WE

483
00:15:52,076 --> 00:15:55,379
WERE GETTING NEW TITERS IN THE

484
00:15:55,379 --> 00:15:57,582
HUNDREDS AND WITH THE PREFUSION

485
00:15:57,582 --> 00:15:59,550
FORM, WE WERE GETTING TITERS IN

486
00:15:59,550 --> 00:16:00,985
THE HIGH THOUSANDS CLOSE TO

487
00:16:00,985 --> 00:16:03,254
10,000 SO A SUBSTANTIAL INCREASE

488
00:16:03,254 --> 00:16:04,956
USING THE PREFUSION CONFIRMATION

489
00:16:04,956 --> 00:16:06,691
OF THE FPROTEIN AS AN ANTIGEN,

490
00:16:06,691 --> 00:16:09,660
SO LATER WHEN I WAS PROFESSOR AT

491
00:16:09,660 --> 00:16:11,596
DARTMOUTH, WE WORKED WITH A

492
00:16:11,596 --> 00:16:14,599
COMPANY CALLEDAD WHAT AND LAURA

493
00:16:14,599 --> 00:16:16,501
WALKER TRIED TO PROVIDE AN

494
00:16:16,501 --> 00:16:18,436
IMMUNOLOGICAL BASIS FOR WHY

495
00:16:18,436 --> 00:16:20,872
USING THE IMMUNO ILLICITTED SUCH

496
00:16:20,872 --> 00:16:21,839
HIGH ANTIBODY TITERS, SO WORKING

497
00:16:21,839 --> 00:16:24,142
WITH LAUREANO PEELING AWE WERE

498
00:16:24,142 --> 00:16:26,878
ABLE TO ISOLATE 364 RSV F

499
00:16:26,878 --> 00:16:27,879
DIRECTED ANTIBODIES FROM 3 ADULT

500
00:16:27,879 --> 00:16:28,646
DONORS.

501
00:16:28,646 --> 00:16:30,948
ALL OF THESE WERE EXPRESSED AND

502
00:16:30,948 --> 00:16:34,051
PURIFIED AND WE CHARACTERIZED

503
00:16:34,051 --> 00:16:35,887
FOR AFFINITY, EPITOPE,

504
00:16:35,887 --> 00:16:36,854
NEUTRALIZATION POTENCY AND IF WE

505
00:16:36,854 --> 00:16:39,557
LOOK AT THE MOST POTENTLY

506
00:16:39,557 --> 00:16:40,825
NEUTRALIZING ANTIBODIES WE CAN

507
00:16:40,825 --> 00:16:45,263
SEE THAT 60% OF THEM TARGET ONLY

508
00:16:45,263 --> 00:16:47,331
2 EPITOPES, ANTIGENIC SITES THAT

509
00:16:47,331 --> 00:16:49,367
WE CALL ANTIGENIC SITE 5 AND 0.

510
00:16:49,367 --> 00:16:52,069
AND IMPORTANTLY THESE ARE THE

511
00:16:52,069 --> 00:16:53,571
PREFUSION SPECIFIC ANTIGENIC

512
00:16:53,571 --> 00:16:55,306
SITES, SO THOSE SITES ARE ONLY

513
00:16:55,306 --> 00:16:56,174
FOUNDOT PREFUSION FORM OF THE

514
00:16:56,174 --> 00:16:57,909
PROTEIN AND THEY'RE IN A

515
00:16:57,909 --> 00:16:58,409
COMPLETELY DIFFERENT

516
00:16:58,409 --> 00:16:59,443
CONFIRMATION AND POST FUSION.

517
00:16:59,443 --> 00:17:01,179
THEY DON'T EXIST IN POST.

518
00:17:01,179 --> 00:17:02,246
SO IF YOU IMMUNIZE WITH POST,

519
00:17:02,246 --> 00:17:04,148
YOU WILL NEVER BE ABLE TO

520
00:17:04,148 --> 00:17:05,716
ILLICIT ALL OF THESE PREFUSION

521
00:17:05,716 --> 00:17:08,252
SPECIFIC ANTIBODIES THAT ARE

522
00:17:08,252 --> 00:17:08,986
HIGHLY NEUTRALIZING.

523
00:17:08,986 --> 00:17:12,089
SO THE EXTENT TO WHICH PREFUSION

524
00:17:12,089 --> 00:17:12,690
STABILIZATION WORKS REALLY

525
00:17:12,690 --> 00:17:14,158
DEPENDS ON THE PERCENT OF

526
00:17:14,158 --> 00:17:15,826
ANTIBODIES THAT PEOPLE MAKE THAT

527
00:17:15,826 --> 00:17:17,361
ARE TARGETING EPITOPES

528
00:17:17,361 --> 00:17:19,597
EXCLUSIVELY FOUNDOT PREFUSION

529
00:17:19,597 --> 00:17:20,031
CONFIRMATION.

530
00:17:20,031 --> 00:17:21,632
SO WE HAVE ALL THAT WORK DONE

531
00:17:21,632 --> 00:17:23,167
BACK IN 2013 WITH THE

532
00:17:23,167 --> 00:17:24,902
STABILIZATION OF THE ANTIGEN, IT

533
00:17:24,902 --> 00:17:28,272
WEPT THROUGH THE NORMAL DECADE

534
00:17:28,272 --> 00:17:31,108
OR SO OF CLINICAL TRIALS AND

535
00:17:31,108 --> 00:17:33,544
THEN IN 2022, BOTH GSK AND

536
00:17:33,544 --> 00:17:34,979
PFIZER AND NOW IT'S TOP LINE

537
00:17:34,979 --> 00:17:36,948
PHASE 3 DATA FROM THE RSV

538
00:17:36,948 --> 00:17:38,516
VACCINE CANDIDATES IN OLDER

539
00:17:38,516 --> 00:17:40,451
ADULTS AND THEN, LAST YEAR IN

540
00:17:40,451 --> 00:17:46,524
MAY ISSUES THE FDA APPROVED THE

541
00:17:46,524 --> 00:17:48,926
FIRST RSV VACCINE, AREX BEE FROM

542
00:17:48,926 --> 00:17:49,894
GSK WHICH IS BASED ON THE

543
00:17:49,894 --> 00:17:51,629
MOLECULE THAT WE CREATED SO THIS

544
00:17:51,629 --> 00:17:53,264
IS THE PICTURE BARNY SENT TO ME

545
00:17:53,264 --> 00:17:56,834
IN THE FALL OF LAST YEAR WHERE

546
00:17:56,834 --> 00:17:58,336
HE GETTING VACCINATED MOLECULE

547
00:17:58,336 --> 00:17:59,637
WHILE HOLDING A PREFUSION

548
00:17:59,637 --> 00:18:00,605
MOLECULE THAT HE HELPED CREATE

549
00:18:00,605 --> 00:18:01,906
SO I THINK THAT'S REALLY COOL

550
00:18:01,906 --> 00:18:03,307
AND SOME OF THE POWER OF THE

551
00:18:03,307 --> 00:18:04,275
VACCINE RESEARCH CENTER AND WHAT

552
00:18:04,275 --> 00:18:06,611
CAN BE DONE HERE.

553
00:18:06,611 --> 00:18:10,381
I THEN LEFT THE VRC IN 2000

554
00:18:10,381 --> 00:18:12,450
THREEN TO START MY OWN LAB AT

555
00:18:12,450 --> 00:18:13,684
DARTMOUTH AND BARNY AND I WANTED

556
00:18:13,684 --> 00:18:15,419
TO KEEP WORKING TOGETHER, WE

557
00:18:15,419 --> 00:18:17,989
WERE THINKING WHAT ELSE COULD WE

558
00:18:17,989 --> 00:18:19,991
APPLY STRUCTURE BASED VACCINE TO

559
00:18:19,991 --> 00:18:21,259
WITH OTHER VIRUSES AND THIS WAS

560
00:18:21,259 --> 00:18:23,828
AROUND THE TIME THAT THE MITSD

561
00:18:23,828 --> 00:18:26,697
EAST RESPIRATORY VIRUS HAD

562
00:18:26,697 --> 00:18:28,165
EMERGED IN 2012-2013 IN SAUDI

563
00:18:28,165 --> 00:18:30,801
ARABIA, AND IT WAS THE SECOND

564
00:18:30,801 --> 00:18:34,705
COVID VIRUS, SARS IN 2002, AND

565
00:18:34,705 --> 00:18:36,173
MERS IN 2012, AND WE THOUGHT WE

566
00:18:36,173 --> 00:18:41,245
SHOULD TRY TO FIGURE OUT HOW TO

567
00:18:41,245 --> 00:18:44,248
MAKE OPTIMAL CORONA VIRUSES

568
00:18:44,248 --> 00:18:45,650
ANTICIPATING SPILL OVERS IN THE

569
00:18:45,650 --> 00:18:45,883
FUTURE.

570
00:18:45,883 --> 00:18:48,986
THE OTHER THING IS THEY'RE BOTH

571
00:18:48,986 --> 00:18:50,054
SPIKE PROTEINS, AND WE FELT LIKE

572
00:18:50,054 --> 00:18:52,456
WE COULD USE A SIMILAR PARADIGM,

573
00:18:52,456 --> 00:18:55,293
WHERE WE FIRST NEEDED TO OBTAIN

574
00:18:55,293 --> 00:18:57,028
A 3 DIMENSIONAL TRUCTURE OF THE

575
00:18:57,028 --> 00:18:59,363
PREFUSION STATE OF THE CORONA

576
00:18:59,363 --> 00:19:00,498
VIRUS SPIKE, IDENTIFY

577
00:19:00,498 --> 00:19:01,332
STABILIZING SUBSIDIARY

578
00:19:01,332 --> 00:19:03,768
CONSTITUTIONS AND TEST IT AS AN

579
00:19:03,768 --> 00:19:04,702
IMMUNE VACCINE IMMUNOGEN, BUT

580
00:19:04,702 --> 00:19:07,305
THAT'S WHEN WE SET OUT TO DO

581
00:19:07,305 --> 00:19:08,939
BACK THEN, IT WAS -- TOOK

582
00:19:08,939 --> 00:19:10,374
SEVERAL YEARS AND COMPLICATED,

583
00:19:10,374 --> 00:19:12,243
TRYING TO WORK ON MERS, WHERE WE

584
00:19:12,243 --> 00:19:14,478
COULD NOT GET THE STRUCTURE,

585
00:19:14,478 --> 00:19:17,114
ULTIMATELY WORKED AT THE SCRIPTS

586
00:19:17,114 --> 00:19:18,616
RESEARCH INSTITUTE AND 1 OF THE

587
00:19:18,616 --> 00:19:22,720
OTHER HUMAN CORONA VIRUS, HKU1,

588
00:19:22,720 --> 00:19:25,690
THE COMMON COLD, WAS ABLE TO GET

589
00:19:25,690 --> 00:19:29,160
THIS STRUCTURALLY ARE OF THE

590
00:19:29,160 --> 00:19:30,461
HKU1 SPIKE, AND THIS PROVIDED A

591
00:19:30,461 --> 00:19:31,629
LOT OF INFORMATION ON THE

592
00:19:31,629 --> 00:19:33,931
BIOLOGY AND SPIKE PROTEIN, WE

593
00:19:33,931 --> 00:19:35,733
SAW THE BYPASSING DOMAINS WERE

594
00:19:35,733 --> 00:19:36,667
MEDIATING, WE KNEW THEY WOULD

595
00:19:36,667 --> 00:19:38,002
HAVE TO UPDATER GO A

596
00:19:38,002 --> 00:19:39,503
CONFIRMATIONAL CHANGE TO BIND

597
00:19:39,503 --> 00:19:41,238
RECEPTORS OTHERWISE THERE WOULD

598
00:19:41,238 --> 00:19:42,506
BE SUBSTANTIAL CLASSES, BUT

599
00:19:42,506 --> 00:19:43,908
WHATEVER REASON IN THIS BASE

600
00:19:43,908 --> 00:19:46,811
STATE, ALL THE RBDs WERE IN

601
00:19:46,811 --> 00:19:52,750
THE DOWN CONFIRMATION AND

602
00:19:52,750 --> 00:19:54,385
IDENTIFIED 2 SMALL SUBDOMAINS,

603
00:19:54,385 --> 00:19:56,187
SD1 AND 2, AND MOST IMPORTANTLY

604
00:19:56,187 --> 00:19:59,123
IT PROVIDED STRUCTURE OF THE

605
00:19:59,123 --> 00:20:00,324
SPRING LOADED PROFUSION IMAGERY

606
00:20:00,324 --> 00:20:03,761
WHICH LOOKED A LOT LIKE THE

607
00:20:03,761 --> 00:20:05,296
RSV-F PROTEIN, SINCE THAT TIME,

608
00:20:05,296 --> 00:20:06,964
MY LAB, DAVID'S LAB AND OTHERS

609
00:20:06,964 --> 00:20:09,166
HAVE SOLVED A LOT OF CORONA

610
00:20:09,166 --> 00:20:11,268
VIRUS SPIKE STRUCTURES BOUND TO

611
00:20:11,268 --> 00:20:12,970
ANTIBODIES BOUND TO RECEPTORS

612
00:20:12,970 --> 00:20:14,972
AND NOW WE COULD MAKE A NICE

613
00:20:14,972 --> 00:20:16,307
MOVIE OF HOW THIS WORKS, I THINK

614
00:20:16,307 --> 00:20:17,475
THIS IS BETTER THAN THE

615
00:20:17,475 --> 00:20:19,443
ANIMATION IN THE BEGONING.

616
00:20:19,443 --> 00:20:22,546
SO THE FUSION S-1 DOMAIN, FUSION

617
00:20:22,546 --> 00:20:24,715
MACHINERY IN S2, WE KNOW THE

618
00:20:24,715 --> 00:20:27,718
RBDs HINGE INTO AN UPSTATE,

619
00:20:27,718 --> 00:20:29,787
THOSE BIND RECEPTOR,

620
00:20:29,787 --> 00:20:30,988
DESTABILIZES S1 WHICH FALLS OFF,

621
00:20:30,988 --> 00:20:32,623
AND YOU GET THE FOLDING AND

622
00:20:32,623 --> 00:20:35,393
ALPHA HELIX IN HARPOONING OF THE

623
00:20:35,393 --> 00:20:36,761
HYDROPHOBIC FUSION OF THE TARGET

624
00:20:36,761 --> 00:20:40,398
CELL MEMBRANE AND THEN THE PAIR

625
00:20:40,398 --> 00:20:41,665
INTERMEDIATE COLLAPSES AS THEY

626
00:20:41,665 --> 00:20:43,434
HAVE TO HAVE RESEATS AND COILED

627
00:20:43,434 --> 00:20:46,237
COILS START TO FORM THE 6 HELIX

628
00:20:46,237 --> 00:20:47,938
BUNDLE, IT ZIPPERED UP AND

629
00:20:47,938 --> 00:20:49,607
BRINGS THE VIRAL MEMBRANES AND

630
00:20:49,607 --> 00:20:51,208
HOST CELL MEMBRANES TOGETHER.

631
00:20:51,208 --> 00:20:52,777
SO THESE ARE IMPRESSIVE MACHINES

632
00:20:52,777 --> 00:20:54,412
THAT HAVE EVOLVED TO FUSE THEIR

633
00:20:54,412 --> 00:20:56,580
MEMBRANES WITH OUR MEMBRANES AND

634
00:20:56,580 --> 00:20:57,982
INFECT US WHICH WE'RE CONSTANTLY

635
00:20:57,982 --> 00:21:00,518
TRYING TO STOP THAT FROM

636
00:21:00,518 --> 00:21:00,785
HAPPENING.

637
00:21:00,785 --> 00:21:03,220
SO OUR GOAL AT THIS POINT WAS TO

638
00:21:03,220 --> 00:21:06,524
-- YEAH, BACK IN LIKE 2015

639
00:21:06,524 --> 00:21:09,727
MAYBE, TRYING TO STABILIZE THE

640
00:21:09,727 --> 00:21:10,494
SPIKE PROTEINS.

641
00:21:10,494 --> 00:21:14,865
SO HERE YOU SEE THE COMPAREISON

642
00:21:14,865 --> 00:21:18,769
OF PREFUSION S2, FOR CORONA

643
00:21:18,769 --> 00:21:21,071
VIRUSES, AND THERE'S A LOT OF

644
00:21:21,071 --> 00:21:22,473
SIMILARITY, THEY ALL HAVE --

645
00:21:22,473 --> 00:21:24,442
THEY HAVE A CENTRAL HELIX IN

646
00:21:24,442 --> 00:21:26,377
BLUE THAT DOES NOT UNDERGO MUCH

647
00:21:26,377 --> 00:21:28,345
CHANGE BETWEEN PREAND POST.

648
00:21:28,345 --> 00:21:30,681
IT'S JUST SMALLER AND RSV-F, AND

649
00:21:30,681 --> 00:21:31,982
YOU HAVE THE ELEMENTS IN THE

650
00:21:31,982 --> 00:21:35,319
FIRST TO HAVE REPEAT IN GREEN,

651
00:21:35,319 --> 00:21:36,754
YELLOW, ORANGE, RED, SAME, ALL

652
00:21:36,754 --> 00:21:38,155
THOSE SAME COLORS AND ALL OF

653
00:21:38,155 --> 00:21:40,224
THAT'S GOING TO POLYMERIZE AND

654
00:21:40,224 --> 00:21:41,959
STACK AND FORM THAT REALLY LONG

655
00:21:41,959 --> 00:21:43,828
ALPHA HELIX THAT THEN SHOOTS THE

656
00:21:43,828 --> 00:21:45,830
FUSION PEPTIDE INTO THE TARGET

657
00:21:45,830 --> 00:21:47,298
CELL MEMBRANE, SO WE TRIED TO DO

658
00:21:47,298 --> 00:21:50,000
SOME OF THE SIMILAR TRICKS WITH

659
00:21:50,000 --> 00:21:51,101
DISULPHIDE BONDS, CAVITY FILLING

660
00:21:51,101 --> 00:21:53,604
SUBSIDIARY TUITIONS, BUT WE ARE

661
00:21:53,604 --> 00:21:54,839
HAVING ISSUES, BECAUSE FOR RSV,

662
00:21:54,839 --> 00:21:56,340
WE HAD THE STRUCTURE AND WE WERE

663
00:21:56,340 --> 00:21:58,776
TRYING TO MAKE RSV F VERYIANTS.

664
00:21:58,776 --> 00:22:01,178
HERE WE HAVE THE HK1 STRUCTURE

665
00:22:01,178 --> 00:22:03,781
BUT WE'RE TRYING TO MAKE

666
00:22:03,781 --> 00:22:05,883
VERIANTS OF MERS, AND THOSE ARE

667
00:22:05,883 --> 00:22:08,719
ONLY 35% SEQUENCE IESH DEPTITY

668
00:22:08,719 --> 00:22:10,488
AND THINGS LIKE CAVITY FILLING

669
00:22:10,488 --> 00:22:13,123
AND DISULPHIDE BONDS HAVE TO BE

670
00:22:13,123 --> 00:22:14,191
MORE PRECISE THAN THAT.

671
00:22:14,191 --> 00:22:16,026
SO WE WENT BACK TO USING

672
00:22:16,026 --> 00:22:18,863
PROLEANS WHICH WORKED WELL FOR

673
00:22:18,863 --> 00:22:20,931
RSVF, FROM HANS AND HIS GROUP AT

674
00:22:20,931 --> 00:22:21,298
[INDISCERNIBLE].

675
00:22:21,298 --> 00:22:23,267
THEY ENDED UP PUTTING A PROLEAN

676
00:22:23,267 --> 00:22:25,135
BETWEEN THE CENTRAL HELIX OF

677
00:22:25,135 --> 00:22:27,271
RSVF AND THE FIRST HAD TO HAVE

678
00:22:27,271 --> 00:22:29,473
REPEAT ELEMENT AND THAT DEPENDS

679
00:22:29,473 --> 00:22:30,341
ON CONFIRMATION OF SECONDARY

680
00:22:30,341 --> 00:22:32,843
STRUCTURE AND WHEN WE LOOK AT

681
00:22:32,843 --> 00:22:34,612
THAT SAME REGION IN CORONA VIRUS

682
00:22:34,612 --> 00:22:36,514
SPIKES WE SEE IT'S HIGHLY CON7ED

683
00:22:36,514 --> 00:22:39,283
SO THESE ARE DIFFERENT BETA

684
00:22:39,283 --> 00:22:42,052
CORONA VIRUSES, DIFFERENT

685
00:22:42,052 --> 00:22:44,688
LINEAGES, HK1, MERS, SARS, THEY

686
00:22:44,688 --> 00:22:47,858
ALL HAVE 3 CONSERVED IMMUNO

687
00:22:47,858 --> 00:22:50,761
ACIDS, RLD, 2 NONCONSERVED AMINO

688
00:22:50,761 --> 00:22:51,595
ACIDS, A CONSERVED TBLIEWT MATE

689
00:22:51,595 --> 00:22:53,998
AND MOST OF IT IS CONSERVED, SO

690
00:22:53,998 --> 00:22:56,934
MY POST DOC STARTED   PERFORMING

691
00:22:56,934 --> 00:22:58,102
PROLEAN SCANNING OR MUTATING

692
00:22:58,102 --> 00:23:00,104
EACH OF THESE AMINO ACIDS FOR

693
00:23:00,104 --> 00:23:01,539
PROLEAN IN MERS AND THEN WE LOOK

694
00:23:01,539 --> 00:23:03,307
AT THE AMOUNT OF PROTEIN

695
00:23:03,307 --> 00:23:04,675
EXPRESSION, GENERALLY USING THAT

696
00:23:04,675 --> 00:23:07,077
AS A PROXY FOR IMPROVED

697
00:23:07,077 --> 00:23:09,613
STABILITY AND SO THE WILD-TYPE

698
00:23:09,613 --> 00:23:11,115
MERS SPIKE USING WILD-TYPE

699
00:23:11,115 --> 00:23:12,716
SEQUENCE, WE COULD BARELY

700
00:23:12,716 --> 00:23:14,451
PRODUCE ANY, IT'S JUST THE FAINT

701
00:23:14,451 --> 00:23:16,620
BAND BUT A SINGLE PROLEAN

702
00:23:16,620 --> 00:23:18,489
SUBSIDIARY TUITION GAVE US

703
00:23:18,489 --> 00:23:19,957
ALMOST A 20 FOLD BOOST IN

704
00:23:19,957 --> 00:23:21,091
PROTEIN EXPRESSION WHICH IS

705
00:23:21,091 --> 00:23:23,594
AMAZING BECAUSE THESE ARE 1200

706
00:23:23,594 --> 00:23:25,462
PROTEINS THAT TRIEMERRIZE THEIR

707
00:23:25,462 --> 00:23:26,530
METASTABLE, GLYCOSYLATEDDED AND

708
00:23:26,530 --> 00:23:27,731
MAINTAINING A SINGLE ACID TO

709
00:23:27,731 --> 00:23:30,167
PROLEAN COULD GIVE YOU THAT MUCH

710
00:23:30,167 --> 00:23:31,502
OF A BOOST.

711
00:23:31,502 --> 00:23:35,039
SEVERAL ON PROLEANS IN THIS

712
00:23:35,039 --> 00:23:36,574
REGION ALSO IMPROVED EXPRESSION

713
00:23:36,574 --> 00:23:38,976
AND WE HAD 2 PRO LINES THAT WE

714
00:23:38,976 --> 00:23:41,645
CALLED 2 P AND THOSE WERE THE 50

715
00:23:41,645 --> 00:23:42,780
FOLD BOOST.

716
00:23:42,780 --> 00:23:46,216
WHEN WE FIEWRIFY THESE SPIKE

717
00:23:46,216 --> 00:23:49,520
PROTEIN AND LOOK AT THEM BY

718
00:23:49,520 --> 00:23:52,256
CHROMEATOGRAPHY, THERE'S THE

719
00:23:52,256 --> 00:23:55,125
WILD STIEP, THE 2 PROLINE SPIKE,

720
00:23:55,125 --> 00:23:56,727
WILD-TYPE MERS SPIKE IS A

721
00:23:56,727 --> 00:23:58,696
MIXTURE OF PREFUSION AND POST

722
00:23:58,696 --> 00:24:00,331
FUSION THAT OVERTIME

723
00:24:00,331 --> 00:24:01,398
IRREVERSIBLY TRIGGERS AND ADOPTS

724
00:24:01,398 --> 00:24:04,435
THE POST FUSION CONFIRMATION,

725
00:24:04,435 --> 00:24:08,639
WHERE THE 2 PROLINE MERS WAS

726
00:24:08,639 --> 00:24:10,274
HOMOGENIUS PREFUSION SPIKE, WE

727
00:24:10,274 --> 00:24:15,479
SEND THIS TO BARNY AT THE LAB IN

728
00:24:15,479 --> 00:24:18,682
HIS TIME AND THEY IMMUNIZED MICE

729
00:24:18,682 --> 00:24:20,217
WITH THE 2 PROLEAN DOSE, THE

730
00:24:20,217 --> 00:24:22,086
WILD-TYPE IN BLUE OR S1 SUBUNIT

731
00:24:22,086 --> 00:24:25,189
IN ORANGE AND THEN LOOKED AT THE

732
00:24:25,189 --> 00:24:26,256
NEUTRALIZING ANTIBODY TITER SO

733
00:24:26,256 --> 00:24:27,524
HIGHER IS BETTER AND AGAIN WE

734
00:24:27,524 --> 00:24:28,859
SAW IMMUNIZING WITH THE 2

735
00:24:28,859 --> 00:24:30,894
PROLEAN FORM OF SPIKE,

736
00:24:30,894 --> 00:24:33,864
ILLICITTED A 5-10 FOLD HIGHER

737
00:24:33,864 --> 00:24:34,898
NEUTRALIZING ANTIBODY TITER THAN

738
00:24:34,898 --> 00:24:35,866
WHILED TYPE OR S1.

739
00:24:35,866 --> 00:24:37,968
IT WASN'T AS BIG AS WHAT WE SAW

740
00:24:37,968 --> 00:24:40,738
FOR RSV, BUT STILL A SIGNIFICANT

741
00:24:40,738 --> 00:24:41,138
DIFFERENCE.

742
00:24:41,138 --> 00:24:43,073
IT WAS ALSO NICE ABOUT THE

743
00:24:43,073 --> 00:24:43,974
STABILIZATION TRIP IS BECAUSE

744
00:24:43,974 --> 00:24:45,576
THE REGION IS SO WELL CONSERVED

745
00:24:45,576 --> 00:24:48,545
WE COULD PUT THE SAME 2 PROLINES

746
00:24:48,545 --> 00:24:50,547
IN ANY 2 BATTA CORONA VIRUS SO

747
00:24:50,547 --> 00:24:53,083
WE DID THIS FOR SARS FROM 2002

748
00:24:53,083 --> 00:24:55,953
AND WE COULD SEE THE WILD-TYPE

749
00:24:55,953 --> 00:25:00,357
IN RED, TO PROLINE IN BLUE,

750
00:25:00,357 --> 00:25:03,794
WILD-TYPE SARS IN PROFUSION 2

751
00:25:03,794 --> 00:25:09,933
FUSION, 2 PROLINE SARS WAS FOR

752
00:25:09,933 --> 00:25:12,336
PREFUSION, THIS WAS SUFFICIENT

753
00:25:12,336 --> 00:25:15,205
FOR THE CRYOEM STUDIES, AND WE

754
00:25:15,205 --> 00:25:17,241
CLONED A BAT CARONA VIRUS, AND

755
00:25:17,241 --> 00:25:20,878
WE HAD 1 AND SHOWED THAT THE 2

756
00:25:20,878 --> 00:25:23,447
PROLINE AND WE PUBLISHED BACK IN

757
00:25:23,447 --> 00:25:25,282
2017 AND PATENTED IT.

758
00:25:25,282 --> 00:25:27,084
WE WERE DISAPPOINTED IT GOT

759
00:25:27,084 --> 00:25:28,452
REJECTED FROM 5 JOURNALS AND SO

760
00:25:28,452 --> 00:25:29,620
THAT WAS TOUGH, NOBODY FOUND

761
00:25:29,620 --> 00:25:38,996
THIS TO BE SIGNIFICANT AND

762
00:25:38,996 --> 00:25:41,031
CORONA VIRUSES ARE REGIONALLY

763
00:25:41,031 --> 00:25:42,266
CONTAINS AND SOME OTHER THINGS

764
00:25:42,266 --> 00:25:44,034
BUT SO THAT WAS DISHEARTENING.

765
00:25:44,034 --> 00:25:53,877
SO THEN I MOVED THE LAB TO HAVE

766
00:25:53,877 --> 00:25:54,778
ACCESS TO ELECTRON MICROSCOPES,

767
00:25:54,778 --> 00:26:02,319
AND THEN IN 2018, WE HEARD ABOUT

768
00:26:02,319 --> 00:26:03,987
THE WUHAN, AND THEY HAD

769
00:26:03,987 --> 00:26:06,824
IEE, AUDIENCE DEBTIFIED IT BY

770
00:26:06,824 --> 00:26:09,693
THE NOVEL CORONA VIRUS, ON

771
00:26:09,693 --> 00:26:13,097
JANUARY 10th THEY RELEASED THE

772
00:26:13,097 --> 00:26:18,736
SEQUENCE ONLINE, AND WITHIN

773
00:26:18,736 --> 00:26:20,370
DAYS, NIANSHUANG WANG STARTED

774
00:26:20,370 --> 00:26:22,840
WORKING ON IT, AND BY AROUND

775
00:26:22,840 --> 00:26:25,275
FEBRUARY 10th OR 11th WE HAD

776
00:26:25,275 --> 00:26:27,444
SUBMITAD I MANUCRYPT TO SCIENCE

777
00:26:27,444 --> 00:26:29,747
AND BIOARCHIVE DESCRIBING THE

778
00:26:29,747 --> 00:26:31,014
STRUCTURE OF THE PROLINE 2

779
00:26:31,014 --> 00:26:31,248
SPIKES.

780
00:26:31,248 --> 00:26:34,318
WE WENT FROM A GENOME SEQUENCE

781
00:26:34,318 --> 00:26:36,019
ONLINE TO SURVEYS SUBMITTED

782
00:26:36,019 --> 00:26:37,588
MANUCRYPT IN 1 MONTH AND WE WILL

783
00:26:37,588 --> 00:26:39,223
NEVER DO THAT AGAIN.

784
00:26:39,223 --> 00:26:39,490
[LAUGHTER]

785
00:26:39,490 --> 00:26:40,758
BUT IT RESULT INDEED A SCIENCE

786
00:26:40,758 --> 00:26:42,292
PAPER, CAME BACK WITH THE

787
00:26:42,292 --> 00:26:44,161
REVIEWS IN 48 HOURS AND NO

788
00:26:44,161 --> 00:26:45,796
REVISIONS, WHICH WAS AMAZING, WE

789
00:26:45,796 --> 00:26:48,398
WERE TRENDING ON REDIT, SO THAT

790
00:26:48,398 --> 00:26:51,502
WAS MY PHONE SCREEN CAPTURE.

791
00:26:51,502 --> 00:26:53,771
THE PAPER'S BEEN CITED OVER

792
00:26:53,771 --> 00:26:56,473
10,000 TIMES SO IT'S ALL DOWN

793
00:26:56,473 --> 00:26:57,941
HILL FOR ME FROM HERE, BUT IT'S

794
00:26:57,941 --> 00:26:59,777
GOOD TO ARE A GOOD 1 AND WHAT

795
00:26:59,777 --> 00:27:01,278
WE'RE MOST EXCITED ABOUT IS ALL

796
00:27:01,278 --> 00:27:03,413
4 OF THE COVID VACCINES

797
00:27:03,413 --> 00:27:05,249
AUTHORIZED FOR USE IN THE UNITED

798
00:27:05,249 --> 00:27:07,050
STATES USED STABILIZED SPIKE

799
00:27:07,050 --> 00:27:07,284
PROTEIN.

800
00:27:07,284 --> 00:27:14,024
SO  MODERNA'S CONTAIN 986 AND 7

801
00:27:14,024 --> 00:27:16,326
AS DOES PFIZER AND BION TECH'S

802
00:27:16,326 --> 00:27:16,727
COMMUNITY.

803
00:27:16,727 --> 00:27:20,230
JOHNSON AND JOHNSON HAD THE

804
00:27:20,230 --> 00:27:22,332
ADENOVIRUS, THEY ALSO USED THE

805
00:27:22,332 --> 00:27:24,868
ON 2 PROLINES AND AS DID

806
00:27:24,868 --> 00:27:26,470
NOVAVACS, SO ANOTHER GREAT

807
00:27:26,470 --> 00:27:27,104
COLLABORATION BETWEEN ACADEMIA

808
00:27:27,104 --> 00:27:29,640
AND GOVERNMENT AND WORKING WITH

809
00:27:29,640 --> 00:27:31,308
BARNY THAT'S LED TO ANTIGENS

810
00:27:31,308 --> 00:27:33,744
BEING INCORPORATED INTO HIGHLY

811
00:27:33,744 --> 00:27:34,211
SUCCESSFUL VACCINES.

812
00:27:34,211 --> 00:27:37,047
WE THEN WENT ON TO MAKE AN EVEN

813
00:27:37,047 --> 00:27:39,616
MORE STABILIZED VERSION THAT WE

814
00:27:39,616 --> 00:27:42,119
CALLED HEXAPRO, CONTAINED 4

815
00:27:42,119 --> 00:27:45,088
ADDITIONAL PROLEANS, THAT

816
00:27:45,088 --> 00:27:46,089
SUBSTANTIALLY BOOSTS EXPRESSION

817
00:27:46,089 --> 00:27:49,426
OF 2 P, SO 2 P WE COULD MAKE A

818
00:27:49,426 --> 00:27:51,862
LITTLE BIT OF, MAYBE AROUND, 10

819
00:27:51,862 --> 00:27:55,833
NO PROBABLY MORE -- A COUPLE MIG

820
00:27:55,833 --> 00:27:58,135
DUALAS PER LITER, AND THEN

821
00:27:58,135 --> 00:27:59,937
HEXAPRO WE DID GET CLOSER, WE

822
00:27:59,937 --> 00:28:01,371
DID DETERMINE THE CRYOEM

823
00:28:01,371 --> 00:28:02,973
STRUCTURE, WASN'T MUCH OF A

824
00:28:02,973 --> 00:28:04,141
CHANGE BETWEEN HEXAPRO AND 2 P,

825
00:28:04,141 --> 00:28:08,712
THIS WAS LED BY POST DOC

826
00:28:08,712 --> 00:28:09,079
[INDISCERNIBLE].

827
00:28:09,079 --> 00:28:10,247
RATHER THAN SENDING THE PLASMA

828
00:28:10,247 --> 00:28:12,249
OUT TO A BUNCH OF LABS WE ADD

829
00:28:12,249 --> 00:28:14,084
THEM TO ADD GENE AND THEY

830
00:28:14,084 --> 00:28:15,752
DISTRIBUTED TO 227 LABS AROUND

831
00:28:15,752 --> 00:28:17,421
THE WORLD, SO A LOT OF

832
00:28:17,421 --> 00:28:19,056
RESEARCHERS USING AND WORKING ON

833
00:28:19,056 --> 00:28:21,091
CORONA VIRUS ARE USING THE 6

834
00:28:21,091 --> 00:28:22,993
PIECE SPIKE FOR STRUCTURAL

835
00:28:22,993 --> 00:28:24,294
STUDIES, ANTIBODY ISOLATION AND

836
00:28:24,294 --> 00:28:25,495
IT'S BEEN INCORPORATED INTO

837
00:28:25,495 --> 00:28:27,097
SEVERAL NEW VACCINES FOR LOW AND

838
00:28:27,097 --> 00:28:28,198
MIDDLE INCOME COUNTRIES THAT

839
00:28:28,198 --> 00:28:30,467
WERE REALLY EXCITED ABOUT, AND

840
00:28:30,467 --> 00:28:34,104
THIS IS NOW APPROVED FOR USE IN

841
00:28:34,104 --> 00:28:36,173
THAILAND THAT WAS PARTNERED WITH

842
00:28:36,173 --> 00:28:41,979
PATH, SO IT'S CALLED HXPGPO

843
00:28:41,979 --> 00:28:43,447
VACCINES AND THAT'S HEXAPRO AND

844
00:28:43,447 --> 00:28:47,751
IN MEXICO IT'S CALLED THE PAT

845
00:28:47,751 --> 00:28:53,090
RIA VACCINE, SO THAT'S USED AS A

846
00:28:53,090 --> 00:28:53,724
BOOSTER AS WELL.

847
00:28:53,724 --> 00:28:54,958
WE'VE BEEN WORKING ON VIRAL

848
00:28:54,958 --> 00:28:56,460
PROTEINS BUT WE'VE BEEN TRYING

849
00:28:56,460 --> 00:28:57,995
TO PUSH STRUCTURE BASED ANTIGEN

850
00:28:57,995 --> 00:29:00,597
DESIGN TO OTHER VIRUSES AND EVEN

851
00:29:00,597 --> 00:29:01,331
SOME BACTERIA.

852
00:29:01,331 --> 00:29:02,633
THE VIRAL FUSION PROTEINS, THE

853
00:29:02,633 --> 00:29:08,272
CLASS 1S THAT I MENTIONED, YOU

854
00:29:08,272 --> 00:29:10,274
HAVE CLASS 2s THAT GENERALLY

855
00:29:10,274 --> 00:29:11,508
-- THEY'RE A LITTLE DIFFERENT.

856
00:29:11,508 --> 00:29:14,011
SOMETIMES THEY START OFF AS

857
00:29:14,011 --> 00:29:15,178
DIMERS, TETRAMERS, HIGHER ORDER

858
00:29:15,178 --> 00:29:16,813
AND THEN GO THROUGH AN

859
00:29:16,813 --> 00:29:17,948
INTERMEDIATE AND THEN END UP AS

860
00:29:17,948 --> 00:29:22,219
A FOAOF THE FUSION MOLECULE LIKE

861
00:29:22,219 --> 00:29:26,590
FLAVI VIRUSES AND BUNYA VIRUSES,

862
00:29:26,590 --> 00:29:30,260
AND THEN CLASS 3 LIKE HERPES

863
00:29:30,260 --> 00:29:31,895
VIRUSES, AND I WAS GOING TO TALK

864
00:29:31,895 --> 00:29:33,030
ABOUT WORK IN CLASS 2.

865
00:29:33,030 --> 00:29:34,698
ONE OF THE VIRUSES THAT WE'VE

866
00:29:34,698 --> 00:29:37,267
BEEN FOCUSING ON IS USING THE

867
00:29:37,267 --> 00:29:41,204
CLASS 2 VERSION PROTEINS IS THE

868
00:29:41,204 --> 00:29:41,705
HEMORRHAGIC FEVER FIELD

869
00:29:41,705 --> 00:29:43,674
FUNCTIONS HAVE YOU SEEN, THIS IS

870
00:29:43,674 --> 00:29:46,209
THE MOST WIDE SPREAD TICK-BORNE

871
00:29:46,209 --> 00:29:47,544
INFECTION IN HUMANS, IT USES THE

872
00:29:47,544 --> 00:29:49,379
HARD BODY TICKS AS THE VECTOR.

873
00:29:49,379 --> 00:29:50,681
GENERALLY THE LIFE CYCLE

874
00:29:50,681 --> 00:29:52,115
INVOLVES THE SMALL MAMMALS AND

875
00:29:52,115 --> 00:29:58,188
BIRDS IT CAN EVENTUALLY GET ON

876
00:29:58,188 --> 00:29:59,256
LIVESTOCK AND UNDULATES, THE

877
00:29:59,256 --> 00:30:01,425
INFECTION IN THESE ANIMALS

878
00:30:01,425 --> 00:30:02,960
CAUSES A TRANSIENT VIREMIA, THE

879
00:30:02,960 --> 00:30:05,062
ANIMALS DON'T GET SICK BUT WHEN

880
00:30:05,062 --> 00:30:07,831
HUMANS GET INFECTED YOU GET A

881
00:30:07,831 --> 00:30:10,367
HEMONNAGIC FEVER WITH A CASE

882
00:30:10,367 --> 00:30:11,835
FATALITY RATE OF 10-40%.

883
00:30:11,835 --> 00:30:14,371
SO WE'RE NOT NORMALLY PART OF

884
00:30:14,371 --> 00:30:16,473
ITS LIFE CYCLE, WE'RE MORE OF A

885
00:30:16,473 --> 00:30:17,774
DEAD END HOST BUT IT

886
00:30:17,774 --> 00:30:19,643
PARTICULARLY BAD FOR HUMANS AND

887
00:30:19,643 --> 00:30:21,111
THE INDEMMIC ZONES ARE

888
00:30:21,111 --> 00:30:21,445
EXPANDING.

889
00:30:21,445 --> 00:30:24,314
THERE'S BEEN SOME CASES IN

890
00:30:24,314 --> 00:30:26,416
EUROPE, SPAIN AND ITALY AND IN

891
00:30:26,416 --> 00:30:28,652
PART DUE TO INCREASING

892
00:30:28,652 --> 00:30:34,491
TEMPERATURES, MIEG RATTERY BIRDS

893
00:30:34,491 --> 00:30:42,599
AND LIVESTOCK TRADE. 

894
00:30:42,599 --> 00:30:44,134
CCHFV BELONGS TO THE VIRUS AND

895
00:30:44,134 --> 00:30:46,470
THESE ARE A MAJOR FOCUS OF SOME

896
00:30:46,470 --> 00:30:49,339
OF THE INITIATIVES FUNDED BY

897
00:30:49,339 --> 00:30:51,775
NIAID, LIKE THESE REVAMP GRANTS

898
00:30:51,775 --> 00:30:54,011
THAT WE'RE A PART OF AND TRY TO

899
00:30:54,011 --> 00:30:56,880
GENERATE MORE, TOOLS REAGENTS,

900
00:30:56,880 --> 00:30:59,983
ANTIBODY ANDS VACCINES FOR BUNYA

901
00:30:59,983 --> 00:31:02,452
VIRUSES, THESE ARE TRI SEGMENTED

902
00:31:02,452 --> 00:31:03,854
VIRUSES, THESE GENOMES ARE TRI

903
00:31:03,854 --> 00:31:05,255
SEGMENTED THEY HAVE SMALL,

904
00:31:05,255 --> 00:31:07,791
MEDIUM AND LARGE GENOME

905
00:31:07,791 --> 00:31:08,725
SEQUENTS.

906
00:31:08,725 --> 00:31:12,162
THE MEDIUM SEGMENT ENCODES THE

907
00:31:12,162 --> 00:31:15,399
GLYCOPROTEIN PRECURSOR COMPLEX.

908
00:31:15,399 --> 00:31:20,137
AND SO, FOR HANTA VIRUSES, IT

909
00:31:20,137 --> 00:31:21,638
HAS THE RELATIVELY SIMPLE

910
00:31:21,638 --> 00:31:24,007
SEGMENT CAN HAS THE M-PROTEIN

911
00:31:24,007 --> 00:31:27,644
AND GC, GC IS THE VIRAL FUSION

912
00:31:27,644 --> 00:31:30,313
MEMBRANE, AND GN IS AN ACCESSORY

913
00:31:30,313 --> 00:31:32,049
PROTEIN THAT HELPS KEEP GC IN

914
00:31:32,049 --> 00:31:33,917
THE PREFUSION STATE AND

915
00:31:33,917 --> 00:31:36,219
SOMETIMES INVOLVED IN RECEPTOR

916
00:31:36,219 --> 00:31:38,989
BINDING BUT FOR CCHFV, THE

917
00:31:38,989 --> 00:31:40,657
SEGMENT IS MORE COMPLICATED.

918
00:31:40,657 --> 00:31:42,659
IT STILL HAS GC WHICH IS THE

919
00:31:42,659 --> 00:31:44,961
CONSERVED FUSION PROTEIN, IT HAS

920
00:31:44,961 --> 00:31:47,064
NSN, SMALLER GN, PROTEIN CALLED

921
00:31:47,064 --> 00:31:50,200
GP38 THAT WAS THOUGHT TO BE A

922
00:31:50,200 --> 00:31:52,169
SECRETED MOLECULE AND THEN A

923
00:31:52,169 --> 00:31:53,070
MUSEON LIKE DOMAIN.

924
00:31:53,070 --> 00:31:54,971
SO WE'VE BEEN WORKING PART OF

925
00:31:54,971 --> 00:31:55,772
THIS LARGE CONSORTIUM, I WILL

926
00:31:55,772 --> 00:31:58,775
SHOW YOU A PICTURE CALLED

927
00:31:58,775 --> 00:32:00,043
PROMETHUOUS, FUNDED BY U19 TO

928
00:32:00,043 --> 00:32:01,945
REALLY TRY TO UNDERSTAND AND GET

929
00:32:01,945 --> 00:32:03,580
MORE STRUCTURES AND ANTIBODIES

930
00:32:03,580 --> 00:32:06,283
IN CREATE ANTIGENS FOR CCHFV, 1

931
00:32:06,283 --> 00:32:09,719
OF THE INTERESTING THINGS ABOUT

932
00:32:09,719 --> 00:32:14,558
BUNYA VIRUSES IS THAT THE GNG C

933
00:32:14,558 --> 00:32:15,992
DIMERS OLIGMERRIZE TO HIGHER

934
00:32:15,992 --> 00:32:17,194
ORDER STATES.

935
00:32:17,194 --> 00:32:19,096
SO WE CAN SEE FOR THE VIRUSES

936
00:32:19,096 --> 00:32:23,066
THESE WILL END UP FORMING THESE

937
00:32:23,066 --> 00:32:26,203
TRI PORTAL COMPLEXES FOR JUNTA

938
00:32:26,203 --> 00:32:30,507
VIRUSES GN AND GC FORM TETRAMERS

939
00:32:30,507 --> 00:32:34,377
AND THOSE TETRAMERS FORM

940
00:32:34,377 --> 00:32:35,445
LATTICES.

941
00:32:35,445 --> 00:32:38,115
FOR FLAVIVIRUSES YOU GET

942
00:32:38,115 --> 00:32:38,748
PENTAMERS AND HEXAMERS, 1 THING

943
00:32:38,748 --> 00:32:41,518
WE DON'T KNOW IS WHAT THE HIGHER

944
00:32:41,518 --> 00:32:44,054
ORDER IS FOR CCHFV, WE'RE STILL

945
00:32:44,054 --> 00:32:46,189
TRYING TO ANALYZE THAT, WE CAN'T

946
00:32:46,189 --> 00:32:48,125
DIRECTLY VISUALIZE IT UNDER THE

947
00:32:48,125 --> 00:32:50,026
MICROSCOPE, THERE WAS A GROUP IN

948
00:32:50,026 --> 00:32:52,629
2018 THAT PUBLISHED USING HAZARA

949
00:32:52,629 --> 00:32:55,665
VIRUS WHICH IS RELATED TO CCHFV,

950
00:32:55,665 --> 00:32:56,967
BUT ONLY EFFECTS ANIMALS BUT IT

951
00:32:56,967 --> 00:32:58,068
WAS SO DIFFICULT TO TELL, IF

952
00:32:58,068 --> 00:33:00,337
THERE WAS A HIGHER ORDER ASSEM

953
00:33:00,337 --> 00:33:02,472
MYELIN, SO THAT'S STILL AN

954
00:33:02,472 --> 00:33:03,306
UNKNOWN QUESTION.

955
00:33:03,306 --> 00:33:05,742
THIS IS THE PROMETHUOUS GROUP,

956
00:33:05,742 --> 00:33:09,346
SO IT WAS A CEDR, LED BY

957
00:33:09,346 --> 00:33:10,147
[INDISCERNIBLE]'S GROUP AT

958
00:33:10,147 --> 00:33:11,715
ALBERT EINSTEIN AND WE'VE BEEN

959
00:33:11,715 --> 00:33:14,885
WORKING TOGETHER FOR 5 YEARS NOW

960
00:33:14,885 --> 00:33:16,486
AND I THINK I'VE REALLY HELPED

961
00:33:16,486 --> 00:33:17,587
PUSH THE FIELD FORWARD AND

962
00:33:17,587 --> 00:33:19,122
CREATED A LOT OF INTERESTING

963
00:33:19,122 --> 00:33:22,259
REAGENTS AND INSIGHT INTOS THE

964
00:33:22,259 --> 00:33:22,492
CCHFV.

965
00:33:22,492 --> 00:33:26,263
SOME OF THE INITIAL WORK WE'RE

966
00:33:26,263 --> 00:33:29,733
EXCITED WITH, MOSTLY WITH CAR

967
00:33:29,733 --> 00:33:31,635
TECH, MAP BIOAND ADAM AB, THEY

968
00:33:31,635 --> 00:33:35,205
WERE ABLE TO ISOLATE 361

969
00:33:35,205 --> 00:33:42,746
MONOCLONAL ANTIBODIES FROM 4

970
00:33:42,746 --> 00:33:44,247
CCHFV UGANDAN DONEARS, MORE THAN

971
00:33:44,247 --> 00:33:46,016
75% OF THEM WERE GC SPECIFIC,

972
00:33:46,016 --> 00:33:48,518
WHEREAS SOME WERE ABLE TO BIND

973
00:33:48,518 --> 00:33:49,619
THIS PROTEIN CALLED GP38, WHICH

974
00:33:49,619 --> 00:33:54,224
IS THOUGHT TO BE SECRETED.

975
00:33:54,224 --> 00:33:55,825
LAURA'S GROUP   PERFORMED YEAST

976
00:33:55,825 --> 00:33:57,627
BASED COMPETITION BINDING

977
00:33:57,627 --> 00:34:00,864
STUDIES AND THEY WERE ABLE TO

978
00:34:00,864 --> 00:34:03,400
IDENTIFY 6 ANTIGENIC SITES WITH

979
00:34:03,400 --> 00:34:07,704
ANTIGENIC SITE 1 BEING THE MOST

980
00:34:07,704 --> 00:34:09,072
DOMINANT.

981
00:34:09,072 --> 00:34:13,076
COMPARED TO SMALLER NUMBERS FOR

982
00:34:13,076 --> 00:34:15,245
THE ANTIGENIC SITES.

983
00:34:15,245 --> 00:34:17,714
NUMEROUS SITES WERE POLARIZING

984
00:34:17,714 --> 00:34:20,584
AND OTHER 38 ANTIBODIES WERE

985
00:34:20,584 --> 00:34:20,984
NONNEUTRALLIZING.

986
00:34:20,984 --> 00:34:23,587
THESE WERE THEN TESTED AT USAM

987
00:34:23,587 --> 00:34:27,524
RID, ANDREW HERBERT'S GROUP, AND

988
00:34:27,524 --> 00:34:29,626
THE LEAD NEUTRALIZING

989
00:34:29,626 --> 00:34:30,961
ANTIBODIESS AND COMBINATIONS AND

990
00:34:30,961 --> 00:34:34,297
WERE ABLE TO AFFORD PROPHYLACTIC

991
00:34:34,297 --> 00:34:36,700
PROTECTION BUT NOT THERAPEUTIC

992
00:34:36,700 --> 00:34:37,634
PROTECTION FROM CHALLENGE.

993
00:34:37,634 --> 00:34:39,102
THESE ARE MOUSE EXPERIMENTS AND

994
00:34:39,102 --> 00:34:47,611
YOU HAVE TO DO THESE WITH IFNAR,

995
00:34:47,611 --> 00:34:50,013
YOU CAN SEE IF THESE ARE GIVEN,

996
00:34:50,013 --> 00:34:52,949
IF THE ANTIBODIES WERE GIVEN 1

997
00:34:52,949 --> 00:34:54,751
DAY BEFORE CHALLENGE THEN THESE

998
00:34:54,751 --> 00:34:55,785
NEUTRALIZING ANTIBODIES WERE

999
00:34:55,785 --> 00:34:57,053
ABLE TO PROTECT, BUT IF THEY

1000
00:34:57,053 --> 00:35:00,123
WERE GIVEN 1 DAY AFTER THEN

1001
00:35:00,123 --> 00:35:03,693
THERE'S VERY LITTLE PROTECTION

1002
00:35:03,693 --> 00:35:04,261
THAT WAS AFFORDED.

1003
00:35:04,261 --> 00:35:06,429
BUT STILL IN TERMS OF PROVE LAX

1004
00:35:06,429 --> 00:35:07,897
EXCITATORY THESE COULD BE

1005
00:35:07,897 --> 00:35:09,666
INTERESTING ANTIBODIES TO MAYBE

1006
00:35:09,666 --> 00:35:11,601
HELP PROTECT PEOPLE WHO ARE

1007
00:35:11,601 --> 00:35:13,236
GOING INTO AND OUTBREAK OF AN

1008
00:35:13,236 --> 00:35:15,438
INDEMMIC ZONE, IT WAS REALLY BS

1009
00:35:15,438 --> 00:35:18,308
SIGHTING IS JOHN'S GROUP PART OF

1010
00:35:18,308 --> 00:35:19,709
THE CONSORTIUM CREATED A BI

1011
00:35:19,709 --> 00:35:20,710
SPECIFIC ANTIBODY AND THEY TOOK

1012
00:35:20,710 --> 00:35:22,746
2 OF THE BEST ANTIBODIES, 1

1013
00:35:22,746 --> 00:35:24,481
AGAINST SITE 3, AND 1 AGAINST

1014
00:35:24,481 --> 00:35:28,818
SITE 1 AND THEY MADE THIS DUAL

1015
00:35:28,818 --> 00:35:31,821
V-DOMAIN CHIMERA AND

1016
00:35:31,821 --> 00:35:33,523
INTERESTINGLY, THIS BY SPECIFIC

1017
00:35:33,523 --> 00:35:35,759
WAS PROTECTIVE WHEN GIVEN 1 DAY

1018
00:35:35,759 --> 00:35:38,928
AFTER CHALLENGE AND SO, WE'RE

1019
00:35:38,928 --> 00:35:41,331
VERY EXCITED BY THE SPECIFIC AND

1020
00:35:41,331 --> 00:35:43,099
THEY'RE WORKING UP METHODS OF

1021
00:35:43,099 --> 00:35:44,134
PRODUCING IT IN SCALE.

1022
00:35:44,134 --> 00:35:45,802
BUT WE WANT TO UNDERSTAND THE

1023
00:35:45,802 --> 00:35:47,671
MECHANISM BEHIND THE ANTIBODIES

1024
00:35:47,671 --> 00:35:49,272
WERE NEUTRALIZING AND PERHAPS

1025
00:35:49,272 --> 00:35:51,708
THE BASIS OF THE SYNERGY, SO A

1026
00:35:51,708 --> 00:35:53,376
GRAD STUDENT IN MY GROUP AT THE

1027
00:35:53,376 --> 00:35:55,178
TIME [INDISCERNIBLE] WAS ABLE TO

1028
00:35:55,178 --> 00:35:56,246
CRYSTALLIZE THE INDIVIDUAL FABS

1029
00:35:56,246 --> 00:35:59,115
AS WELL AS COMPLEX OF THE GC

1030
00:35:59,115 --> 00:36:01,484
PROTEIN BOUND TO EACH OF THOSE 2

1031
00:36:01,484 --> 00:36:03,253
SITE 1 AND SITE 3 ANTIBODIES.

1032
00:36:03,253 --> 00:36:05,722
AND SO IN THIS CASE WE SAW A GC,

1033
00:36:05,722 --> 00:36:08,391
WE WERE JUST GETTING A MONOMERIC

1034
00:36:08,391 --> 00:36:09,292
FORM OF GC.

1035
00:36:09,292 --> 00:36:11,494
WE ALSO WERE PUT IN TOUCH WITH

1036
00:36:11,494 --> 00:36:13,630
FELIX RAY'S GROUP WHO WE HEARD

1037
00:36:13,630 --> 00:36:15,298
HAD A POST FUSION TRI MERRIC

1038
00:36:15,298 --> 00:36:17,500
STRUCTURE OF GC SO WE COMBINED

1039
00:36:17,500 --> 00:36:19,369
FORCES TO MAKE 1 NICE MANUSCRIPT

1040
00:36:19,369 --> 00:36:21,137
TO PROVIDE MORE INSIGHT INTO THE

1041
00:36:21,137 --> 00:36:23,139
GC PROTEIN, WE COULD SEE THE

1042
00:36:23,139 --> 00:36:26,076
MONOMERIC FORM, THERE'S A DOMAIN

1043
00:36:26,076 --> 00:36:27,010
MISSING DOMAIN 3 WE COULD

1044
00:36:27,010 --> 00:36:29,145
OBSERVE BUT IN THE POST FUSION

1045
00:36:29,145 --> 00:36:31,448
TRIEMER, THIS FLIPS AROUND AND

1046
00:36:31,448 --> 00:36:33,583
HELPS STABILIZE THE LOW ENERGY

1047
00:36:33,583 --> 00:36:34,117
POST FUSION STATE.

1048
00:36:34,117 --> 00:36:35,819
IF WE LOOK AT THE SITE 1

1049
00:36:35,819 --> 00:36:37,554
ANTIBODIES WHICH WERE MOST

1050
00:36:37,554 --> 00:36:39,055
IMMUNO DOMINANT, THESE RECOGNIZE

1051
00:36:39,055 --> 00:36:40,590
THE FUSION LOOPS, SO FOR THE

1052
00:36:40,590 --> 00:36:42,659
CLASS 1S, THEY HAVE A FUSION

1053
00:36:42,659 --> 00:36:47,197
PEPTIDE, WHICH SHOOTS INTO THE

1054
00:36:47,197 --> 00:36:48,932
MEMBRANE, FOR CLASS 2S THEY

1055
00:36:48,932 --> 00:36:51,434
CONTAIN 2 OR 3 LOOPS THAT HAVE

1056
00:36:51,434 --> 00:36:54,337
HIDE O PHOBIC ACIDS LIKE

1057
00:36:54,337 --> 00:36:55,505
TRYPTOPHAN AND [INDISCERNIBLE],

1058
00:36:55,505 --> 00:36:56,873
THAT WILL INSERT INTO THE OUTER

1059
00:36:56,873 --> 00:36:58,675
LEAF OF THE MEMBRANE.

1060
00:36:58,675 --> 00:37:00,276
WHAT'S INTERESTING THAT THE

1061
00:37:00,276 --> 00:37:01,211
FUSION LOOPS THEMSELVES CAN

1062
00:37:01,211 --> 00:37:02,479
EXIST IN A PREFUSION AND POST

1063
00:37:02,479 --> 00:37:03,613
FUSION STATE.

1064
00:37:03,613 --> 00:37:06,383
SO THIS WAS -- WE CAN LOOK AT

1065
00:37:06,383 --> 00:37:08,551
THE STRUCTURES FROM A PORTAL

1066
00:37:08,551 --> 00:37:11,621
VIRUS WHICH IS A JUNTA VIRUS,

1067
00:37:11,621 --> 00:37:12,589
THAT THEY DETERMINED STRUCTURES

1068
00:37:12,589 --> 00:37:14,090
OF AND YOU CAN SEE THAT THE GC

1069
00:37:14,090 --> 00:37:15,492
FUSION LOOP ANDS IN THE POST

1070
00:37:15,492 --> 00:37:18,695
FUSION STATE HAD ALL THE

1071
00:37:18,695 --> 00:37:22,031
HYDROPHOBIC RESIDUES STICKS OUT,

1072
00:37:22,031 --> 00:37:23,066
THE TRYPTOPHANS, READY TO INSERT

1073
00:37:23,066 --> 00:37:24,834
IN THE MEMBRANE BUT IN THEIR

1074
00:37:24,834 --> 00:37:28,204
PREFUSION STRAWKURE BOUND TO GN,

1075
00:37:28,204 --> 00:37:30,740
NOW THE FEIGNAL ALANINE IS IN

1076
00:37:30,740 --> 00:37:32,909
THIS POSITION AND THE TRYPTOPHAN

1077
00:37:32,909 --> 00:37:34,644
HAS MOVED DOWN SO IT HAS

1078
00:37:34,644 --> 00:37:37,947
REPACKED THE LOOPS AND HIDE THE

1079
00:37:37,947 --> 00:37:38,681
HYDROPHOBIC RESIDUES.

1080
00:37:38,681 --> 00:37:41,017
SO WE SAW IN THE POST FUSION TRI

1081
00:37:41,017 --> 00:37:42,185
MERRIC STRUCTURE, THE FUSION

1082
00:37:42,185 --> 00:37:45,021
LOOPS WERE IN THE POST

1083
00:37:45,021 --> 00:37:46,322
FUSIONITATE, BUT THE ANTIBODY

1084
00:37:46,322 --> 00:37:47,891
THAT WAS POTENTLY NEUTRALIZING

1085
00:37:47,891 --> 00:37:50,360
IS ACTUALLY RECOGNIZING THE POST

1086
00:37:50,360 --> 00:37:52,796
FUSION CONFIRMATION OF THESE

1087
00:37:52,796 --> 00:37:53,863
FUSION LOOPS SUGGESTING IT'S

1088
00:37:53,863 --> 00:37:57,467
ENGAGING THE FUSION LOOPS AFTER

1089
00:37:57,467 --> 00:37:58,601
GN HAS DISASSOCIATED BUT PRIOR

1090
00:37:58,601 --> 00:38:01,137
TO FUSION IN THE LOOPS IN THE

1091
00:38:01,137 --> 00:38:03,173
TARGET CELL MEMBRANE.

1092
00:38:03,173 --> 00:38:05,475
ANTIBODY 36121, WHICH IS AGAINST

1093
00:38:05,475 --> 00:38:09,245
ANTIGEN EXCITE 3 AND MOST OF THE

1094
00:38:09,245 --> 00:38:11,080
OTHER ANTIGENIC SITES FOR NOW,

1095
00:38:11,080 --> 00:38:13,616
THESE BIND THE MONOMERBUT ARE

1096
00:38:13,616 --> 00:38:15,919
INCOMPATIBLE WITH THE BOINDING

1097
00:38:15,919 --> 00:38:17,620
POST FUSION TRIEMER, SO IF THE

1098
00:38:17,620 --> 00:38:19,022
ANTIBODY IS BOUND, THE OTHER

1099
00:38:19,022 --> 00:38:19,856
PROTEIN COMPLEX MERS CANNOT

1100
00:38:19,856 --> 00:38:20,323
BIND.

1101
00:38:20,323 --> 00:38:23,460
THERE WILL BE SUBSTANTIAL

1102
00:38:23,460 --> 00:38:24,661
CLASSES AND SO ULTIMATELY YOU

1103
00:38:24,661 --> 00:38:27,664
THINK THAT YOU GET GN'S

1104
00:38:27,664 --> 00:38:28,364
ASSOCIATION, GC REFOLDING,

1105
00:38:28,364 --> 00:38:29,899
INSERTION OF THE FUSION LOOPS AT

1106
00:38:29,899 --> 00:38:34,604
THE TARGET CELL MEMBRANE,

1107
00:38:34,604 --> 00:38:36,239
COLLAPSE OF THE PREINTERMEDIATE

1108
00:38:36,239 --> 00:38:37,407
AND ADOPTION OF THE POST FUSION

1109
00:38:37,407 --> 00:38:39,042
STATE AND THESE ANTIBODIES ARE

1110
00:38:39,042 --> 00:38:40,443
TARGETING 2 DIFFERENT STEPS OF

1111
00:38:40,443 --> 00:38:43,146
THE FUSION PROCESS, THE SITE 1

1112
00:38:43,146 --> 00:38:44,948
ANTIBODIES COMBINED THE RELEASED

1113
00:38:44,948 --> 00:38:47,283
LOOPS AFTER THEY REFOLD INTO THE

1114
00:38:47,283 --> 00:38:49,385
POST FUSION CONFIRMATION, THIS

1115
00:38:49,385 --> 00:38:50,987
WILL PREVENT MEMBRANE INSERTION

1116
00:38:50,987 --> 00:38:52,956
AND THE SITE 3 WOULD PREVENT THE

1117
00:38:52,956 --> 00:38:55,158
ASSEMBLY OF THE HIGHLY STABLE

1118
00:38:55,158 --> 00:38:56,793
POST FUSION CONFIRMATION, SO

1119
00:38:56,793 --> 00:38:58,061
YOU'RE TARGETING DIFFERENT STEPS

1120
00:38:58,061 --> 00:39:01,898
AND PERHAPS THAT'S WHY WE'RE

1121
00:39:01,898 --> 00:39:02,398
GETTING SYNERGY.

1122
00:39:02,398 --> 00:39:04,667
WE STILL HAVE BEEN TRYING TO DO

1123
00:39:04,667 --> 00:39:06,202
MORE WORK ON ASSEMBLING

1124
00:39:06,202 --> 00:39:10,106
STRUCTURES OF THE LARGER COMPLEX

1125
00:39:10,106 --> 00:39:10,940
FOR CCHFV, BACK THIS 2020 WE

1126
00:39:10,940 --> 00:39:12,942
ALSO SAW THE STRUCTURE OF GP38

1127
00:39:12,942 --> 00:39:14,544
BUT THAT DIDN'T PROVIDE A LOT OF

1128
00:39:14,544 --> 00:39:14,811
INSIGHTS.

1129
00:39:14,811 --> 00:39:16,346
WE WERE HOPING IT WOULD LOOK

1130
00:39:16,346 --> 00:39:17,614
LIKE SOMETHING AND PROVIDE

1131
00:39:17,614 --> 00:39:20,316
FUNCTION BUT IT DID NOT.

1132
00:39:20,316 --> 00:39:21,584
AGAIN, IT'S THOUGHT TO BE

1133
00:39:21,584 --> 00:39:25,488
SECRETED AND IS THE TARGET OF

1134
00:39:25,488 --> 00:39:26,789
PROTECTED BUT NONNEUTRALLIZING

1135
00:39:26,789 --> 00:39:28,391
ANTIBODYINGS AND SO WE TRIED TO

1136
00:39:28,391 --> 00:39:29,592
GET STRUCTURES OF GN AND A

1137
00:39:29,592 --> 00:39:30,660
COMPLEX OF ALL OF THESE TOGETHER

1138
00:39:30,660 --> 00:39:33,496
AND A HIGHER ORDER OF OLIGMERRIC

1139
00:39:33,496 --> 00:39:34,764
STATE, ALPHA FOLD 2 COMING OUT

1140
00:39:34,764 --> 00:39:37,967
WAS A REALLY BIG ADVANCE AND

1141
00:39:37,967 --> 00:39:39,269
FELIX PUBLISHED A NICE REVIEW ON

1142
00:39:39,269 --> 00:39:40,470
THIS WHERE THEY USE ALPHA FOLD

1143
00:39:40,470 --> 00:39:43,706
AND SHOWED THAT THE STRUCTURE OF

1144
00:39:43,706 --> 00:39:45,575
JUNTA VIRUS GN WOULD LOOK VERY

1145
00:39:45,575 --> 00:39:49,546
SIMILAR TO THE ALPHA 2 FOLD 2

1146
00:39:49,546 --> 00:39:52,782
MODEL, OF CCHFV GN AND PLUS

1147
00:39:52,782 --> 00:39:55,351
GP38, SO GP38 ISN'T JUST A

1148
00:39:55,351 --> 00:39:56,352
SECRETED PROTEIN, IT'S ACTUALLY

1149
00:39:56,352 --> 00:39:59,422
SORT OF GN LIKE, BUT ULTIMATELY

1150
00:39:59,422 --> 00:40:00,523
GETS CUT AND DISASSOCIATES.

1151
00:40:00,523 --> 00:40:04,527
SO WE WANTED TO TEST THIS MODEL,

1152
00:40:04,527 --> 00:40:05,895
SO ELIZABETH MCFADDEN A GRAD

1153
00:40:05,895 --> 00:40:09,599
STUDENT IN MY LAB, SHE USED THE

1154
00:40:09,599 --> 00:40:12,168
AF2 MODEL TO IDENTIFY AND DESIGN

1155
00:40:12,168 --> 00:40:13,870
A STABILIZING DISULPHIDE BOND

1156
00:40:13,870 --> 00:40:16,439
THAT WOULD LINK GN IN ORANGE TO

1157
00:40:16,439 --> 00:40:17,340
GP38 IN BLUE.

1158
00:40:17,340 --> 00:40:19,042
ALL RIGHT, WE MADE THIS

1159
00:40:19,042 --> 00:40:22,345
CONSTRUCT, SO WE WOULD EXPRESS

1160
00:40:22,345 --> 00:40:26,282
THIS PROTEIN, THE SELECT CRYPTS

1161
00:40:26,282 --> 00:40:28,618
AND SINGLE BAN FOR GP38 AND GN

1162
00:40:28,618 --> 00:40:30,320
WHICH WE COULD SEE THERE.

1163
00:40:30,320 --> 00:40:32,622
IF WE ADDED IN PREDICTED

1164
00:40:32,622 --> 00:40:33,790
DISULPHIDE BOND THEN WE GOT A

1165
00:40:33,790 --> 00:40:36,993
VERY LARGE BOOST IN PROTEIN

1166
00:40:36,993 --> 00:40:37,627
EXPRESSION INDICATING THAT THE

1167
00:40:37,627 --> 00:40:38,995
DISULPHIDE IS FORMING AND THAT

1168
00:40:38,995 --> 00:40:40,330
THE MODEL IN THAT REGION IS

1169
00:40:40,330 --> 00:40:43,166
LIKELY TO BE CORRECT.

1170
00:40:43,166 --> 00:40:45,034
WE WOULD THEN ENGINEER AN IRPT

1171
00:40:45,034 --> 00:40:47,570
FERON SITE THAT WOULD ALLOW

1172
00:40:47,570 --> 00:40:50,974
CLEAVAGE BETWEEN GP38 AND GN, SO

1173
00:40:50,974 --> 00:40:53,076
ON A NONREDUCING GEL, WE COULD

1174
00:40:53,076 --> 00:40:59,582
SEE 2 BANDS FOR GP38, AND THEN

1175
00:40:59,582 --> 00:41:00,917
ON THE NONREDUCING GEL, WE

1176
00:41:00,917 --> 00:41:02,785
SHOWED THAT IT WAS FORMING AND

1177
00:41:02,785 --> 00:41:04,420
WITHOUT THE DISULPHIDE BOND IN

1178
00:41:04,420 --> 00:41:06,189
ALLOWING CLEAVAGE TO, OCCUR WE

1179
00:41:06,189 --> 00:41:09,058
GET NO EXPRESSION SO IT'S VERY

1180
00:41:09,058 --> 00:41:13,696
UNSTABLE, JUST GP38 AND GN

1181
00:41:13,696 --> 00:41:14,530
WITHOUT THE STABILIZING BOND.

1182
00:41:14,530 --> 00:41:16,232
INTERESTINGLY THE PROTEIN IS

1183
00:41:16,232 --> 00:41:18,735
QUITE STABLE, THE GP38

1184
00:41:18,735 --> 00:41:21,404
DISULPHIDE BOND HAD A MELTING

1185
00:41:21,404 --> 00:41:22,705
TIP OF AROUND 60-DEGREES.

1186
00:41:22,705 --> 00:41:24,674
ENTIOUS LIZ BETH WAS ABLE TO

1187
00:41:24,674 --> 00:41:26,643
CRYSTALLIZE AND SOLVE THE

1188
00:41:26,643 --> 00:41:28,144
STRUCTURE OF GP38 N AND THEN WE

1189
00:41:28,144 --> 00:41:29,879
WANT OFFICE OF DIVERSITY TO GET

1190
00:41:29,879 --> 00:41:32,181
THE FULL COMPLEX WITH GC AND WE

1191
00:41:32,181 --> 00:41:34,617
TOOK THE APPROACH THAT FELIX'S

1192
00:41:34,617 --> 00:41:37,620
GROUP USED FOR JUNTA VIRUS WHERE

1193
00:41:37,620 --> 00:41:41,024
THEY LINK WITH A GLIESER LINKER

1194
00:41:41,024 --> 00:41:42,525
AND WHICH COULD BE CLEAVED AND

1195
00:41:42,525 --> 00:41:45,228
THEN WE ADD A DISULPHIDE BOND

1196
00:41:45,228 --> 00:41:48,431
AND ADD GC, AND HAD A MELTING

1197
00:41:48,431 --> 00:41:53,636
TEMP OF AROUND  65-DEGREES AND

1198
00:41:53,636 --> 00:41:56,839
ALLOWED ELIZABETH TO SHOW THE

1199
00:41:56,839 --> 00:41:58,307
STRUCTURES OF GM, CPC, 38 AND

1200
00:41:58,307 --> 00:41:59,308
IMPORTANTLY SOME OF THE

1201
00:41:59,308 --> 00:42:01,310
ANTIBODIES WE HAD ISOLATED

1202
00:42:01,310 --> 00:42:02,378
PREVIOUSLY, WERE USED HERE TO

1203
00:42:02,378 --> 00:42:06,649
ADD SOME MASS AND HELP IMPROVE

1204
00:42:06,649 --> 00:42:08,584
SIGNAL IN CONTRAST SO WE COULD

1205
00:42:08,584 --> 00:42:09,185
GET THE STRUCTURE.

1206
00:42:09,185 --> 00:42:11,554
WHAT IT SHOW SYSTEM THAT GN IS

1207
00:42:11,554 --> 00:42:14,757
WEDGED IN BETWEEN GP38 AND GC,

1208
00:42:14,757 --> 00:42:19,228
AND OVERALL THE GP38, GN FOR

1209
00:42:19,228 --> 00:42:25,535
CCHFV LOOKS LIKE JUNTA VIRUS GN,

1210
00:42:25,535 --> 00:42:27,403
INTERESTINGLY WHERE IN JUNTA

1211
00:42:27,403 --> 00:42:29,105
VIRUS THEY USE THIS LOOP TO HELP

1212
00:42:29,105 --> 00:42:32,275
COVER THE FUSION LOOPS FROM GC,

1213
00:42:32,275 --> 00:42:34,811
HERE AT AN NLIFE LINK GLYCAN

1214
00:42:34,811 --> 00:42:36,312
THAT'S EMANATING OUT FROM GN

1215
00:42:36,312 --> 00:42:39,082
THAT INTERACTING WITH AND

1216
00:42:39,082 --> 00:42:40,349
STABILIZES THE HYDROPHOBIC

1217
00:42:40,349 --> 00:42:42,085
FUSION RESIDUES OF GC WHICH WE

1218
00:42:42,085 --> 00:42:45,922
THOUGHT WAS REALLY INTERESTING

1219
00:42:45,922 --> 00:42:47,990
AND THEN ELIZABETH MADE A MOVIE

1220
00:42:47,990 --> 00:42:49,625
TO SHOW THE PREFUSION AND POST

1221
00:42:49,625 --> 00:42:50,359
FUSION DYNAMICS AND STATE.

1222
00:42:50,359 --> 00:42:51,728
SO CAN YOU START TO APPRECIATE

1223
00:42:51,728 --> 00:42:54,697
HOW EVEN JUST THESE LOOPS CAN

1224
00:42:54,697 --> 00:42:56,399
STILL UNDERGO CONFIRMATIONAL

1225
00:42:56,399 --> 00:42:57,800
CHANGE IN BOTH HIGH AND THEN

1226
00:42:57,800 --> 00:43:00,470
EXPOSE THE FUSION RESIDUES AND

1227
00:43:00,470 --> 00:43:01,003
HYDROPHOBIC RESIDUES FOR

1228
00:43:01,003 --> 00:43:03,806
INSERTION INTO THE TARGET CELL

1229
00:43:03,806 --> 00:43:06,809
MEMBRANE. 

1230
00:43:06,809 --> 00:43:10,012
WE THEN WORKED WITH SIDE WHAT

1231
00:43:10,012 --> 00:43:11,447
AND SHELLY'S GROUP TO IMMUNIZE

1232
00:43:11,447 --> 00:43:14,183
THESE PROTEIN ANDS SEE HOW THEY

1233
00:43:14,183 --> 00:43:14,383
WORK.

1234
00:43:14,383 --> 00:43:16,986
SO HERE WE'RE USING C57 MICE

1235
00:43:16,986 --> 00:43:19,188
WITH THE ANTIBODY AGAINST AN

1236
00:43:19,188 --> 00:43:19,622
INTERFERON RECEPTOR.

1237
00:43:19,622 --> 00:43:21,090
THERE'S A PRIME BOOST FOLLOWED

1238
00:43:21,090 --> 00:43:23,226
BY A CHALLENGE.  AND WHAT WE SAW

1239
00:43:23,226 --> 00:43:25,795
WAS THAT ALL THE PROTEINS WITH

1240
00:43:25,795 --> 00:43:28,431
GP38, PROVIDED SOME PARTIAL

1241
00:43:28,431 --> 00:43:33,402
PROTECTION, LIKE 40%, GC ALONE,

1242
00:43:33,402 --> 00:43:34,570
DESPITE ILLICITTING NEUTRALIZED

1243
00:43:34,570 --> 00:43:35,772
ANTIBODIES DOES NOT PROVIDE A

1244
00:43:35,772 --> 00:43:37,273
LOT OF PROTECTION, WHEN WE LOOK

1245
00:43:37,273 --> 00:43:39,242
MORE CLOSELY, AND WE LOOK AT

1246
00:43:39,242 --> 00:43:41,544
THOSE GROUPS, AND THEIR ABILITY

1247
00:43:41,544 --> 00:43:43,880
TO ILLICIT GP38 AND THE BINDING

1248
00:43:43,880 --> 00:43:45,281
ANTIBODIES ARE ENGINEERED

1249
00:43:45,281 --> 00:43:49,552
CONSTRUCT IN PINK THE

1250
00:43:49,552 --> 00:43:51,621
HETEROTRIEMER THAT WE GOT THE

1251
00:43:51,621 --> 00:43:54,957
STRUCTURE ON, WORKED REALLY WELL

1252
00:43:54,957 --> 00:43:57,226
ON ELICITING GP38 ANTIBODIES AND

1253
00:43:57,226 --> 00:44:00,463
4 OUT OF 5 MICE THAT ILLICITTED

1254
00:44:00,463 --> 00:44:01,998
STRONG ANTIBODY RESPONSES

1255
00:44:01,998 --> 00:44:02,665
SURVIVED, WHEREAS 4 DIDN'T.

1256
00:44:02,665 --> 00:44:04,534
SO WE THINK THIS IMMUNOGEN IS

1257
00:44:04,534 --> 00:44:06,402
DOING SOMETHING AND IF WE CAN

1258
00:44:06,402 --> 00:44:07,770
IMPROVE AND GET A BETTER

1259
00:44:07,770 --> 00:44:09,272
RESPONSE FROM ALL THE MICE WE

1260
00:44:09,272 --> 00:44:11,607
CAN GET UP TO 80 OR NIEBT%

1261
00:44:11,607 --> 00:44:14,010
PRODUCTION EMPLOY SO TO

1262
00:44:14,010 --> 00:44:16,679
SUMMARIZE THE WORK ON CCHFV,

1263
00:44:16,679 --> 00:44:18,581
THIS BIG CONSORTIUM THAT'S

1264
00:44:18,581 --> 00:44:21,117
ENDING ALTHOUGH WILL BE

1265
00:44:21,117 --> 00:44:23,085
REINCARNATED UNDER A NEW U19

1266
00:44:23,085 --> 00:44:25,822
CALLED REVAMP, WE'VE BEEN ABLE

1267
00:44:25,822 --> 00:44:29,158
TO ISOLATE GN, GC, NO GN

1268
00:44:29,158 --> 00:44:30,760
ISOLATED TO DATE BECAUSE THAT'S

1269
00:44:30,760 --> 00:44:34,330
BECAUSE GN IS SMALL RELATIVE, -

1270
00:44:34,330 --> 00:44:36,699
IT'S WEDGED BETWEEN GP38 AND GC,

1271
00:44:36,699 --> 00:44:40,169
WE DETERMINED STRUCTURES OF

1272
00:44:40,169 --> 00:44:41,737
GP38, GC, HETEROTRIEMER, WE

1273
00:44:41,737 --> 00:44:43,005
THINK THIS SUGGESTS THAT GP 38

1274
00:44:43,005 --> 00:44:45,141
IS NOT JUST A SECRETED PROTEIN,

1275
00:44:45,141 --> 00:44:47,109
IT ACTUALLY IS A STRUCTURAL

1276
00:44:47,109 --> 00:44:50,646
PROTEIN INITIALLY AND THEN AFTER

1277
00:44:50,646 --> 00:44:52,682
PROTEOLYSIS, GP 38, DISSOCIATES

1278
00:44:52,682 --> 00:44:55,451
FROM GN AND THEN GP 38 MAY HAVE

1279
00:44:55,451 --> 00:44:57,653
AN ADDITIONAL ROLE WORKING WITH

1280
00:44:57,653 --> 00:45:00,189
HARRIS' GROUP, SHE SHOWED IT IS

1281
00:45:00,189 --> 00:45:02,225
SIMILAR TO DENGUE NS1 AND

1282
00:45:02,225 --> 00:45:04,227
PRODUCES VASCULAR LEAK AND MAYBE

1283
00:45:04,227 --> 00:45:07,563
THAT'S WHY ANTIBODIES TARGETING

1284
00:45:07,563 --> 00:45:08,965
GP38 ARE NONNEUTRALLIZING BUT

1285
00:45:08,965 --> 00:45:09,866
PROTECTIVE.

1286
00:45:09,866 --> 00:45:11,434
WEAVER CONTINUING TO ENGINEER

1287
00:45:11,434 --> 00:45:13,603
THE HETEROTRIEMER AS A VACCINE

1288
00:45:13,603 --> 00:45:15,771
ASPECT GEN, DIFFERENT WAYS OF

1289
00:45:15,771 --> 00:45:17,073
THE DISPLAYING IT, WE'RE STILL

1290
00:45:17,073 --> 00:45:19,508
TRYING TO CHARACTERIZE THE

1291
00:45:19,508 --> 00:45:21,077
HIGHER ORDER OLIGMERRIZATION

1292
00:45:21,077 --> 00:45:23,346
STATE FOR KRRK CHFV, CLIEK O

1293
00:45:23,346 --> 00:45:25,715
PROTEINS AND IMPORTANTLY WE NOW

1294
00:45:25,715 --> 00:45:26,649
HAVE THESE ANTIGENS AS NEW

1295
00:45:26,649 --> 00:45:30,086
PROBES TO GO BACK AND TRY TO

1296
00:45:30,086 --> 00:45:32,355
ISOLATE ANTIBODIES THAT MAYBE

1297
00:45:32,355 --> 00:45:35,925
BRIDGE ACROSS GC, GN AND GP38

1298
00:45:35,925 --> 00:45:37,560
THAT COULD USEFUL

1299
00:45:37,560 --> 00:45:37,960
PROPHYLACTICALLY.

1300
00:45:37,960 --> 00:45:40,196
ADDITIONALLY WE DOING A LOT OF

1301
00:45:40,196 --> 00:45:44,867
WORK WITH FUNDING FROM SEPE, NEW

1302
00:45:44,867 --> 00:45:47,503
ARP A-H GRANT AND TRYING TO

1303
00:45:47,503 --> 00:45:49,372
DEVELOP THESE ANTIGEN LIBRARIES

1304
00:45:49,372 --> 00:45:54,877
FOR DISEASE X, ARP A-H IS MORE

1305
00:45:54,877 --> 00:46:02,051
FOR HE WERIES VIRUSES, CEPI IS

1306
00:46:02,051 --> 00:46:04,420
WORKING TO MAKE MORE OF THESE,

1307
00:46:04,420 --> 00:46:06,088
AND CREATING THESE ANTIGENS,

1308
00:46:06,088 --> 00:46:07,690
CREATING THEM TESTING THEM AND

1309
00:46:07,690 --> 00:46:08,257
HAVING THEM READY.

1310
00:46:08,257 --> 00:46:10,359
MUCH LIKE WHAT WE DID WITH MERS

1311
00:46:10,359 --> 00:46:12,795
AND HAVING THE 2 P READY FOR

1312
00:46:12,795 --> 00:46:15,097
SARS-COV-2, WE WANT TO IDENTIFY

1313
00:46:15,097 --> 00:46:15,598
STABILIZING SUBSIDIARY

1314
00:46:15,598 --> 00:46:16,999
CONSTITUTIONS THAT COULD BE USED

1315
00:46:16,999 --> 00:46:19,568
WHEN THE NEXT VIRUS SPILLS OVER.

1316
00:46:19,568 --> 00:46:24,340
WORKING WITH JIMMY GOLLIHAR, WE

1317
00:46:24,340 --> 00:46:25,408
MADE STABILIZING PROTEINS FOR

1318
00:46:25,408 --> 00:46:27,276
ALL THESE DIFFERENT VIRUSES AND

1319
00:46:27,276 --> 00:46:28,744
VIRAL ANTIIENS AND SO IN LESS

1320
00:46:28,744 --> 00:46:32,214
THAN 1 YEAR WE MADE 8 VIRAL

1321
00:46:32,214 --> 00:46:32,915
GLYCOPROTEINS AND OVER 32

1322
00:46:32,915 --> 00:46:33,783
VARIANT VS BEEN ARK ASSESSESSED

1323
00:46:33,783 --> 00:46:35,952
AND WE HAVE MANY MORE IN THE CUE

1324
00:46:35,952 --> 00:46:36,986
NOW.

1325
00:46:36,986 --> 00:46:38,521
SO I HIGHLIGHTED A LOT OF PEOPLE

1326
00:46:38,521 --> 00:46:42,191
IN MY LAB, AGAIN THIS HAS BEEN

1327
00:46:42,191 --> 00:46:43,693
REALLY COLLABORATIVE, WITH GREAT

1328
00:46:43,693 --> 00:46:44,827
COLLABORATION WITH BARNY GRAHAM

1329
00:46:44,827 --> 00:46:47,163
AND COLLEAGUES AT THE VACCINE

1330
00:46:47,163 --> 00:46:47,964
RESEARCH CENTER, ANDREW WARD'S

1331
00:46:47,964 --> 00:46:51,133
GROUP FOR THE INITIAL WORK ON

1332
00:46:51,133 --> 00:46:53,402
CRYOEM OF HK1.

1333
00:46:53,402 --> 00:46:55,671
ALTHOUGH THE PROMETHUOUS,

1334
00:46:55,671 --> 00:46:58,441
COLLEAGUES, IN THE CCHFV GROUP

1335
00:46:58,441 --> 00:47:00,776
EMPLOY GENEROUS NIH FUNDING

1336
00:47:00,776 --> 00:47:01,143
RO-1S AND U19S.

1337
00:47:01,143 --> 00:47:01,844
THANK YOU VERY MUCH FOR YOUR

1338
00:47:01,844 --> 00:47:06,449
ATTENTION AND HAPPY TO TAKE ANY

1339
00:47:06,449 --> 00:47:06,716
QUESTIONS.

1340
00:47:06,716 --> 00:47:09,118
[ APPLAUSE ]

1341
00:47:09,118 --> 00:47:10,252
>> THANK YOU.

1342
00:47:10,252 --> 00:47:10,820
TOUR DEFORCE INDEED.

1343
00:47:10,820 --> 00:47:12,421
ANY QUESTIONS FROM THE AUDIENCE,

1344
00:47:12,421 --> 00:47:15,124
NOTHING HAS WOMAN IN ONLINE YET.

1345
00:47:15,124 --> 00:47:18,527
>> THAT MAY HAVE BEEN MORE

1346
00:47:18,527 --> 00:47:20,863
STRUCTURED --

1347
00:47:20,863 --> 00:47:28,704
>> [LAUGHTER]

1348
00:47:28,704 --> 00:47:29,872
>> HELLO, GREAT TALK, SO I
HAVE

1349
00:47:29,872 --> 00:47:31,707
A QUESTION FOR YOUR ANTIBODIES

1350
00:47:31,707 --> 00:47:36,445
THAT TARGET POST FUSION?

1351
00:47:36,445 --> 00:47:39,048
>> ONLY POST FUSION OR
ONLY --

1352
00:47:39,048 --> 00:47:40,149
>> POST FUSION IS THAT
HAPPENING

1353
00:47:40,149 --> 00:47:44,820
OUTSIDE THE CELL, WHEN THE CELL

1354
00:47:44,820 --> 00:47:48,657
IS INFECTED, ENDO ZONE, RECEPTOR

1355
00:47:48,657 --> 00:47:50,860
BINDING WHEN THOSE ARE POSED?

1356
00:47:50,860 --> 00:47:52,328
>> GOOD QUESTION.

1357
00:47:52,328 --> 00:47:53,863
ANTIBODIES THAT ALSO BIND POST,

1358
00:47:53,863 --> 00:47:56,632
THEY BIND PREAS WELL, THAT'S WHY

1359
00:47:56,632 --> 00:47:57,433
THEY'RE NEUTRALIZING IS BECAUSE

1360
00:47:57,433 --> 00:47:59,168
OF THE ACTIVITY TO BIND PRE, AND

1361
00:47:59,168 --> 00:48:01,237
WE THINK THOSE ARE BINDING

1362
00:48:01,237 --> 00:48:02,405
PREFUSIONOT SURFACE OF THE

1363
00:48:02,405 --> 00:48:02,671
VARIANTS.

1364
00:48:02,671 --> 00:48:04,407
SOME OF THE OTHER 1S MAY BE MORE

1365
00:48:04,407 --> 00:48:06,142
INTERESTING IF THEY'RE BINDING

1366
00:48:06,142 --> 00:48:08,444
-- LIKE EPITOPES THAT BECOME

1367
00:48:08,444 --> 00:48:09,845
TRANSIENTLY EXPOSED AND IN SOME

1368
00:48:09,845 --> 00:48:12,014
CASES THERE ARE SOME VIRUSES

1369
00:48:12,014 --> 00:48:13,215
WHERE MAYBE THEY NEED TO BE

1370
00:48:13,215 --> 00:48:16,519
TAKEN UP IN THE ENDOSOME, AND

1371
00:48:16,519 --> 00:48:17,586
CLEAVAGE OCCURS AND SO IN THAT

1372
00:48:17,586 --> 00:48:19,989
CASE YOU NEED THE ANTIBODY TO

1373
00:48:19,989 --> 00:48:23,492
GET TAKEN UP INTO THE ENDOSOME,

1374
00:48:23,492 --> 00:48:26,529
SO I'M ALSO THINK OF EBOLA, AND

1375
00:48:26,529 --> 00:48:27,797
[INDISCERNIBLE] GROUP HAS DONE

1376
00:48:27,797 --> 00:48:28,864
SOME SPECIFICS WHERE 1 ARM BINDS

1377
00:48:28,864 --> 00:48:30,833
AND THE OTHER ARM IS READY ONCE

1378
00:48:30,833 --> 00:48:32,735
IT'S TAKEN UP IN THE ENDOSOME,

1379
00:48:32,735 --> 00:48:33,702
WHICH IS KIND OF INTERESTING, SO

1380
00:48:33,702 --> 00:48:35,571
I THINK A LOT OF COOL ANTIBODY

1381
00:48:35,571 --> 00:48:38,107
ENGINEERING COULD BE APPLIED

1382
00:48:38,107 --> 00:48:38,340
HERE.

1383
00:48:38,340 --> 00:48:45,347
>> YEAH, REALLY GOOD TALK.

1384
00:48:45,347 --> 00:48:49,185
AND YOU SHOWED IN CCHFV, PREDICT

1385
00:48:49,185 --> 00:48:52,121
1 STATE CLOSE TO THE REAL

1386
00:48:52,121 --> 00:48:53,255
STRUCTURE SO I WONDER BECAUSE

1387
00:48:53,255 --> 00:48:55,224
YOU HAVE ALREADY HAD PREFUSION,

1388
00:48:55,224 --> 00:48:58,060
POST FUSION, CAN ALPHA FOLD

1389
00:48:58,060 --> 00:49:01,330
PREDICT BOTH IN KNOWN VIRUSES?

1390
00:49:01,330 --> 00:49:02,465
>> GREAT QUESTION.

1391
00:49:02,465 --> 00:49:04,066
IT DEPENDS A LITTLE BIT.

1392
00:49:04,066 --> 00:49:05,468
PEOPLE HAVE CREATED SOME MODELS

1393
00:49:05,468 --> 00:49:07,703
WHERE YOU USE TEMPLATES TO HELP

1394
00:49:07,703 --> 00:49:08,104
BIAS IT.

1395
00:49:08,104 --> 00:49:11,574
BUT THEN YOU'RE KIND OF BIASING

1396
00:49:11,574 --> 00:49:14,977
IT, YEAH, SO ON ITS OWN, IT MAY

1397
00:49:14,977 --> 00:49:18,280
PICK A PREOR A POST OR WE'VE

1398
00:49:18,280 --> 00:49:20,149
SEEN IT CAN PROVIDE LIKE A

1399
00:49:20,149 --> 00:49:21,450
CHIMERA, WHICH SOME OF THE

1400
00:49:21,450 --> 00:49:22,952
SECONDARY STRUCTURES IS MORE IN

1401
00:49:22,952 --> 00:49:24,753
PREAND OTHERS HAVE FLIPPED OUT

1402
00:49:24,753 --> 00:49:27,623
AND ARE MORE IN POST.

1403
00:49:27,623 --> 00:49:30,226
YEAH, THAT HAS BEEN A LIMITATION

1404
00:49:30,226 --> 00:49:31,460
BUY-IN THAT WILL PROBABLY

1405
00:49:31,460 --> 00:49:32,761
IMPROVE AS MORE STRUCTURES ARE

1406
00:49:32,761 --> 00:49:34,930
AVAILABLE AND THE TEMPLATES DO

1407
00:49:34,930 --> 00:49:37,099
HELP BIAS IT IN THAT DIRECTION

1408
00:49:37,099 --> 00:49:39,635
EMPLOY THE GOAL FOR CEPI IS TO

1409
00:49:39,635 --> 00:49:42,204
GO FROM A NOVEL VIRUS SPILLING

1410
00:49:42,204 --> 00:49:44,640
OVER, THE SEQUENCE BEING

1411
00:49:44,640 --> 00:49:45,841
ICE'SALATED, ALPHA FOLD

1412
00:49:45,841 --> 00:49:47,877
STRUCTURALLY STRUCTURES OF ALL

1413
00:49:47,877 --> 00:49:50,679
THE DEFINITE STATES, AI ML BASED

1414
00:49:50,679 --> 00:49:56,385
SUBSTITUTION IDEBTICTION AND MR

1415
00:49:56,385 --> 00:49:57,186
NA MANUFACTURING WITHOUT EVER

1416
00:49:57,186 --> 00:49:59,088
GOING INTO A WET LAB.

1417
00:49:59,088 --> 00:50:00,356
>> FUTURE.

1418
00:50:00,356 --> 00:50:04,026
>> FUTURE. 

1419
00:50:04,026 --> 00:50:04,960
>> YEAH, MEMBRANES,
MEMBRANES,

1420
00:50:04,960 --> 00:50:06,095
THE MEMBRANES OF THE CELLULAR

1421
00:50:06,095 --> 00:50:08,264
MEMBRANES AND THE CELL AND THE

1422
00:50:08,264 --> 00:50:11,767
ENDO PLASMA, MEMBRANE THEY HAVE

1423
00:50:11,767 --> 00:50:12,301
DIFFERENT [INDISCERNIBLE]

1424
00:50:12,301 --> 00:50:13,869
>> THE VIRAL MEMBRANES
COME FROM

1425
00:50:13,869 --> 00:50:14,870
THE CELL MEMBRANES, THEY'RE

1426
00:50:14,870 --> 00:50:17,406
PULLED, THAT'S WHERE THE VIRUS

1427
00:50:17,406 --> 00:50:19,175
GETS THE MEMBRANE.

1428
00:50:19,175 --> 00:50:21,043
>> AND THE PEPTIDE
EMBEDDED INTO

1429
00:50:21,043 --> 00:50:26,782
THESE MEMBRANES, NOW HAS A

1430
00:50:26,782 --> 00:50:28,050
LENGTH OF ABOUT 16, 17 OR

1431
00:50:28,050 --> 00:50:30,686
SOMETHING LIKE THAT BUT IF YOU

1432
00:50:30,686 --> 00:50:37,092
HAVE GO INTO OTHER MEMBRANE, AND

1433
00:50:37,092 --> 00:50:37,993
IN THE [INDISCERNIBLE], THERE'S

1434
00:50:37,993 --> 00:50:40,095
SMALL LENGTH IF YOU EXTENDED

1435
00:50:40,095 --> 00:50:42,498
LENGTH THE PROTEIN WILL GO TO

1436
00:50:42,498 --> 00:50:43,799
THE CELL SURFACE MEMBRANE SO

1437
00:50:43,799 --> 00:50:45,100
THAT IS IMPORTANT TO BE TAKEN

1438
00:50:45,100 --> 00:50:48,137
INTO CONSIDERATION, WHAT IS THE

1439
00:50:48,137 --> 00:50:48,871
MEMBRANE [INDISCERNIBLE] OR THE

1440
00:50:48,871 --> 00:50:51,140
THICKNESS OF THE MEMBRANE?

1441
00:50:51,140 --> 00:50:52,575
>> YEAH, I WOULD SAY, MOST
OF

1442
00:50:52,575 --> 00:50:54,843
ALL OF THESE STRUCTURES I'VE

1443
00:50:54,843 --> 00:50:57,880
PRESENTED HAVE BEEN FROM SOLUBLE

1444
00:50:57,880 --> 00:51:00,082
ECTODOMAINS, WE'RE NOW DOING

1445
00:51:00,082 --> 00:51:02,518
MORE STRUCTURESOT SURFACE OF

1446
00:51:02,518 --> 00:51:03,352
VESICLES OR VIRUSES THEMSELVES

1447
00:51:03,352 --> 00:51:05,287
AND WE'RE STARTING TO SEE THE

1448
00:51:05,287 --> 00:51:07,590
TMs AND MAYBE EVEN SOME BOUND

1449
00:51:07,590 --> 00:51:08,791
LIPIDS AND THINGS INTO THE

1450
00:51:08,791 --> 00:51:10,092
PROTEIN SO WE'RE EXCITED TO

1451
00:51:10,092 --> 00:51:11,327
MOVE,A WAY FROM PURIFIED PROTEIN

1452
00:51:11,327 --> 00:51:14,396
ANDS INTO MORE OF THE NATIVE

1453
00:51:14,396 --> 00:51:14,630
CONTEXT.

1454
00:51:14,630 --> 00:51:15,064
>> OKAY.

1455
00:51:15,064 --> 00:51:17,166
>> QUESTION FROM THE SOUTH
SIDE

1456
00:51:17,166 --> 00:51:17,933
HERE.

1457
00:51:17,933 --> 00:51:21,770
>> SO IT MAKES PERFECT
SENSE

1458
00:51:21,770 --> 00:51:23,405
THAT LOCKING THE PREFUSION

1459
00:51:23,405 --> 00:51:25,341
DOMAIN FROM INTERACTING WITH THE

1460
00:51:25,341 --> 00:51:27,409
RECEPTOR ON THE INFECTED CELL

1461
00:51:27,409 --> 00:51:28,510
PROFESSIONAL INTEGRITY PREVENTS

1462
00:51:28,510 --> 00:51:29,745
INFECTION BUT WHAT ACTUALLY

1463
00:51:29,745 --> 00:51:32,948
HAPPENS TO THE VIRUS THAT IS

1464
00:51:32,948 --> 00:51:38,754
CODED WITH THE ANTIPREFUSION

1465
00:51:38,754 --> 00:51:39,788
ANTIBODIES.

1466
00:51:39,788 --> 00:51:41,657
DOES THAT GET FAIG O

1467
00:51:41,657 --> 00:51:42,958
SIGNIFYITOSED, REPRESENTED AS

1468
00:51:42,958 --> 00:51:44,460
CROSS PRESENTED ANTIIENS AS

1469
00:51:44,460 --> 00:51:44,693
WELL?

1470
00:51:44,693 --> 00:51:46,362
>> YEAH, WE KNOW THEY CAN
GET

1471
00:51:46,362 --> 00:51:49,331
TAKEN UP BY MACROPHAGES, IT CAN

1472
00:51:49,331 --> 00:51:52,468
ALSO BE ENDOSIGNIFYITOSED AND

1473
00:51:52,468 --> 00:51:52,801
DESTROYED.

1474
00:51:52,801 --> 00:51:55,104
THERE MAY BE OTHER OUTCOMES.

1475
00:51:55,104 --> 00:51:56,672
>> DO THEY CAUSE RENAL
PROBLEMS?

1476
00:51:56,672 --> 00:52:00,409
>> THAT I DO NOT KNOW.

1477
00:52:00,409 --> 00:52:03,045
>> I DO HAVE A QUESTION
ONLINE.

1478
00:52:03,045 --> 00:52:04,880
I NOTICE THAD YOUR GROUP DIDN'T

1479
00:52:04,880 --> 00:52:10,419
TRY TO TACKLE THE HIV 1 ENV

1480
00:52:10,419 --> 00:52:12,087
PROTEIN, ENVELOPE, WHICH IS ALSO

1481
00:52:12,087 --> 00:52:13,322
A CLASS 1 FUSION PEPTIDE, IS

1482
00:52:13,322 --> 00:52:15,491
THERE A REASON FOR THAT?

1483
00:52:15,491 --> 00:52:16,625
>> BECAUSE THERE'S ALREADY
GREAT

1484
00:52:16,625 --> 00:52:18,260
INVESTIGATORS WORKING ON IT HERE

1485
00:52:18,260 --> 00:52:20,796
AT THE VACCINE RESEARCH CENTER

1486
00:52:20,796 --> 00:52:23,399
AND ELSEWHERE, SO WE TRY TO

1487
00:52:23,399 --> 00:52:25,267
MAYBE GO TO SOME FIELDS THAT

1488
00:52:25,267 --> 00:52:27,436
PEOPLE AREN'T WORKING ON OR ARE

1489
00:52:27,436 --> 00:52:28,537
A LITTLE UNDERSTUDIED RATHER

1490
00:52:28,537 --> 00:52:30,039
THAN COMPETING WITH THE HEAVY

1491
00:52:30,039 --> 00:52:31,307
WEIGHTS FOR HIV AND UNIVERSAL

1492
00:52:31,307 --> 00:52:33,542
FLU AND SOME OF MY COLLEAGUES

1493
00:52:33,542 --> 00:52:34,710
HERE.

1494
00:52:34,710 --> 00:52:36,278
>> OKAY, VERY WELL.

1495
00:52:36,278 --> 00:52:39,248
>> DIPLOMATIC ANSWER.

1496
00:52:39,248 --> 00:52:39,882
>> DR. SHORE?

1497
00:52:39,882 --> 00:52:41,984
>> YEAH, WONDERFUL TALK.

1498
00:52:41,984 --> 00:52:45,421
I'M JUST WONDERING, SO YOU'VE

1499
00:52:45,421 --> 00:52:50,259
SHOWN LOTS OF DATA DERIVED FROM

1500
00:52:50,259 --> 00:52:51,860
SEQUENTIAL EXPERIMENTS WITH

1501
00:52:51,860 --> 00:52:53,495
DIFFERENT CONFIGURURATIONS OF

1502
00:52:53,495 --> 00:52:57,099
THE VARIOUS PROTEINS, CAN YOU

1503
00:52:57,099 --> 00:52:59,034
NOW USE THAT INFORMATION THAT

1504
00:52:59,034 --> 00:53:02,237
YOU'VE GAINED TO GO BACK AND A

1505
00:53:02,237 --> 00:53:06,875
PRIORI LOOK AT A GIVEN PROTEIN

1506
00:53:06,875 --> 00:53:08,377
AND PREDICT WHICH

1507
00:53:08,377 --> 00:53:10,512
CONFIGURURATION WILL BE MOST

1508
00:53:10,512 --> 00:53:12,381
IMMUNOGENIC IN A DIFFERENT

1509
00:53:12,381 --> 00:53:14,249
VIRUS, OR DO YOU -- EACH TIME

1510
00:53:14,249 --> 00:53:15,784
YOU WORK WITH A VIRUS, DO YOU

1511
00:53:15,784 --> 00:53:18,420
HAVE TO GO THROUGH THE SAME

1512
00:53:18,420 --> 00:53:19,755
SEQUENCE OF EXPERIMENTS?

1513
00:53:19,755 --> 00:53:23,325
>> YEAH, I THINK IT STILL
HAS TO

1514
00:53:23,325 --> 00:53:24,760
BE DONE IM  PERICALLY, THE

1515
00:53:24,760 --> 00:53:26,295
IMMUNE SYSTEM IS TOO MUCHAVE

1516
00:53:26,295 --> 00:53:27,463
BLACK BOX, PEOPLE ARE TRYING TO

1517
00:53:27,463 --> 00:53:29,331
COME UP WITH AI BASED IMMUNE

1518
00:53:29,331 --> 00:53:31,166
SYSTEM AND THINGS BUT EVEN THEN

1519
00:53:31,166 --> 00:53:33,702
-- YOU KNOW DIFFERENT ANIMALS IN

1520
00:53:33,702 --> 00:53:34,436
THEIR REPERTOIRES COULD BE

1521
00:53:34,436 --> 00:53:34,903
DIFFERENT.

1522
00:53:34,903 --> 00:53:36,338
SO I THINK YOU REALLY HAVE TO

1523
00:53:36,338 --> 00:53:36,939
TEST IT OUT.

1524
00:53:36,939 --> 00:53:39,441
IDEALLY WE WOULD LIKE TO USE

1525
00:53:39,441 --> 00:53:40,876
ANTIBODIES AS THE GUIDE, RIGHT?

1526
00:53:40,876 --> 00:53:43,445
AND SO, THAT WORKS VERY WELL

1527
00:53:43,445 --> 00:53:45,981
WITH RSV IN PARTICULAR, GROUPS

1528
00:53:45,981 --> 00:53:47,349
ALREADY ISOLATED PREFUSION

1529
00:53:47,349 --> 00:53:48,517
SPECIFIC ANTIBODIES, WE KNEW

1530
00:53:48,517 --> 00:53:49,585
THEY WERE SUPER POTENT AND THE

1531
00:53:49,585 --> 00:53:52,721
GOAL IS TRYING TO ILLICIT THEM.

1532
00:53:52,721 --> 00:53:54,456
FOR THESE OTHER PATHOIENS IT'S

1533
00:53:54,456 --> 00:53:57,292
HARD TO GENERATE ANTIBODIES FROM

1534
00:53:57,292 --> 00:53:58,894
OR GET CONVALESCENT DONOR SO WE

1535
00:53:58,894 --> 00:54:02,431
HAVE TO START OVER, I THINK TEST

1536
00:54:02,431 --> 00:54:02,931
IM  PERICALLY.

1537
00:54:02,931 --> 00:54:04,900
AND THEN SOMETIMES YOU DON'T

1538
00:54:04,900 --> 00:54:07,136
KNOW -- MAYBE 1 FORM TESTSAs A

1539
00:54:07,136 --> 00:54:08,437
SUBPROTEIN UNIT COULD GIVE A

1540
00:54:08,437 --> 00:54:10,305
DEFINITE RESULT AS AN MRNA

1541
00:54:10,305 --> 00:54:11,707
DELIVERED SO I THINK YOU NEED TO

1542
00:54:11,707 --> 00:54:14,109
TEST IT WITH DIFFERENT

1543
00:54:14,109 --> 00:54:15,144
MODALITIES, DIFFERENT DELIVERY

1544
00:54:15,144 --> 00:54:16,345
ADJUVANTS AND TEASE IT APART.

1545
00:54:16,345 --> 00:54:18,347
WE ALSO THINK THAT REGARDLESS OF

1546
00:54:18,347 --> 00:54:19,715
WHAT THE OPTIMAL ANTIGEN IS,

1547
00:54:19,715 --> 00:54:22,885
IT'S PROBABLY NOT WHAT NATURE

1548
00:54:22,885 --> 00:54:24,420
EVOLVED, SO NATURE'S EVOLVING IT

1549
00:54:24,420 --> 00:54:25,821
TO FUNCTION OR NOT EVOLVING IT

1550
00:54:25,821 --> 00:54:28,290
TO BE AN OPTIMAL ANTIGEN SO WE

1551
00:54:28,290 --> 00:54:29,925
THINK WE SHOULD BE ABLE TO DO

1552
00:54:29,925 --> 00:54:31,460
BETTER THAN NATURE, WE SHOULD BE

1553
00:54:31,460 --> 00:54:32,594
ABLE TO BRING ANTIGEN

1554
00:54:32,594 --> 00:54:33,562
ENGINEERING AND PROVIDE BENEFIT,

1555
00:54:33,562 --> 00:54:35,431
AND IT MAY NOT ALWAYS BE PRE,

1556
00:54:35,431 --> 00:54:38,700
BUT WE NEED A LOT OF IMMUNOLOGY

1557
00:54:38,700 --> 00:54:40,035
AND VIROLOGY AND THAT'S WHY THE

1558
00:54:40,035 --> 00:54:41,503
WORK IS SO COLLABORATIVE.

1559
00:54:41,503 --> 00:54:44,573
>> THANK YOU.

1560
00:54:44,573 --> 00:54:45,240
>> THANKS.

1561
00:54:45,240 --> 00:54:46,675
>> HI, JASON, THE FUSION
PEPTIDE

1562
00:54:46,675 --> 00:54:48,377
IS SO IMPORTANT YOU KNOW BASED

1563
00:54:48,377 --> 00:54:50,813
ON ALL YOUR STRUCTURE ANALYSIS,

1564
00:54:50,813 --> 00:54:53,215
AND IT'S ALSO QUITE CONSERVED,

1565
00:54:53,215 --> 00:54:55,951
SO WHY HAVEN'T WE SEEN THE

1566
00:54:55,951 --> 00:54:57,786
FUSION PEPTIDE FOR THE ANTIBODY

1567
00:54:57,786 --> 00:55:01,190
IN ALL KINDS OF SAY CLASS 1

1568
00:55:01,190 --> 00:55:01,790
VIRUSES.

1569
00:55:01,790 --> 00:55:04,092
SHOULD WE SEE MORE OFTEN OF THIS

1570
00:55:04,092 --> 00:55:05,561
TYPE OF ANTIBODY?

1571
00:55:05,561 --> 00:55:06,495
>> YEAH, GOOD QUESTION,
YOU KNOW

1572
00:55:06,495 --> 00:55:08,163
-- I THINK PART OF IT DEPENDS

1573
00:55:08,163 --> 00:55:09,698
PERHAPS ON THE LOCATION OF THE

1574
00:55:09,698 --> 00:55:12,634
FUSION PEPTIDE AND THE PREFUSION

1575
00:55:12,634 --> 00:55:12,968
STATE.

1576
00:55:12,968 --> 00:55:14,069
SO FOR HIV ENVELOPE AS YOU KNOW,

1577
00:55:14,069 --> 00:55:17,739
IT'S MORE ON THE LATERAL SIDE,

1578
00:55:17,739 --> 00:55:19,741
SOMEWHAT EXPOSED, THAT'S TRUE

1579
00:55:19,741 --> 00:55:22,845
FOR CORONA VIRUSES, PARAMIX O

1580
00:55:22,845 --> 00:55:24,613
VIRUSES FOR RSVF, IT'S VARIED

1581
00:55:24,613 --> 00:55:26,815
INSIDE SO IT'S REALLY ONLY

1582
00:55:26,815 --> 00:55:27,282
TRANSIENTLY EXPOSED.

1583
00:55:27,282 --> 00:55:29,485
I WOULD SAY THE B-CELLS HAVE A

1584
00:55:29,485 --> 00:55:30,919
VERY SMALL WINDOW BETWEEN AFTER

1585
00:55:30,919 --> 00:55:33,121
THE VIRUS HAS ATTACHED AND THEN

1586
00:55:33,121 --> 00:55:34,690
YOU HAVE TRIGGERING SO I THINK

1587
00:55:34,690 --> 00:55:37,526
FOR RSV, YOU MAY NOT SEE A LOT

1588
00:55:37,526 --> 00:55:37,893
OF THEM.

1589
00:55:37,893 --> 00:55:39,027
IT'S ALSO POSSIBLE THEY EXIST

1590
00:55:39,027 --> 00:55:41,463
AND WE JUST HAVEN'T FOUND THEM,

1591
00:55:41,463 --> 00:55:41,697
RIGHT?

1592
00:55:41,697 --> 00:55:42,698
MANY TIMES YOU FIND WHAT YOU GO

1593
00:55:42,698 --> 00:55:45,968
LOOKING FOR AND A LOT OF IS

1594
00:55:45,968 --> 00:55:47,369
BASED DISCOVERY SO I'M UNAWARE

1595
00:55:47,369 --> 00:55:49,171
OF PEOPLE THAT HAVE TRIED TO

1596
00:55:49,171 --> 00:55:54,776
LIKE USE FUSION PEPTIDE AS BAIT

1597
00:55:54,776 --> 00:55:56,311
TO ISOLATE RSV ANTIBODIES BUT

1598
00:55:56,311 --> 00:55:57,279
MAYBE PEOPLE HAVE, YOU GO YEAH,

1599
00:55:57,279 --> 00:56:04,119
A LOT OF IT IS BAIT DERIFFED

1600
00:56:04,119 --> 00:56:04,553
ANTIBODY ISOLATION.

1601
00:56:04,553 --> 00:56:06,021
>> [INDISCERNIBLE] SO IT
SHOULD

1602
00:56:06,021 --> 00:56:06,688
BE ACCESSIBLE?

1603
00:56:06,688 --> 00:56:07,789
>> IT SHOULD BE ACCESSIBLE
BUT I

1604
00:56:07,789 --> 00:56:14,963
THINK IN SOME CASES IN THE CASE

1605
00:56:14,963 --> 00:56:17,733
OF RSVF, THE VIRUS IS ATTACHED

1606
00:56:17,733 --> 00:56:19,501
SO YOU WOULD NEED B-CELLS TO GET

1607
00:56:19,501 --> 00:56:21,670
IN THERE SO I THINK

1608
00:56:21,670 --> 00:56:22,971
THERE'SSTERRIC AS WELL AS

1609
00:56:22,971 --> 00:56:25,340
TEMPERRAL THINGS TO CONSIDER.

1610
00:56:25,340 --> 00:56:26,375
>> HEY, JASON.

1611
00:56:26,375 --> 00:56:26,909
>> HEY CHRIS.

1612
00:56:26,909 --> 00:56:29,211
SO YOU SHOWED THIS VERY NICE

1613
00:56:29,211 --> 00:56:32,080
PIPELINE THAT YOU USUALLY START

1614
00:56:32,080 --> 00:56:37,286
WITH ANTIBODIES DERIVED FROM

1615
00:56:37,286 --> 00:56:37,553
PATIENTS.

1616
00:56:37,553 --> 00:56:38,086
>> IF POSSIBLE.

1617
00:56:38,086 --> 00:56:39,121
>> IF POSSIBLE, SO WHAT
ARE

1618
00:56:39,121 --> 00:56:40,322
OTHER MEANS OF HAVING GOOD

1619
00:56:40,322 --> 00:56:40,989
STARTING [INDISCERNIBLE].

1620
00:56:40,989 --> 00:56:44,226
DO YOU START BY IMMUNIZING FOR

1621
00:56:44,226 --> 00:56:46,094
EXAMPLE, LLAMAS OR ALPACAS OR

1622
00:56:46,094 --> 00:56:48,297
OTHER SOURCES OF ANTIBODIES,

1623
00:56:48,297 --> 00:56:48,931
LIKE RABBITS?

1624
00:56:48,931 --> 00:56:50,866
>> SO THAT'S A GREAT WAY,
WE'VE

1625
00:56:50,866 --> 00:56:52,367
DONE ANTIBODY INDEPENDENT AS

1626
00:56:52,367 --> 00:56:54,970
WELL, WHICH IS REALLY PAIN

1627
00:56:54,970 --> 00:56:56,705
STAKING BECAUSE WE CAN'T REALLY

1628
00:56:56,705 --> 00:56:57,806
ASSESS THE CONFIRMATION OF ANY

1629
00:56:57,806 --> 00:56:59,408
OF THE VARIANTS AND WE

1630
00:56:59,408 --> 00:57:01,343
ULTIMATELY NEED TO LOOK BY EM

1631
00:57:01,343 --> 00:57:02,945
WHICH IS VERY SLOW AND TEDIOUS,

1632
00:57:02,945 --> 00:57:06,448
IF YOU DON'T HAVE THE HUMAN

1633
00:57:06,448 --> 00:57:08,250
DERIVED ANTIBODIES YOU SHOULD BE

1634
00:57:08,250 --> 00:57:09,885
ABLE TO DERIVE THESE BY

1635
00:57:09,885 --> 00:57:10,719
IMMUNIZATION OF SMALL ANIMALS

1636
00:57:10,719 --> 00:57:13,855
AND BEST IS TO DO SOME SORT OF

1637
00:57:13,855 --> 00:57:15,591
MRNA BASED IMMUNIZATION OF THE

1638
00:57:15,591 --> 00:57:17,459
FULL WILD-TYPE PROTEIN WHICH WE

1639
00:57:17,459 --> 00:57:20,929
WOULD ASSUME INITIALLY FOLDS IN

1640
00:57:20,929 --> 00:57:22,264
THE PREFUSION CONFIRMATION AND

1641
00:57:22,264 --> 00:57:23,732
RELATIVELY STABLE AND YOU COULD

1642
00:57:23,732 --> 00:57:26,768
IMMUNIZE WITH POST FUSION AS

1643
00:57:26,768 --> 00:57:27,970
WELL, HAVING ANTIBODIES, IDEALLY

1644
00:57:27,970 --> 00:57:29,705
YOU WANT AN ANTIBODY THAT

1645
00:57:29,705 --> 00:57:31,740
RECOGNIZES ALL FORMS AND THEN A

1646
00:57:31,740 --> 00:57:32,274
ANTIBODY THAT RECOGNIZES

1647
00:57:32,274 --> 00:57:33,475
PREFUSION AND YOU COULD ALSO

1648
00:57:33,475 --> 00:57:34,643
HAVE AN ANTIABOUT THAT

1649
00:57:34,643 --> 00:57:35,978
RECOGNIZES POST FUSION AND THEN

1650
00:57:35,978 --> 00:57:37,479
THE RATIO GIVES YOU THE

1651
00:57:37,479 --> 00:57:38,714
PREFUSION PERCENTAGE SO YOU

1652
00:57:38,714 --> 00:57:40,916
COULD -- PEOPLE OF IMMUNIZE WITH

1653
00:57:40,916 --> 00:57:43,218
PEPTIDES THAT FORM THE HELIX 6

1654
00:57:43,218 --> 00:57:44,186
BUNDLE SO SOMETIMES WE HAVE TO

1655
00:57:44,186 --> 00:57:46,355
START OFF AND FOR HAD OF THESE

1656
00:57:46,355 --> 00:57:49,024
REVAMPS WE HAVE TO -- WE START

1657
00:57:49,024 --> 00:57:50,192
OFF WITH REAGENT IMENERATION AND

1658
00:57:50,192 --> 00:57:51,627
TRY TO GET THOSE JUST FROM

1659
00:57:51,627 --> 00:57:54,062
ANIMALS AND DO YOU HAVE AN

1660
00:57:54,062 --> 00:57:58,367
ESTIMATE IF IT IS -- IF YOU GET

1661
00:57:58,367 --> 00:57:59,267
BETTER NEUTRALIZING ANTIBODIES

1662
00:57:59,267 --> 00:58:04,506
FROM PATIENTS COMPARED TO OTHER

1663
00:58:04,506 --> 00:58:04,740
SOURCES?

1664
00:58:04,740 --> 00:58:05,173
>> GOOD QUESTION.

1665
00:58:05,173 --> 00:58:06,708
I FEEL LIKE MANY OF THE BEST 1S

1666
00:58:06,708 --> 00:58:08,944
IN THE DIFFERENT FIELDS ARE

1667
00:58:08,944 --> 00:58:13,415
USUALLY FROM HUMANS.

1668
00:58:13,415 --> 00:58:15,150
YEAH, THAT'S A CASE WHERE

1669
00:58:15,150 --> 00:58:16,451
NEARING THE ANTIBODY WAS REALLY

1670
00:58:16,451 --> 00:58:17,753
GOOD COMPARED TO A HUMAN.

1671
00:58:17,753 --> 00:58:20,422
AGAIN, SOME OF THAT'S JUST BIAS

1672
00:58:20,422 --> 00:58:22,457
MAYBE PEOPLE HAVEN'T LOOKED AS

1673
00:58:22,457 --> 00:58:25,293
HARD IN THE 1 ANIMAL AS THE

1674
00:58:25,293 --> 00:58:25,494
OTHER.

1675
00:58:25,494 --> 00:58:26,962
>> MAYBE 1 LAST QUESTION
FROM

1676
00:58:26,962 --> 00:58:28,130
ONLINE, IF YOU'RE HOLDING UP.

1677
00:58:28,130 --> 00:58:29,398
>> I WILL MAKE IT.

1678
00:58:29,398 --> 00:58:29,831
>> BEAUTIFUL TALK.

1679
00:58:29,831 --> 00:58:30,832
THANK YOU VERY MUCH.

1680
00:58:30,832 --> 00:58:33,835
REGARDING THE STUDIES LOOKING AT

1681
00:58:33,835 --> 00:58:42,844
GC STABILIZATION VIA THE END

1682
00:58:42,844 --> 00:58:44,546
LINKED GLYCON, COULD THE

1683
00:58:44,546 --> 00:58:45,614
MACHINERY BETWEEN HUMANS AND

1684
00:58:45,614 --> 00:58:49,051
TICKS OR WHATEVER MODEL USED TO

1685
00:58:49,051 --> 00:58:50,318
PROBE THIS INTERACTION GAVE

1686
00:58:50,318 --> 00:58:52,287
DIFFERENT RESULTS THAN WHAT WAS

1687
00:58:52,287 --> 00:58:52,721
OBSERVED?

1688
00:58:52,721 --> 00:58:55,824
NI  --

1689
00:58:55,824 --> 00:58:59,461
>> I DON'T THINK SO, MOST

1690
00:58:59,461 --> 00:59:00,062
GLYCOSYLATION WE'RE SEEING

1691
00:59:00,062 --> 00:59:02,364
LAYING ON TO THE GC FUSION LOOPS

1692
00:59:02,364 --> 00:59:05,467
IS JUST THE BASE DPLI

1693
00:59:05,467 --> 00:59:06,802
COSALATION, THAT'S BETA NANOS

1694
00:59:06,802 --> 00:59:11,773
AND THAT'S GENERALLY CONSERVED

1695
00:59:11,773 --> 00:59:14,076
IN ALL EUKARYOTES, SO TO THAT'S

1696
00:59:14,076 --> 00:59:16,645
DIFFERENTS ON THE BRANCHING AND

1697
00:59:16,645 --> 00:59:17,245
TERMINAL RESIDUES, ABOUT YOU

1698
00:59:17,245 --> 00:59:19,247
THAT IS THE MORE CONSERVED CORE

1699
00:59:19,247 --> 00:59:20,415
GLYCANS THAT ARE RESPONSIBLE SO

1700
00:59:20,415 --> 00:59:22,250
I DON'T THINK THAT WOULD HAVE AS

1701
00:59:22,250 --> 00:59:27,622
MUCH OF AN IMPACT.

1702
00:59:27,622 --> 00:59:29,958
>> I WILL REMIND EVERYONE,
NO

1703
00:59:29,958 --> 00:59:30,959
MOW QUESTIONS, THERE'S'

1704
00:59:30,959 --> 00:59:34,896
RECEPTION OUTSIDE, READY TO GO. 

1705
00:59:34,896 --> 00:59:36,865
CME NUMBER CODE 57666.

1706
00:59:36,865 --> 00:59:37,232
57666.

1707
00:59:37,232 --> 00:59:42,204
AND LASTLY LET'S THANK OWEVER

1708
00:59:42,204 --> 00:59:42,437
SPEAKER.

1709
00:59:42,437 --> 00:59:52,681
[ APPLAUSE ]