>> MY NAME IS MOLL MARION GRUBER, AND ON BEHALF OF THE OFFICE OF IMMUNOLOGY, I WOULD LIKE TO WELCOME YOU TO THIS WORKSHOP ON IMMUNOLOGY AGAINST EBOLA VIRUS, I WANT TO MENTION AND PAY CREDIT TO THE PEOPLE AND THE AGENCIES INVOLVED IN CO-SPONSORING THIS WORKSHOP. MAINLY THE NATIONAL INSTITUTES OF ALLERGY AND INFECTIOUS DISEASES, THE BIOMEDICAL ADVANCED RESEARCH AND DEVELOPMENT AUTHORITY, THE DEPARTMENT OF DEFENSE, THE CENTER FOR DEC CONTROL AND PREVENTION AND THE FOOD AND DRUG ADMINISTRATION. NOW THE PURPOSE OF THE WORKSHOP IS TO DISCUSS THE CRITICAL ASPECTS OF EBOLA I HAVE RAWS AND VACCINE IMMUNOLOGY IN ORDER TO INFORM FUTURE CLINICAL AND SCIENTIFIC REGULATORY DECISION MAKING RELATED TO THE DEVELOPMENT OF VACCINES TO PROTECT AGAINST EBOLA VIRUS DISEASE. AND OF COURSE UNDERSTANDING THE IMMUNE RESPONSE FOLLOWING EITHER EBOLA VIRUS DISEASE OR VACCINATION IS IMPORTANT AS IT MAY HELP TO INFORM THE DESIGN OF EFFICACY STUDIES THAT COULD POTENTIALLY LEAD TO IDENTIFICATION OF A NEW MARKER OF PROTECTION TO IDENTIFY IMMUNE PARAMETERS TO BE ABLE TO COMPARE DIFFERENT VACCINE ANTIGEN, DIFFERENT VACCINES, CANDIDATES TO EACH OTHER AND ALSO AID IN DEFINING IMMUNOLOGICAL END POINTS TO SUPPORT REGULATORY DECISION MAKING ACTIONS. SO AS THE CHAIR PERSON ONE, I HAVE THE HONOR AND PLEASURE TO INTRODUCE TO YOU THE COMMISSIONER OF THE U.S. FOOD AND DRUG ADMINISTRATION DR. PEGLE HAMBURG. THANK YOU FOR BEING HERE. >> WELL, THANK YOU SO MUCH, I WILL NOT TAKE UP MUCH TIME BECAUSE HAVE YOU A VERY IMPORTANT AGENDA TO WORK ON TODAY BUT I DID REALLY WANT TO COME TO EXPRESS MY ENTHUSIASM AND SUPPORT FOR THE CRITICAL WORK OF THIS CONFERENCE AND THE WORK THAT YOU'RE ALL DOING EVERY DAY IN THE WORK THAT WE WILL BE DOING HOPEFULLY TOGETHER GOING FORWARD AND TO REALLY THANK YOU FOR JOINING US. WE REALLY ARE SO PLEASED AND DELIGHTED TO HAVE A RANGE OF INTERNATIONALLY RECOGNIZED EXPERTS IN VACCINE DEVELOPMENT AND IN EBOLA WITH US TODAY AND MEMBERS OF THE PUBLIC HEALTH AND SCIENTIFIC COMMUNITY. THIS IS REALLY A KEY ISSUE AS WE LOOK AT HOW TO BETTER ADDRESS THE EBOLA OUTBREAK AND THINK ABOUT WAYS TO PREVENT FUTURE OUTBREAKS FROM HAPPENING AND I REALLY DO BELIEVE THAT ALL OF YOU ARE PARTICIPATING IN THIS WORKSHOP WILL MAKE A VERY MEANINGFUL AND ENDURING DIFFERENCE AND I UNDERSTAND THAT NOT ONLY IS THIS ROOM FULL BUT WE ACTUALLY ARE OVERFLOWING, SO OBVIOUSLY THE INTEREST AND COMMITMENT TO THIS IMPORTANT ISSUE IS CLEAR. WE ALL RECOGNIZE THE EBOLA OUTBREAK HAS REALLY BEEN AN EXTRAORDINARY EVENT AND NOT JUST GLOBAL PUBLIC HEALTH AND MORE BROADLY AND IT HAS I THINK REALLY FOR FDA, REQUIRED US TO STEP UP TO THE PLATE AND RESPOND IN EXTRAORDINARY WAYS AND WE ARE NOT ALONE IN THAT EFFORT. AND IT'S OF COURSE HIGHLIGHTED THE NEED FOR ONGOING COOPERATION ACROSS SECTORS, ACROSS DISCIPLINES AND ACROSS NATIONS CERTAINLY FOR US, THE ABILITY TO WORK CLOSELY WITH SO MANY OTHERS HAS BEEN VITAL AND WILL CONTINUE TO BE SO. I CERTAINLY WANT TO THANK OUR OTHER PARTNERS IN GOVERNMENT FOR THE WORK WE'VE BEEN DOING TOGETHER AND FOR HELPING TO COSPONSOR THIS WORKSHOP. NIAID OF COURSE FOR GIVING US ALL OF THE SCIENTIFIC PARTNERSHIPS BUT ALSO THIS LOVELY SPACE. I'VE NEVER BEEN HERE BEFORE AND IT REALLY IS QUITE REMARKABLE BUT ALSO CDOD, AND B. A. R. T. A., VITAL PARTNERS IN IN EFFORT, AND OF COURSE I WORK WITH THE SCIENTIFIC COMMUNITY AND INDUSTRY AND A RANGE OF OTHER ORGANIZATIONS, AND REALLY TO BOTH ADDRESS WAYS TO DEEPEN THE KNOWLEDGE BASE ABOUT THERAPIES AND VACCINES AND DIAGNOSTICS MAKE EXPERIMENTAL PRODUCTS AVAILABLE AS INDICATED BUT IMPORTANTLY, ASK AND ANSWER THE CRITICAL QUESTIONS ABOUT WHAT WORKS AND WHAT DOES, WHAT DOES THE VALUE FOR PATIENTS AND FOR PEOPLE AT RISK FOR EBOLA AND MAKE SURE THAT AS WE LEARN MORE, WE AS RAPIDLY AS POSSIBLE TRANSLATE THAT KNOWLENTO ACTION FOR PEOPLE THAT WILL MAKE A DIFFERENCE, KNOW THAT THIS EPIDEMIC OF EBOLA IS CONTINUING TO EXPAND AND TO MARK REMARK PROGRESS IN BILERRIA @ MOMENT BUT WE CAN'T--IN LIBERIA AT THE MOMENT AND OF COURSE WE FORGET THAT SIERRA LEON CONTINUES TO SUFFER AN UNBEARABLE BURDEN OF THIS DISEASE AND AS WE THINK ABOUT WHAT WHAT ARE THE TOOLS THAT HAVE MADE DIFFERENCE, AND THAT WE NEED IN THE FUTURE THAT BASIC MEDICAL CARE, SUPPORT OF CARE IS ESSENTIAL. BASIC PUBLIC HEALTH MEASURES IN SECTIONS CONTROL AND CONTACT TRACING ARE ESSENTIAL BUT VACCINE CAN AND WILL PLAY A VERY SPECIAL POTENTIALLY NOT JUST IN PERFORMING THIS. SO THE WORK YOU'RE DOING AND DEEPEN OUR UNDERSTANDING OF THE DISEASE AND THE PATHOPHYSIOLOGY AND AS YOU ALL KNOW BETTER THAN I VITAL TO TAKING A AND WORK YOU'RE DOING AS PART OF THIS WORKSHOP AND NATURE AND SCOPE EVER THE IMMUNE AND UNDERSTAND FULLY HOW THIS HOW THE RESPONSE OF WHAT NEED TOS TO BE TO PREVENT IT. WE KNOW THAT EBOLA IS A COMPLEX DISEASE. WE KNOW THERE'S INFORMATION OUT THERE THAT IS SHAPING STRATEGIES TO DEEPEN AND EXTEND SO THAT WE CAN BROADEN OUR WORK AND REALLY DEVELOP THE PRODUCTS THAT WILL MAKE THE DIFFERENCE AND WE KNOW THAT THERE ARE A RANGE OF STRATEGIC PLAN EDGESIES AND INTERVENTIONS THAT WILL BUILD ON THE WORK YOU ARE DOING. SO IT REALLY IS ABSOLUTELY ESSENTIAL, THE COMING TOGETHER OF THIS GROUP, I THINK IS HISTORIC IN TERMS OF THE DIFFERENT DISCIPLINES, PERSPECTIVES, KNOWLEDGE BASES AND SKILLS THAT YOU BRING TO BEAR BUT IT IS THE COMING TOGETHER AND THE SENSE OF--SYNTHESIS OF KNOWLEDGE COMBINED WITH THE DEDICATION TO MAKE A DIFFERENCE THAT WE ARE REALLY COUNTING ON AS WE ARE MOVING FORWARD AS RAPIDLY AS POSSIBLE TO BE ABLE TO PROVIDE THE PEOPLE OF WEST AFRICA AND THE PEOPLE OF OUR GLOBAL COMMUNITY WITH PREVENTIVE STRATEGY THAT WE NEED TO REALLY TURN THIS EPIDEMIC AROUND AND CERTAINLY TO HELP BETTER PROTECT ALL COMMUNITIES OF THE WORLD AGAINST FUTURE DEVASTATING OUTBREAKS OF THIS KIND. SO I REALLY DON'T WANT TO SAY A LOT MORE BECAUSE I WANT ALL OF YOU TO ROLL UP YOUR SLEEVES AND GET TO WORK TO WORK ON THE CHALLENGES BEFORE US AND HELP US KEFINE THESE TRUTHFUL AND MEANINGFUL SOLUTIONS. BUT I DID WANT TO COME TO SAY HOW MUCH WE APPRECIATE THE WORK YOU'VE BEEN DOING AND THE WORK THAT YOU WILL DO OVER THE COURSE OF THIS WORKSHOP AND WITH US GOING FORWARD BECAUSE THERE ARE FEW, FEW ISSUES WHERE THE TIME URGENCY OF ALIGNING THE BEST POSSIBLE SCIENCE WITH THE REAL ON THE GROUND MEDICAL SOLUTION SYSTEM MORE CLEAR. SO THANK YOU FOR GIVING ME A BIT MORE ATTENTION THIS MORNING. THANK YOU FOR YOUR WILLINGNESS TO WORK WITH US AND AS A COLLABORATIVE TEAM ON THIS CRITICAL ISSUE AND I REALLY WISH YOU THE BEST OF LUCK. I AM CONFIDENT WITH THE AMAZING TALENT IN THIS ROOM THAT REAL PROGRESS WILL BE MADE AND I'M GOING TO GET OUT OF YOUR WAY AND LET YOU GET TO THAT IMPORTANT WORK. SO THANK YOU SO MUCH. [ APPLAUSE ] >> SO BEFORE I INTRODUCE THE NEXT SPEAKER, I WANT TO COMMUNICATE IMPORTANT HOUSEKEEPING ITEMS. ONE IS I'VE BEEN STRESS THE POINT THAT SPEAKERS NEED TO KEEP ON TIME AND THAT THE SESSION CHAIRS WILL NEED TO SPEAK UP NEXT TO THE SPEAKER WHEN IS ONE MINUTE REMAINS SO WE HAVE TO MAKE AN EFFORT TO KEEP THE AGENDA ON TIME AND ALSO IF WE HAVE SOME TIME AFTER EACH TALK, THEN SPEAKERS CAN TAKE QUICK CLARIFYING QUESTIONS BUT MORE DETAILED QUESTIONS SHOULD BE ADDRESSED DURING THE SESSION, AND OF COURSE, PARTICIPANTS IN THE OVERFLOW ROOM INTO THE MAIN ROOM WILL ASK QUESTIONS AND BECAUSE THIS WILL BE TRANSCRIBED IT IS ALSO IMPORTANT FOR SPEAKERS TO IDENTIFY THEMSELVES BEFORE THEY'RE ASKED THEIR QUESTIONS OR MAKE COMMENTS. SO WITH THAT IT'S MY PLEASURE TO INTRODUCE TO YOU THE NEXT SPEAKER WITH DR. PHIL KRAUSE, WHO IS WITH THE OFFICE OF FDA, I WOULD LIKE TO THANK HIS COLLEAGUES AND HIS AGENCY AND OTHER AGENCIES TO HELP PULL THIS WORKSHOP TOGETHER SO QUICKLY. AND HE WILL TALK ABOUT REGULATORY PATH TOWARDS LICENSURE OF AN EBOLA VACCINE AND RELEVANCE OF IMMUNO GENERATEDISSITY DATA IN THAT REGARD. >> THANKS. I WOULD LIKE TO THANK DRS. HAMBURG AND GRUBER, I WOULD LIKE TO SET A TONE IN THIS TALK OR PROVIDE AN EXPLANATION ABOUT WHY WE'RE IN THE REGULATORY COMMUNITY SO INTERESTED IN UNDERSTANDING THE IMMUNOLOGY OF THIS VIRUS, AND SOME OF THESE MAY BE OBVIOUS AND SOME LESS OBVIOUS, BUT IT'S IMPORTANT AS WE WORK ON THIS SCIENTIFIC MEETING TO TALK ABOUT IMMUNOLOGY, ASSAYS, TO TALK ABOUT THE NEXT STEPS GOING FORWARD, IF WE THINK ABOUT HOW THE INFORMATION WE'RE TALKING ABOUT IS GOING TO BE USED. AND THAT IS WHY THE ORGANIZING COMMITTEE PUT THIS TALK IN THIS SLIDE. WHEN WE THINK ABOUT LICENSING AND EBOLA VACCINES, THERE ARE THREE PATHWAYS THAT CAN BE CONTEMPLATED. THERE IS TRADITIONAL APPROVAL WHICH JUST A STANDARD WAY IN WHICH VACCINES ARE APPROVED INVOLVING RANDOMIZED CONTROL CLINICAL TRIALS, WITH EFFECTIVENESS END POINTS, THEN THERE'S ACCELERATED APPROVAL WHICH ALLOWS PRODUCTS TO BE APPROVED WHEN THERE'S NOT QUITE AS MUCH DATA AVAILABLE AND YET THERE'S INFORMATION THAT SHOWS THAT THE PRODUCT IS REASONABLY LIKELY TO SHOW BENEFIT AND THEN THERE'S THE ANIMAL RULE WHICH CAN BE USED WHEN THESE OTHER APPROACHES CAN'T BE USED IN WHICH THE EFFECTIVENESS DATA CAN COME FROM ANIMAL STUDIES. REGARDLESS OF WHICH PATHWAY IS USED TO LICENSE A VACCINE, CLINICAL SAFETY DATA IS REQUIRED AND HAS NO IMPACT AND IS NOT RELATED TO THE PATHWAYS, SO THERE HAS TO BE CLEAR DEMONSTRATION THAT THE PRODUCT WILL BE SAFE AND THAT CONSIDERATION OF SAFETY CONSIDERS THE NATURE OF THE PRODUCT, THE INTENDED USE AND THE SEVERITY OF THE DISEASE TO BE PREVENTED. AND TRUE TO WHAT I JUST SAID IN MY INTRODUCTION, THIS IS AN IMMUNOLOGY WORKSHOP, THIS IS NOT A SAFETY WORKSHOP. THERE ARE MANY THINGS WE COULD BE TALKING ABOUT TODAY THAT ARE VERY IMPORTANT FOR VACCINE DEVELOPMENT BUT GIVEN THE TIME AVAILABLE TO US AND THE FOCUS ON IMMUNOLOGY, I WILL NOT SAY ANYMORE ABOUT SAFETY THAN THAT BUT OF COURSE SAFETY IS ONE OF THE MOST IMPORTANT THINGS WE CONSIDER IN VACCINE DEVELOPMENT. DEMONSTRATION OF EFFECTIVENESS IS REQUIRED FOR ALL OF THESE PATHWAYS AS WELL AND THE DIFFERENCE AMONG THE PATHWAY SYSTEM THE APPROACH TO DEMONSTRATING EFFECTIVENESS, WHETHER IT'S THROUGH THE STANDARD TRADITIONAL METHOD ACCELERATING APPROVAL OR THE ANIMAL RULE. AND THE ACCELERATED ANIMAL RULE HAD ELIGIBILITY CRITERIA REQUIREMENTS AND I'LL SAY MORE ABOUT EACH OF THESE PATHWAYS ON EACH OF THE NEXT THREE SLIDES. SO IN TRADITIONAL APPROVAL. PRELICENSEURES CLINICAL STUDIES PROVIDE EVIDENCE EFFECTS BASED ON PROTECTION AGAINST CLINICAL DISEASE. USUALLY, IN SOME CASES IMMUNOLOGICAL RESPONSES CAN BE USED TO SUPPORT TRADITIONAL APPROVAL BUT THOSE ARE CASE WHERE IS THERE'S A SCIENTIFICALLY WELL ESTABLISHED IMMUNOLOGIC MARKER TO PREDICT PROTECTION THAT CAN BE RELIAISONNABLY MEASURED IN AN ASSAY AND THIS OF COURSE IS FACILITATED BY A DISEASE OF PATHOGENESIS IN A MECHANISM WHICH VACCINE PREVENTS DISEASE. SO WHILE IMMUNOLOGICAL DATA CAN BE USED TO SUPPORT A TRADITIONAL APPROVAL OUR SENSE OF THE FIELD AT THIS POINT IS THE ABILITY TO USE THIS DATA FOR AN EBOLA VACCINE IS NOT THERE BECAUSE WE DON'T HAVE SUCH A SCIENTIFICALLY WELL ESTABLISHED IMMUNOLOGIC MARKER. ALTHOUGH OF COURSE OVER TIME IT WOULD BE VERY NICE TO DEVELOP ONE, AND THAT IS ONE OF THE TOPICS OF THIS MEETING. FOR ACCELERATED APPROVAL, ACCELERATED APPROVAL CAN BE USED FOR PRODUCTS IN SAFETINESS AND EFFECTIVENESS FOR SERIOUS OR LIFE THREATENING DISEASE OR CONDITIONS AND PROVIDE MEANINGFUL BENEFIT OVER EXISTING TREATMENT. EBOLA VACCINE WOULD MEET BOTH OF THOSE CRITERIA. FOR ACCELERATED APPROVAL, THE APPROVAL MAY BE BASED ON ADEQUATE WELL CONTROLLED CLINICAL TRIALS ESTABLISHING AN EFFECT ON A SURROGATE END POINT THAT IS AUTOMOBILELY LIKELY TO PREDICT CLINICAL BENEFITS AND FOR VACCINES THAT USUALLY IS AN IMMUNO GENERATEDISSITY END POINT AND THEN ONCE A PRODUCT RECEIVED ELEVATED APPROVAL THERE'S REQUIREMENT FOR BENEFIT FOR REQUIRES POST MARKING STUDIES UNDERWAY AFTER TIME OF APPROVE AND DO IT WITH DUE DILIGENCE. SO HERE AGAIN, IMMUNO GENERATEDISSITY DATA WHICH DOESN'T MEET THE STANDARD FOR TRADITIONAL APPROVAL BUT YET IS CONSIDERED REASONABLY LIKELY TO PREDICT CLINICAL BENEFIT, CAN BE BASIS FOR APPROVE ALGORITHMS UNDER ACCELERATED APPROVAL. AND THE NEXT RULE IS THE ANIMAL RULE, AND THAT'S PRODUCTS THAT ARE STUDIED FOR SAFETY AND EFFICACY IN EMELIORATING OR PREVENTING EXPOSURE TO LETHAL, RADIOLOGICAL, CHECKICAL OR NUCLEAR SUBSTANCES AND EBOLA WOULD MEET THAT CRITERIA AND WHERE HUMAN EFFICACY STUDIES CANNOT BE CONDUCTED AND WE WILL HEAR LATER THIS MORNING THAT THERE'S A PLAN TO CONDUCT HUMAN EFFICACY STUDIES SO AT LEAST RIGHT NOW THE RULE IS NOT THE PRIMARY WAY IN WHICH ONE WOULD CONSIDER LICENSING AN EBOLA VACCINE. BECAUSE IT'S UNETHICAL TO DELIBERATELY EXPOSE HEALTHY HUMANS OR IN THE FIELD. SO WITH THIS HIGHLIGHTS FOR US IS THE IMPORTANCE OF LOOKING AT OUR ABILITY TO STUDY THIS VACCINE AND THE CONTEXT OF THE IMMUNOLOGY OF EBOLA VIRUS AND UNDERSTANDING WHAT THAT DAT IS TELLING US AND THAT THEN CAN ACTUALS TELL US WHICH OF THESE APPROVAL PATHWAY CANS BE SUPPORTED BY THE DATA THAT ARE MADE AVAILABLE. SO IMMUNO GENERATEDISSITY DATA THEN CAN BE USED TO SUPPORT TRADITIONAL APPROVAL WHEN AN IMMUNE MARKER PREDICTS CLINICAL BENEFIT OR ACCELERATED APPROVAL WHEN AN IMMUNE MARKER IS REASONABLY LIKELY TO PREDICT THE BENEFIT OR SUPPORT ANIMAL RULE APPROVAL WHEN THE MARKETS ARE USED TO BRIDGE EFFECTIVENESS BETWEEN ANIMALS AND HUMANS. THERE ARE OTHER REGULATORY USES OF IMMUNO GENERATEDISSITY DATA THAT ARE VERY IMPORTANT THAT COME UP. AND ONE OF THEM IS TO SUPPORT INFERRING EFFECTIVENESS IN OTHER SETTINGS SO FOR EXAMPLE AN EXAMPLE MIGHT BE TEST INDEED THAT AGE GROUP AND EFFECTIVE IN THAT AGE GROUP AND WE WOULD LOCALIZED --WE WOULD LIKE TO ADD AN EFFECTERRIVENESS STUDY IN THE AGE GROUP, BUT WE CAN USE IMMUNO GENERATEDISSITY DATA TO CREATE THAT BRIDGE FROM ONE AGE GROUP TO ANOTHER. AS WELL AS TO SUPPORT MANUFACTURING CHANGES TO SHOW THAT VACCINE AFTER MANUFACTURING CHANGE IS SIMILAR TO THE VACCINE BEFORE THE MANUFACTURING CHANGE. IMMUNO GENERATEDISSITY DATA CAN BE USED TO SUPPORT THE CONSISTENCY AND ONE OF THE LICENSURE ARE IS ALSO FOR THE MANUFACTURES TO SHOW THAT THE PRODUCT CAN BE CONSIST EPTLY MANUFACTURE AS WELL AS EARLIER IN EVALUATION OF THE VACCINE TO SUPPORT DOSE SELECTION. A COUPLE OF WORDS ABOUT EBOLA IMMUNE RESPONSES FOR TODAY'S MEETING, IT'S IMPORTANT TO BED THAT THE NATURE OF PROTECTIVE IMMUNE RESPONSES TO EBOLA IS INCOMPLETE AND WE HAVE A WAYS TO GOOD. CANDIDATES INCLUDE IMMUNITY, ANTIBODIES CAN BE TESTED AND REASONS WHY THE ANTIBODIES MIGHT BE A GOOD WAY OF LOOKING AT IMMUNE RESPONSE AND A CANDIDATE IF FOR EACH OF THESE THE PRECISE VIRAL TARGETS NEED TO BE DEFINED AND FOR EBOLA THERE'S THE COMPLICATED FACTOR OF VIRAL IMMUNE STRATEGIES INCLUDING SOLUBLE GLYCOPROTEINS THAT THE VIRUS MAKES. AT THE FDA WE'RE CONCERNED ALSO NOT ONLY TO TEST THE IMMUNE RESPONSES BUT THAT THOSE TEST CANS BE PERFORMED AND WE GET RESULTS OF THOSE TESTS WE KNOW WHAT THOSE RESULTS MEAN. SO ASSAYS NEED TO BE VALIDATED SO WE'LL SPEND A FAIR AMOUNT OF TIME TALKING ABOUT ASSAYS AS WELL. VALIDATION ASSURES THAT ASSAYS ARE FIT FOR USE AND THESE INCLUDE SENSITIVITY WHICH MIGHT INCHUTE LIMITED DETECTION OR QUANTITATION, ACCURACY, SPECIFICITY, DECISION OR VARIABILITY, ROBUSTNESS AND RUGGEDNESS. AND OF COURSE INCLUSION OF REFERENCE STANDARD CANS REDUCE COMPARISONS AMONG DIFFERENT ASSAYS. SO, ABOUT THE MEETING TODAY, THEN, THIS IS AS STATED SCIENTIFIC MEANING TO DRILL DOWN ON THESE ISSUES OF WHAT WE CURRENTLY UNDERSTAND ABOUT EBOLA IMMUNOLOGY, IMMUNE IMMUNO GENERATEDISSITY VACCINE AND MOPE HO HAVE A DISCUSHION ON WHAT NEEDS TO BE DONE--DISCUSSION ON WHAT NEEDS TO BE DONE FOR THESE STANDARDS. SO WE'RE STARTING WITH --ING OUT WITH AN INTRODUCTION SESSION FOR THE PHASE THREE STUDIES IN AFRICA, THERE WILL BE BACKGROUND STUDIES, ANIMAL MODELS AND THE VIROLOGY OF THE VIRUS, THERE WILL BE A SESSION ON THE IMMUNOLOGY OF THE VIRUS, TALKS THAT ARE DESIGNED TO GET AT THE QUESTION OF WHAT IMMUNE RESPONSES SHOULD BE DETECTED WHICH ARE THE IMPORTANT ONES AND THEN WE'LL HAVE A SESSION ON ASSAYS WHICH WILL KREUL DOWN ON THE QUESTION OF HOW ACCURATELY AND CONSISTENTLY CAN THE ASSAY ASSESS THE IMMUNE RESPONSES THAT WE BELIEVE TO BE IMPORTANT. AND THEN THE FINAL SESSION WILL BE ON THE TOPIC OF MOVING FORWARD WHICH WILL INCLUDE THE PRESENTATION OF CLINICAL DATA FROM LEADING VACCINE CANDIDATES INCLUDING TO MY KNOWLEDGE THE PUBLIC PRESENTATION FROM THE DATA FROM THE PHASE ONE STUDIES ON THE VSV VECTOR AS WELL AS ADDITIONAL PRESENTATION OF CLINICAL DATA ON THE ADENO VIRUS THREE VACCINE WHICH IS BEING DEVELOPED BY GLAXOSMITHKLINE AND THIS WILL APPROVE ADDITIONAL DATA THAT HAS NOT BEEN PRESENTED PUBLICLY FROM STUDIES AT OXFORD UNIVERSITY. AND THE CRITICAL PART OF THIS DISCUSSION WILL BE HOW WE TALK ABOUT HOW NEEDED INFORMATION CAN BE OBTAINED. SO AS MENTIONED THE THREE DISCUSSIONS DURING THIS MEETING ARE THE MEAT OF THIS. THE ORGANIZING COMMITTING AS LAID OUT THE DISCIPLINARY CUSHIONS FOR THESE SESSIONS. IF WE DON'T ANSWER ALL OF THESE QUESTIONS TODAY THAT'S OKAY. THE WAY THE DISCUSSIONS WILL BE ORGANIZED IS THAT THE PANELISTS ARE AT THE FRONT OF THE ROOM AND THEY WILL PROVIDE THEIR PERSPECTIVES BUT WE HOPE THESE ARE INTERACTIVE DILLS CUSHIONS THAT INVOLVE THE PANELS AS WELL AS YOU THE MEMBERS OF THE AUDIENCE AND WE HOPE THAT THE MEMBERS OF THE AUDIENCE WILL PARTICIPATE FULLY THROUGH QUESTIONS AND STATEMENT OF OPINIONS AND IF FOR THOSE IN THE OVERFLOW ROOM WHO WOULD LIKE TO COME IN TO ASK QUESTIS THAT IS ALSO PERMIT. SO FOR THE IMMUNOLOGY SESSION, WE'LL TALK ABOUT WHAT IS THE RELATIVE IMPORTANCE OF THE IMMUNITY AS WELL AS WHAT'S KNOWN ABOUT THE ROLE OF NEUTRALIZING VERSES NONNEUTRALLIZING AND HOW WE CAN DRIVE DOWN FARTHER ON THOSE. FOR ASSAYS WE ARE GOING TO FOCUS O WHAT ASSAY SHOW PROMULGATE EULS FOR FUTURE DEVELOPMENT AND HOW THAT DEVELOPMENT CAN BE FACILITATED AND IN THE FINAL DISCUSSION MOVING FORWARD, WE WILL TALK ABOUT DOSE SELECTION AND HOW THAT DATA CAN BE USED AS WELL AS WHAT INFORMATION WE NEED TO GET FROM THE NEXT THREE BULLETS FROM FUTURE STUDY, EITHER TO GET THE INFORMATION, WHAT GAPS NEED TO BE FILLED AND HOW THEY CAN BE FILLED AND THEN THE FINAL TWO BULLETS ARE DESIGNED TO STIMULATE DISCUSSION ON WHAT ADDITIONAL INFORMATION ABOUT EBOLA IMMUNOLOGY WE CAN GET FROM STUDYING THE CURRENT OUTBREAK. SO WITH THAT, I WOULD LIKE TO GIVE THANKS TO THE ORGANIZERS OF THIS COMMUNITY AND IT IS A MULTIAGENCY EFFORT INVOLVING TIME AND THOUGHT ALL THE WAY ACROSS THE GOVERNMENT AND IS AN AMAZING COLLABORATION AMONG DIFFERENT GOVERNMENT AGENCIES FROM NIAID AND FROM THE DEPARTMENT OF DEFENSE AND NELSON MICHAEL AND FROM BARTA AND TOM CLARK, AND FROM FDA, ERIC HENSHAW, AND I WOULD LIKE TO SUPPORT THE FDA LEADERSHIP INCLUDING DR. HAMBURG AND LUCIAHA AND ALSO THE TEAMS EVALUATING THESE AT THE FDA AND THIS INCLUDES EVERYBODY FROM THE LEADERSHIP FROM THE CENTER FOR BIOLOGICS BUT ALSO REALLY THE INDIVIDUAL REVIEWERS WHO PUT AN ENORMOUS AMOUNT OF EFFORT INTO RWING ISSUES ASSOCIATED WITH EBOLA VACCINE SO FAR AND I'M HAPPY TO TAKE QUESTIONS BUT I'M ALSO HAPPY TO MOVE ON AND ALLOW TIME FOR LATER SPEAKERS. THANK YOU. [ APPLAUSE ] >> PERHAPS IF WE HAVE A CLARIFYING QUESTIONS FOR DR. KRAUSE, WE COULD TAKE THEM. WE HAVE A FEW MINUTES BEFORE THE NEXT SPEAKER? WELL I THINK WE CAN MOVE ON THEN. OUR NEXT SPEAKER IS MIKE KURILLA, AND SHE WILL BE TALKING ABOUT CURRENT EBOLA VACCINE LANDSCAPE ASK INCLUDING SUMMARY OF CURRENT VACCINE DEVELOPMENT PLANS FOR VACCINE STUDIES. THANK YOU FOR BEING HERE. >> LET ME ADD MY THANKS TO THE ORGANIZING COMMITTEE IN GENERAL FOR PULL THANKSGIVING OFF ON SUCH SHORT NOTICE, AS WELL AS ADDING THE PLAYING CHICKEN SCENARIO OF A POSSIBLE GOVERNMENT SHUT DOWN, I'M STANDING HERE TODAY FOR TONY FAUCI, TO GIVE THIS TALK FOR MOST OF THIS OUTBREAK, TONY HAS BEEN TRIPLE BOOKED MOST OF THE TIME SO I'M FILLING IN FOR HIM AND SO I'M GOING TO GIVE A BROAD VERY--A BRUSH STROKE OVERVIEW OF THE CURRENT EBOLA OUTBREAK. THIS IS--YOU TYPICALLY SEE THOSE TRANSMISSION E. M.s AND THIS IS A MUCH MORE NUANCED AND DETAILED VIEW OF WHAT THE VIRUS LOOKS LIKE, I BEING THE IDEA OF GOING TO A STRAIGHT TRANSITION TO THE END IS--TO CONFER PROTECTION AGAINST THE I HAVE AREEROUS, NOW THE TIMELINE OF THIS OUTBREAK AS BEEN RELATIVELY RAPID. IT WAS ONLY A YEAR AGO THAT THE INITIAL CASE WAS FIRST RECOGNIZED AND W. H. O. WAS NOTIFIED IN MARCH AND THERE WERE LESS THAN 50 CASES AT THIS POINT IN GUINEA THAT HAD BEEN APPRECIATED AND THE INITIAL RESPONSE SEEMED TO ACTUALLY BE MODERATELY POSITIVE BUT THINGS BEGAN TO GO AWRY AS TIME WENT ON. IN JULY THE USG INITIATE SAID MEDICAL COUNTER MEASURE ACELSMENT INCLUDING VACCINE THERAPEUTICS AND DIAGNOSTICS TO SORT OF GEAR UP AND RECOGNIZE THAT THIS WAS GOING TO BE A BIGGER ISSUE AND IN AUGUST, W. H. O. DID DECLARE A PUBLIC HEALTH EMERGENCY OF INTERNATIONAL CONCERN AND BACK IN OCTOBER, A MORE COMPREHENSIVE INTENSIVE USG INTERVENTION HAD BEEN ANNOUNCED AND THE PROGRAMS WERE WELL IN PLACE. NOW, THIS W'T THE FIRST TIME THAT THE USG HAD REALLY ENCOUNTERED THE VIRUS IN GENERAL. THE DEPARTMENT OF DEFENSE AND NIAID OVER 30 YEARS HAS BEEN CONDUCTING BASIC AND CLINICAL RESEARCH ON A MODEST LEVEL TRYING TO UNDERSTAND THE SCIENTIFICALLY INTERESTING AND UNIQUE BUT VERY EXOTIC VIRUSES. IN THE AFTERMATH OF 9/11 AND BIODEFENSE FUNDING WAS INCREASED AND DEPARTMENT OF HOMELAND SECURITY ISSUED A MATERIAL THREAT DETERMINATION FOR EBOLA IN 2006 AND THIS INERBIATED HHS INVOLVEMENT IN TERMS OF SPECIFIC COUNTERMEASURES. THE FIRST HUMAN VACCINE TRIAL WAS INITIATED BY THE VRC IN 2006. AS A RESULT OF THOSE EFFORTS AND D.O.D. WHICH HAD BEEN WORKING IF ARE A LONG TIME ON VACCINES ACTUALLY MOVED THEIR TRI-VALENT VACCINE TO ADVANCED DEVELOPMENT IN 2010. THE RECOGNITION AT THE TIME PRIOR TO THIS OUTBREAK WAS THAT AS FILL AS DISCUSSED THE ANIMAL ROLE, THAT WAS OUR EXPECTATION. WE VALID TO LICENSE THE VACCINE BY THE ANIMAL RULE AND RNIZING THERE WERE A LOT OF QUESTIONS MANY OF WHICH WILL BE DISCUSSED TODAY. WE ESTABLISHED AROUND 2010, A USG WIDE GROUP THAT HAS--PROBABLY THE BEST NAME I THINK HAS THE BEST NAME IN GOVERNMENT FEIGNING, STANDING FOR PHILOVIRUS ANIMAL NONCLINICAL GROUP THAT WOULD BRING TOGETHER THAT WOULD STAND TOGETHER AND TRY TO GET AN UNDERSTANDING. THIS INVOLVED MOST OF THE BSL FOUR LABS FOR STANDARDIZATION AND COOPERATION THAT I DON'T THINK WE'VE SEEN PREVIOUSLY. IN 2011 NIAID PROVIDED I PRECLINICAL SERVICES TO DEVELOPERS ACROSS A WIDE ARRAY OF THREATS AND SINCE 2011 WE EVALUATED UNDER BSL CONDITIONS, PROBABLYOT ORDER OF ABOUT 30 DIFFERENT FORMULATIONS OF PHILOVIRUS CANDIDATES AND THIS HAS BEEN A VALUABLE SERVICE BECAUSE WE RECOGNIZE IT FROM AN INDUSTRY STANDPOINT, AVAILABILITY AND LIMITATIONS OF BSL FOUR WERE REALLY CONSTRAINS THE ABILITY OF THE PRIVATE AND EVEN THE PUBLIC SECTOR TO MOVE THESE TYPES OF PROJECTS FORWARD. SO WHERE WE ARE NOW IN TERMS OF VACCINE SPECIFICALLY, THERE ARE THREE CANDIDATES TO IT WHICH ARE ALREADY IN PHASE ONE TRIALS AND WE'LL HEAR SOME OF THOSE RESULTS, THE THIRD ONE IS READY TO BEGIN VERY EARLY, EARLY NEXT YEAR, THERE'S BEEN A NUMBER OF PHASE ONE TRIALS THAT HAVE BEEN INITIATED NOT ONLY HERE BUT REALLY BOTH IN EUROPE AND IN AFRICA AS WELL AND THAT WORK UP IS PROCEEDING AND THAT'S WHAT WILL BE THE TOPIC OF THIS DISCUSSION. I THINK BEYOND THE CURRENT OUTBREAK, THERE ARE A NUMBER OF ADDITIONAL EBOLA VACCINE CANDIDATES THAT ARE BEING PURSUED, SOME OF WHICH ARE GEARING UP FOR LATER INTO 2015 TO THE INITIATING CLINICAL TRIALS BUT I THINK A LOT OF WHAT GOES ON HERE WILL HELP TO INFORM THE FUTURE DEVELOPMENT AND THE PROGRESS OF THOSE PROJECTS. IN ADDITION THE USG HAS ACCEPTED THAT IN TERMS OF PREPAREDNESS AGAINST FILO THREATS HAVE BEEN DETERMINED AND HOW TO USE THOSE AND THESE ARE EXOTIC VIRUSES WE KNOW THERE'S OTHER FILOs, THERE'S OTHER STRAINS THAT HAVE TO BE ADDRESSED AND WE'RE CONTINUING EVALUATING STRATEGIES AND PLATFORMS THAT NEED TO BE ADDRESSED. IF THERE'S NO MORE, I WILL TAKE A FEW QUESTIONS BUT I THINK IT'S VALUABLE TO MOVE ON TO THE MEET OF THE DISCUSSION. [ APPLAUSE ] PHILOVIRUS >> --YOU ARE VIEWING THE VIDEOCAST FROM, YOU WILL ALLOW YOU TO SUBMIT COMMENTS FOR THE SPEAKERS AND LEARNING PERHAPS WE SHOULD GIVE IT A MINUTE OR SO TO SEE IF WE HAVE QUESTIONS BEFORE YOU KNOW WE--THAT THE NEXT SPEAKER TAKE THE PODIUM. OKAY, I THINK SEEING OR HEARING THIS IS NOT THE CASE LET ME INTRODUCE THE LAST SPEAKER OF SESSION ONE. STANLEY REALLY DOESN'T NEED AN INTRODUCTION SO WE ARE GRATEFUL FOR STANLEY TO BE HERE AND PROVIDE US WITH THE DISCUSSION ON CORRELATES OF VACCINE INDUCED IMMUNITY IN RELATION TO EBOLA. >> THANK YOU MARION. SO MY FIRST SLIDE IS VERY OBVIOUS, NOBODY WILL ARGUE WITH IT THAT CORRELATES OF IMMUNITY ARE IMPORTANT FOR A NUMBER OF REASONS. BASIC IMMUNOLOGY, CHOICE OF VACCINE ANTIGEN, PHIL HAS REFERRED TO MANY OF THESE, PERMISSION SHOWING CONSISTENCY OF POTENCY, DETERMINATIONS, SUSCEPTIBILITY OF AN INDIVIDUAL OR POPULATION AND THEN OF COURSE, RELATION TO REGULATORY ISSUES, LICENSURE OF A VACCINE WHICH INCLUDES BRIDGING FROM FIRST GENERATION VACCINES TO SECOND GENERATION VACCINES WHICH IT'S NO LONGER POSSIBLE TO DO AN EFFICACY STUDY. NOW UNLIKE ALICE IN WONDER LAND, WORDS ARE IMPORTANT HERE, SEMANTICS ARE IMPORTANT. A CORRELATE PROTECTION IS AN IMMUNE RESPONSE THAT IS STATISTICALLY INTERRELATED WITH PROTECTION. THERE ARE ABSOLUTE CORRELATES WHERE THERE IS A THRESHOLD, A SPECIFIC LEVEL OF RESPONSE, BUT IN MANY CASES, THE CORRELATES ARE RELATIVE. THAT IS TO SAY THAT AT CERTAIN LEVELS YOU GET A PERCENTAGE OF PROTECTION. IF HIGHER LEVELS INCREASE LEVELS YOU GET HIGHER LEVELS OF PROTECTION, AND AS I SHOW YOU THERE ARE SITUATIONS WHERE THERE ARE MULTIPLE CORRELATES, NOT JUST ONE IMMUNOLOGIC MARKER. NOW PETER GILBERT AND I TRIED TO DRAW UP A SEMANTIC DEFINITION THAT WOULD ALLOW CLARIFICATION. SO WHAT WE CALL A MECHANISTIC CORRELATE OF PROTECTION IS ACTUALLY THE IMMUNE RESPONSE THAT IS RESPONSIBLE FOR PROTECTION, WHETHER IT'S A NEUTRALIZING RESPONSE OR A CD-EIGHT RESPONSE BUT THAT IS WHAT PROTECTS, THAT'S THE MECHANISTIC CORRELATE. ON THE OTHER HAND A NONMECHANISTIC CORRELATE IS WHAT USED TO BE CALLED A SURROGATE IS AN IMMUNE RESPONSE THAT SUBSTITUTES FOR THE TRUE IMMUNOLOGIC CORRELATE OF PROTECTION WHICH MAY BE UNKNOWN OR NOT EASILY MEASURABLE BUT THIS AGAIN STATISTICALLY CORRELATES WITH PROTECTION. NOW CORRELATES ARE DETERMINED TO HAVE BEEN DETERMINE INDEED A VARIETY OF WAYS, LEVELS OF PASSIVELY ADMINISTERED OR MATERNAL ANTIBODY THAT PROTECT AND HERE'S WHERE PRODUCTS SUCH AS Z-MAP MIGHT BE USEFUL OR OTHER MONOCLONAL ANTIBODIES. ANALYSIS OF THE IMMUNE RESPONSES IN PROTECTED AND UNPROTECTED SUBJECTS AND EFFICACY TRIALS WHICH AS PHIL MENTIONED IS A CLASSIC WAY OF DETERMINING A CORRELATE OF PROTECTION, OBSERVATIONS MADE ON VACCINE FAILURES THAT IS IMMUNO SUPPRESSED OR CONGENITALLY OR ARE OTHERWISE IMMUNO SUPPRESSED INDIVIDUALS. HUMAN CHALLENGE STUDIES WHICH OF COURSE ARE NOT POSSIBLE FOR EBOLA AND EXTRAPOLATION FROM ANIMAL CHALLENGE STUDIES INCLUDING IMMUNO DEFICIENT ANIMALS. NOW I DON'T HAVE TO TELL THIS AUDIENCE THAT THERE ARE MANY DIFFERENT IMMUNE FUNCTIONS THAT COULD BE CORRELATES OF PROTECTION AND I'M NOT GOING TO GO THROUGH THIS LIST BUT A INCLUDE VARIOUS KINDS OF ANTIBODY, VARIOUS KINDS OF CD4 T-CELL RESPONSES PRODUCTION OF CYTOKINES, ET CETERA, MUCOSAL ANTIBODY AND EVEN CDEIGHT T-CELLS AS I WILL MENTION IN PASSING ALSO HAVE DIFFERENT FUNCTIONS THAT MUST BE TAKEN INTO ACCOUNT. SO WHAT ARE THE PRINCIPLES AS A TRIED TO DEFINE THEM. WELL FIRST YOU HAVE TO DEFINE PROTECTION AGAINST WHAT? PROTECTION AGAINST INFECTION OR SEVERITY OF DISEASE? AND THEY--THOSE TWO CORRELATES MAY DIFFER IN FACT. FOR EXAMPLE, PROTECTION AGAINST DISEASE IN POLIO IS MEDIATED BY IGG SERUM ANTIBODIES, WHERE PROTECTION AGAINST NAISAL PHARYNX AND MEDIATION IS PROTECTS AGAINST IGA AND IGG MUCOSAL ANTIBODIES. AND TAKING THE EXAMPLE OF PNEUMOCOCCAL VACCINE, CAN YOU PROTECT AN INDIVIDUAL MORE EASILY AGAINST VIREMIA THAN AGAINST NASAL FAIR AN KNEEL, AND THE VAC REAMIA AGAINST PNEUMONIA, AGAINST OTITIS OR CARRIAGE DIFFER IN KWAUBTITY. THE NEXT IS THE MECHANISM OF PROTECTION BY VACCINATION IS NOT NECESSARILY THE SAME MECHANISM AS RECOVERY FROM INFECTION. THOSE TWO MUST BE DISTINGUISHED. AN INDIVIDUAL AFTER INFECTION MOUNTS DIFFERENT IMMUNE RESPONSES TO CONTROL THE INFECTION. AN EXAMPLE OF THAT IS MEASLES. WE ALL KNOW THAT THERE ARE LEVELS OF MEASLES, ANTIBODIES THAT ARE PROTECTIVE, IF YOU HAVE MORE THAN A 120 MILLION INTERNATIONAL UNITS, YOU'RE PROTECTED AGAINST CLINICAL MEASLES, YOU MAY BE INFECTED WITH MEDIUM TITERS BUT THAT'S A SYMPTOMATIC, AND SOME INDIVIDUALS TO RECOVER FROM THIS AND OTHERS SUFFER FATAL, IN OTHER WORDS THEY CAN'T CONTROL THE INFECTION IF THEY ARE INFECTED DESPITE THE PRESENCE OF ANTIBODIES. AND CAN YOU SHOW THAT IN A PRIMATE SYSTEM THAT MONKEYS VACINATED WITH MEASLES,UME O GLUTEN ALONE WHICH INDUCES A LO CD-FOUR T-CELL RESPONSE ARE PROTECTED AGAINST RASH BUT REMAIN CHRONICALLY I HAVE REAMIC AND CDEIGHT T-CELLS ARE CRITICAL IN CLOSING OFF VIREMIA, AND THE NEXT PRINCIPLE IS THAT A LARGE DOSE CAN OVERCOME IMMUNITY AND I THINK THAT IS OPERATIVE THAT MAY VERY WELL BE OPERATIVE IN THE CASE OF EBOLA. HERE IS THE EXAMPLE OF OPV AND CHALLENGE OF EITHER OPV VAC THESE, PREVIOUSLY VACINATED INDIVIDUALS OR IPV VAC THESE, AND AS A LOW DOSE WAS AS OPPOSE TO A HIGH DOSE WHICH WAS 10 TO THE FOUR OR 10 TO THE FIVE, YOU CAN SEE THE DIFFERENCE IN THE PERCENTAGE OF INFECTION, EVEN IN INDIVIDUALS WHO WERE CORRECTLY VACINATED. THE NEXT PRINCIPLE IS WELL KNOWN AND THAT IS THAT MOST CURRENT VACCINES DO PROTECT THROUGH ADANTIBODIES. AND I WON'T GO THROUGH THIS SLIDE IN DETAIL BUT THE REASON IS THAT MOST OF THE DISEASES FOR WHICH WE HAVE ACSEENS AT LEAST ACT THROUGH VIREMIA OR BACTERIAEREMMIA OR MUCOSAL ANTIBODIES ON THE MUCOSA OR PRODUCE TOXINS WHICH CAN BE NEUTRALIZED. AND IN THE CASE OF RABIES THERE'S AN ATTACHMENT THROUGH THE NERVOUS SYSTEM. THE NEXT EXAMPLE IS THAT CORRELATES MAY BE RELATIVE AND THE EXAMPLE OF THAT IS INFLUENZA. AN ANALYSIS OF A STUDY WAS DONE WITH AN INFLUENZA VACCINE. ON THE X-AXIS IS THE ANTIBODY THAT WAS INDUCED. ON THE Y-AXIS IS THE LEVEL OF PROTECTION. AND YOU CAN SEE THAT THE CLASSICAL ONE-40 WHICH IS ACCEPTABLE TO REGULATORY AUTHORITIES ONLY PROTECTS ABOUT 50% OF SUBJECTS, WHEREAS HIGHER LEVELS OF ANTIBODY GIVE A HIGHER LEVEL OF PROTECTION. SO THIS AGAIN IS AN EXAMPLE OF THE RELATIVE CORRELATE. AND THIS IS ANOTHER RELATIVE IMPORTANT CORRELATE, THIS IS AN EXAMPLE FROM A MENJIN-OCOCCAL STUDY. THIS WAS STUDIED IN QUEBEC AND YOU CAN SEE THE EFFICACY THEREOF IN DIFFERENT AGE GROUPS. AND THE POINT HERE AS YOU KNOW IS THAT WITH A POLYSACCHARIDE VACCINE INFANTS DO NOT DEVELOP BACTERIAER ICIDAL ANTIBODIES AND THEY WERE NOT PROTECTED AND ADULTS AND OLDER CHILDREN TO SOME EXTENT WERE ABLE TO MEANT THE ANTIBODIES AND WERE PROTECTED. SO FUNCTION IS EXTREMELY IMPORTANT AND WE HAVE OTHER EXAMPLES, THE IMPORTANCE OF AGCC ANTIBODY AGAINST HIV IN THE TRIAL, AND COLLEAGUES AND I RECENTLY PUBLISHED A REVIEW, THERE ARE OTHER EXAMPLES, ADCC ANTIBODY AGAINST INFLUENZA, RSV, CMV, ALPHA VIRUS, THESE ARE ALL PUBLISHED DATA. MEDIATED CYTOTOXICITY, FAG - -PHAGOCYTOSIS THAT SHOULD BE STUDIED AS WELL AS EBOLA. NEXT IS THAT T-CELL RESPONSES MAY BE CORRELATES. NOW I HAVE TO ADMIT WE DO NOT KNOW AND THIS IS A BIG PROBLEM--WE DO NOT KNOW WHAT THE CORRELATIVE PROTECTION IS FOR TUBERCULOSIS, HOWEVER WITH BOVINE TB THERE IS THIS STUDY PUBLISHED THAT SHOWED THAT THE INTERFERON-GAMMA SECRETNG T-LYMPHOCYTES DID CORRELATE WITH PROTECTIVE IMMUNITY IN COWS. NOW, I DON'T KNOW WHETHER THAT APPLIES TO HUMAN DISEASE OR NOT. BUT THE POINT HERE IS THAT THIS T-CELL FUNCTION DID CORRELATE WITH PROTECTION IN THAT SYSTEM AND AS FAR AS MALARIA IS CONCERNED AND WE HAVE MALARIA EXPERTS IN THE AUDIENCE, BUT IT DOES SEEM THAT THE COMBINATION OF ANTICIRCUMSPOROZOITE PROTEINS AND TNF ALPHA PRODUCING CD4 + T-CELLS ARE NECESSARY FOR THEM TO PROTECT. SO AN EXAMPLE OF THE COMBINATION OF T-CELL AND ANTIBODY RESULTS. AND EVEN WITH THE SPOROZOITE, THE VACCINE WHEREAS THE ANTIBODY IS IMPORTANT, THE BEST EFFICACY IS ACHIEVED BY GENERATING CD4 T-CELLS IN THE BLOOD AND VERY INTERESTINGLY CD-EIGHT T-CELLS IN THE LIVER EMPLOY ORGAN SPECIFIC T-CELLS. AND THEN THERE'S THE WORK FROM THE LEWIS LAB FOR THE CMV AND IN THESE EXPERIMENTS IT WAS CARRYING IMMUNODEFICIENCY GENES, HE WAS ABLE TO ELICIT 50% PROTECTION AGAINST CHALLENGE SIMPLY WITH THE CDEIGHT RESPONSE. HOWEVER, IT WAS NECESSARY THAT THAT CDEIGHT T-CELL RESPONS BE AN EFFECTOR RESPONSE RATHER THAN A MEMORY RESPONSE AND I THINK THIS ESTABLISHES AN IMPORTANT NEW PRINCIPLE WITH REGARD TO CDEIGHT T-CELLS AND THEN, MORE THAN ONE FACTOR MAY PROTECT THE CO-CORRELATES. ACTIVE INFLUENZA IN THE ELDERLY FOR EXAMPLE. WE KNOW THAT H. A. I. NEUTRALIZING ANTIBODIES AND SERUM CORRELATE WITH PROTECTION AGAINST INFLUENZA THAT STIMULATION OF T-FOLLICULAR HELPER CELLS EXISTS IN PRACTICES ANTIBODIES SO CLEARLY AEBT BODY IS IMPORTANT HOWEVER IN THE ELDERLY ANTIBODY RESPONSES ARE POOR AND CDEIGHT RESPONSES RATHER THAN CD4 RESPONSES CORRELATE WITH THE ANTIBODY RESPONSE AND CDEIGHT, CTL INDEPENDENTLY CORRELATES WITH PROTECTION, AND LIVE ATTENUATE INFLUENZA VIRUS AND THE INTRA NASAL VACCINE, IT HAS BEEN SHOWN MANY YEARS AGO IN FACT THAT EFFICACY DEPENDS ON SERUM IGG, ON MUCOSAL IGA AND ON CDEIGHT, T-CELL RESPONSES SO WE HAVE WITH LAIV, WE HAVE AN EXAMPLE OF THREE CO CORRELATES EACH OF WHICH IS RESPONSIBLE STATISTICALLY FOR PROTECTION. OF COURSE IT'S THE SUM OF THOSE THAT GIVES THE VACCINE IT'S EFFICACY. THEN LASTLY WHAT ABOUT NONMECHANISTIC CORRELATES OF PROTECTION, THE VACCINE CONTAINS LARGE AMOUNTS OF INFECTIOUS AND NONINFECTIOUS VARY CELLOUS VIRUS, AND IT ALSO PROTECTS, NOW THE ANTIGEN STIMULATES THE FLAGGING CELLULAR IMMUNITY IN THE ELDERLY. WE ALL KNOW THAT ZOSTER IS A REPLICATION OF VARICELLA VIRUS LODGED IN THE BASAL ROOT GANGLIA, SOW WHEN WHEN IT IS ESTABLISHED IN THE MERCK STUDIES WAS LICENSE SPOT RESPONSES TO THE VZ ANTIGEN. HOWEVER, THE ANTIBODY TO THE GLYCOPROTEIN OF THE VIRUS, ONE OF THE GLYCOPROTEINS WAS ALSO STATISTICALLY CORRELATED WITH PROTECTION AND PETER GILBERT HAS JUST RECENTLY PUBLISHED A BEAUTIFUL PAPER ON THE ANALYSIS OF THE FACT THAT ANTIBODY IN THIS CASE DOES CORRELATE WITH PROTECTION EVEN THOUGH IT IS UNLIKELY TO BE WILL THE MECHANISTIC CORRELATE. THAT PAPER IS IN--I BELIEVE IN CLINICAL INFECTIOUS DISEASES. AND ANOTHER EXAMPLE IS ROTOVIRUS VACCINES. NOW I PERSONALLY HAVE SPENT SOMETIME IN THIS AREA, BUT I HAVE TO ADMIT THAT WE DO NOT HAVE A FIRM CORRELATE FOR PROTECTION FOR ROTOVIRUS VACCINES. WE KNOW THAT NEUTRA ANTIBODIES ARE RESPONSIBLE FOR HOMOTYPIC IMMUNITY DIRECTED AGAINST THE VPFOUR AND SEVEN SURFACE PROTEINS. WE KNOW THAT ORALLY ADMINISTER GAMMA GLOBULIN CAN PROTECT BUT WE ALSO HAVE FOUND THAT NONNEUTRALLIZING ANTIBODIES MAY ENACTIVATE INTRACELLULAR VIRUS, AND ANTIBODY IN THE INTESTINE BOTH IGA AND IGG IS ASSOCIATED WITH PROTECTION BUT IT'S OF COURSE DIFFICULT TO MEASURE. AND THEN THERE'S AN ANTIGEN CALLED VP SIX WHICH INDUCES BOTH ANTIBODY AND AND CELLULAR RESPONSES AND THERE IS STILL CONTROVERSY ABOUT WHICH OF THOSE IS IMPORTANT. IS THE CELLULAR RESPONSE GIVING YOU SOME HETEROTYPIC IMMUNITY BECAUSE WE SEE A LOT OF HETEROGENEOUS ROW TYPIC IMMUNITY WITH THE VACCINE, IT IS NOT ONLY A QUESTION OF INDUCING A HOMOTYPIC RESPONSE. AND THEN, THE INTERESTING THING IS THAT ON THE OTHER HAND, IF YOU MEASURE SERUM IGA RESPONSES, WHICH ARE UNLIKELY TO BE THE REAL MECHANISM OF PROTECTION BUT NEVERTHELESS, THOSE RESPONSES DO CORRELATE WITH PROTECTION IS SERUM IGA RESPONSES THEREFORE ARE QUITE USEFUL IN MEASURING THE ABILITY OF A ROTOVIRUS VACCINE TO PROTECT. SO LET ME THEN COME TO MY LAST SLIDE AND LET ME TRY TO SUMMARIZE MY VIEW OF THIS ISSUE. ANTIBODY INDUCTION, AGAIN, I SPEAK NOT AS AN EXPERT IN EBOLA, BUT FROM MY POINT OF VIEW, IT APPEARS THAT ANTIBODY INDUCTION IS ESSENTIAL. NOW WHETHER THAT ANTIBODY IS NEUTRALIZING OR NOT, IT SEEMS TO BE IS A CRITICAL ISSUE. THERE AS I IMPICIZED THERE ARE MANY DIFFERENT WAYS ANTIBODY MAY ACT, I WOULD BE INTERESTED TO SEE STUDY OF MACROPHAGE ENTRY OF EBOLA VIRUS AND WHICH MAD NONAPOPTOTIC BODIES PROTECT AGAINST MACROITAGE ENTRY IS IT A FAG O SIGNIFYITOSEIS PHENOMENON OR SOME OTHER PHENOMENON THAT IS OCCURRING FELT ANOTHER POINT IS EPITOPE SPECIFIC ANTIBODY MAY BE KEY. THE EXAMPLE IS DENG UE VACCINE WHERE IT APPEARS THAT ANTIBODY AGAINST THE DOMAIN ONE-TWO HINGE MAY BE MORE IMPORTANT THAN JUST GENERAL ANTIBOS TO DENGUE. THE FOURTH POINT IS THAT CELLULAR IMMUNITY COLLABORATES WITH ANTIBODY AND I CAN WELL IMAGINE THAT IN THE CASE OF EBOLA IF YOU HAVE HIGH LEVELS OF ANTIBODY, HAVE YOU PROTECTION, BUT IF HAVE YOU LOW LEVELS OF ANTIBODY, A CELLULAR RESPONSE MAY BE KEY IN SUPPORTING PROTECTION AND I'VE GIVEN YOU AN EXAMPLES, TULUREAMIA IS AN EXAMPLE OF COLLABORATION OF ANTIBODY AND CMI. MY LAST POINT, I THINK, IN ING OATISM IS AN IMPORTANT ONE AND THAT IS FOR LICENSURE, IN MY VIEW A NONMECHANISTIC CORRELATIVE PROTECTION MAY BE SUFFICIENT IF IT CORRELATES WITH EFFICACY IN A CLINICAL TRIAL OR PERHAPS WE DON'T NEED TO GO TO THE ADENO-RULE ANYMORE BUT IF WE HAVE A STATISTICAL CORRELATION WITH AN ANTIRESPONSE, THAT IN MY OPINION SHOULD BE SUFFICIENT FOR LICENSURE AND THE EXAMPLES I'VE SHOWN YOU ARE ZOSTER AND ROTOVIRUS. AND I LIKE--OOPS. AND I LIKE TO SHOW THIS SLIDE AS THE LAST ONE SHOWING THAT CORRELATES PROTECTION ARE A SPECTRUM FROM ANTIBODY PURE ANTIBODY ON ONE HAND SUCH AS THE NEUTRALIZATION OF THE ANTHRAX TOXIN, THE ZOSTER WHERE THE CELLULAR RESPONSE IS IMPORTANT, BUT NONE OF THIS GAINS A POINT WHERE THEY TRY TO EMPHASIZE THAT A STATISTICAL CORRELATE SHOULD BE SUFFICIENT FOR LICENSURE REGARDLESS OF WHETHER IT IS MECHANISTIC OR NOT. AND THAT'S MY OPINION. THANK YOU VERY MUCH. [ APPLAUSE ] >> SO THANK YOU, STANLEY. WE HAVE A COUPLE OF MINUTES. ARE THERE QUESTIONS? >> HI, ERIC FROM THE FDA, I APPRECIATE YOUR COMMENTS CONCERNING THE CORRELATES OF PROTECTION, BUT I WONDERED AND I DIDN'T NOTICE IN YOUR TALK, ANY DISCUSSION OF THE DURABILITY NECESSARY FOR SOME OF THESE CORRELATES WE MAY FIND IN EBOLA THAT WE HAVE INITIAL RESPONSES IN ANTIBODY TITER OR CMI RESPONSE BUT SIX MONTHS OR MONTHS DOWN THE LINE WE MAY NOT BE ABLE TO DETECT THAT RESPONSE. ALSO I NOTICE THAD YOU DIDN'T MENTION ANYTHING ABOUT THE KINETICS OF THE RESPONSE, MAYBE NECESSARY IN THE CASE OF EBOLA TO HAVE A RAPID RESPONSE SHORTLY AFTER INFECTION AND THAT MIGHT EFFECT SURVIVAL. DO HAVE YOU ANY THOUGHTS ABOUT EITHER OF THOSE TWO ISSUES? >> YEAH, I THINK THOSE POINTS ARE WELL TAKEN. DURATION OR DURABILITY OF PROTECTION IS A KEY ISSUE IN VACCINOLOGY. I MEAN WE HAVE EXAMPLES, UNFORTUNATELY, WE HAVE GOOD EXAMPLES OF WANING IMMUNITY TO VACCINATION BUT, LET'S--LET'S TAKE THE CASE OF PERTUSSIS FOR EXAMPLE, WHICH IS MORE OR LESS THE MOST OBVIOUS ONE AT THE MOMENT. THERE IS A CORRELATION WITH LOS OF ANTIBODY TO PT. AND THAT TO ME SEEMS AGAIN TO FURTHER INTERNATIONAL CLASSIFICATIONICATE THAT ANTIBODIES TO PERTUSSIS TOXIN ARE NOT JUST TO THE SOLE CORRELATE BUT AN IMPORTANT CORRELATE OF PROTECTION AGAINST PERTUSSIS. SO CLEARLY ONE WANTS PREFERABLY A VACCINE TO GIVE A DURABLE MEASURABLE RESPONSE. BUT, THAT BEING SAID, I WOULD STILL MAINTAIN THAT IF YOU CAN SHOW THE CORALATION WITHIN A FEW MONTHS AFTER VACCINATION, THAT REMAINS A USEFUL CORRELATE EVEN IF IT DOES--DOESN'T DISAPPEAR EVENTUALLY. SO, I THINK THAT'S MY RESPONSE TO THAT AS FAR AS KINETICS IS CONCERNED, OF COURSE, ONE DOES WANT A AS RAPID A RESPONSE AS POSSIBLE. AS I UNDERSTAND IT, THE INCUBATION PERIOD OF EBOLA IS ABOUT EIGHT-10 DAYS. AND IF ONE COULD MOUNT A RESPONSE WITHIN THAT PERIOD OF TIME THAT WOULD BE GREAT. >> [INDISCERNIBLE] FROM FDA. STAN, YOU MADE A VERY IMPORTANT POINT ABOUT POTENTIAL USE OF NONMECHANISTIC CORRELATES FOR LICENSURE, MY QUESTION IS: AS PHIL IN HIS PREVIOUS PRESENTATION MENTIONED THAT ONE OF THE WAYS, ONE OF THE USES OF CORRELATIVE PROTECTION BY REGULATORS IS TO BRIDGE TO POPULATIONS WHERE THE EFFICACY STUDY WAS NOT DONE. SO DO HAVE YOU ANY CONCERNS ON USING A NONMECHANISTIC CORRELATIVE PROTECTION TO BRIDGE TO A DIFFERENT AGE POPULATION WHERE IT MAY NOT BE SO STRAIGHT FORWARD. >> WELL, NO. I THINK THAT--LET ME SAY PARENTHETICALLY THAT PEDIATRIC STUDIES NEED TO BE DONE AS SOON AS POSSIBLE. IT'S A GENERALIZATION FOR ALL VACCINES BUT IT'S A PARTICULAR ONE FOR THIS ONE. I DO NOT SEE WHERE THE CORRELATE SHOULD BE DIFFERENT IN CHILDREN THAN IT IS IN ADULTS, MY REDICTION WOULD BE THAT THEY'RE GOING TO RESPOND BETTER THAN ADULTS AND I THINK WE COULD USE THE SAME INDICATOR. NOW, I DON'T MEAN TO SAY THAT I WOULDN'T LIKE TO HAVE A MECHANISTIC CORRELATE. I WOULD LOVE FOR EXAMPLE IF IT COULD BE SHOWN THAT A PARTICULAR TYPE OF ANTIBODY WAS A MECHANISTIC CORRELATE BUT IN THE ABSENCE OF THAT, CONSIDERING THE URGENCY OF HAVING A VACCINE, I WOULD BE IN FAVOR OF USING ANY STATISTICAL CORRELATE THAT WE CAN OBTAIN FROM OUR VACCINE STUDIES. >> I THINK WE CAN TAKE TWO MORE QUESTIONS, THANK YOU. >> [INDISCERNIBLE]--SORRY--NOT WORKING TOO WELL, STANLEY THANKS VERY MUCH. WE HAVE CURRENTLY AND IN THE NEAR FUTURE TWO OR THREE DIFFERENT--VERY DIFFERENT KINDS OF VACCINES AND THE MECHANISM OF PROTECTION COULD POTENTIALLY BE DIFFERENT. SO DO HAVE YOU ANY COMMENTS ON ESTLISHING THE CORRELATES AND THEN TRYING TO LOOK ACROSS DIFFERENT TYPES OF VACCINES? >> WELL, YES, I DO THINK THAT EACH VACCINE WILL HAVE TO BE LOOKED AT SEPARATELY. I MEAN I DON'T THINK ONE CAN NECESSARILY GENERALIZE, HOWEVER, MY IMPRESSION FROM THE LITERATURE IS THAT EACH OF THE VACCINES WE HAVE DO GENERATE AN ANTIBODY RESPONSE AND AGAIN, I LOLLED TO HAVE THE ANTIBODY DEFINED BETTER BUT IF THERE IS A--WHETHER IT'S EAN EALIZA OR ANOTHER CORRELATE, IT SHOULD BE APPLIED TO ALL OF THE VACCINES BUT IF IT CAN BE SHOWN IN LET'S SAY A STUDY WITH VACCINE X, THAT IS NOT ANTIBODY BUT A PARTICULAR CELLULAR RESPONSE THAT IS A STATISTICAL CORRELATE, I WOULD GO WITH THAT. FOR THAT VACCINE. >> [INDISCERNIBLE] FROM INTEGRATED VIRAL THERAPEUTICS, I WANT TO MAKE A COMMENT ABOUT WHAT YOU SAID ABOUT THE T-CELL RESPONSES AND ANTIBODIES. WE DID A STUDY FOR EBOLA AND IN CLOSE TO A HUNDRED MONKEYS WHERE WE LOOKED AT THE PROTECTION VERSES ANTIBODY TITERS AS WELL AS--BASICALLY WE LOOKED AT ANTIBODY TITERS BUT THERE WERE TWO DIFFERENT GROUPS OF VACCINES USING DOSE STUDIES, SOME THAT WOULD INDUCE T-CELL RESPONSES AND SOME THAT ARE NOT EXPECTED TO INDUCE STRONG T-CELL RESPONSES AND WE SAW THAT THE REQUIREMENT FOR ANTIBODY PROTECTIVE ANTIBODY TITER IN THOSE VACCINEES WHO HAD THE VIRUS OR VIRUS PARTICLES I THINK NUCLEAR PROTEIN THAT IS KNOWN TO INDUCE STRONG T-CELL RESPONSES BECAUSE IT'S I THINK IT'S IMPORTANT TO-- >> THANK YOU FOR THAT AND I THINK IT BOLSTERS WHAT I WAS TRYING TO SAY, HIVE LEVELS OF ANTIBODY MAY NOT NEED CELLULAR RESPONSES, LOWER LEVELS THAT THOSE RESPONSES MAY BE QUITE IMPORTANT. THANK YOU. >> WELL, THANK YOU SO MUCH, IT IS TIME TO MOVE ON TO SESSION TWO. WE ADJOURN SESSION ONE. THANKS. >> I'M NELSON MICHAEL FROM THE WALTER REED. WE ARE TWO AND HALF MINUTE PESHIND SCHEDULE SO I WON'T KEEP YOU, OUR FIRST SPEAKER IS DANIEL BAUSCH, WITH THE SUMMARY OF EBOLA INFECTION AND DISEASE. >> WITH THAT I'M HERE TO DEFEND MYSELF. I AM FILLING IN FOR DAN, HE'S NEUROLOGICALLY INCONVENIENCED BY ANOTHER VIRUS, DAN SENDS HIS BEST. DAN AND I SWITCH HIT ON OUTBREAKS AND WE SEE THINGS VERY MUCH THE SAME WAY, BUT SO TOO DOES THE GROWING COMMUNITY OF EBOLA CLINICIANS WHO ARE WREFLTLEING THE PROBLEM WITH HOW WE CONDUCT CLINICAL TRIALS OF ETUs. WELL THE FOCUS OF OUR TALK THIS MORNING IS THE IMMUNITY TO EBOLA NATURALLY ACQUIRED OR INDUCED, I THINK IN OUR PERIPHERAL VISION, THERE'S LESSONS TO BE LEARNED FROM OUR EXPERIENCE WITH ANTIINFECTIVES DESIGNING THE STUDIES SO REPRESENTING HERE IS A LARGER GROUP OF FOLKS, SO THIS IS JAMES LAWLER WHO HAS THE EXPERIENCE OF BOTH BEING IN THE BL-FOUR AND HAVING WORKED IN A NUMBER OF EBOLA OUTBREAKS AS WELL AND ALSO OUR NG Os. WE DEPEND QUITE HEAVILYOT ACCESS TO THEIR ETUs AND THE EXPERIENCE TO ALLOW US TO PRODUCE TREATMENT BENEFIT TO DRIVE DOWN THE CASE FATALITY RATES SO WE HAVE AN INTENTIVE FROM THE COMMUNITY PATIENTS TO BE SEEN AND THEN WE CAN INSTRUCT OR CONSIDER THE R-WORD, RANDOMIZE CASE STUDY. SO WE WILL TALK ABOUT THAT AT THE END OF THE DITION CUSHION, I WANT TO START BY LAWING THE EXTRAORDINARY CONTRIBUTION FOR ALL YEARS INVEST INDEED THE AMAL MODEL FOR EBOLA BUT I WILL TELL YOU AFTER FIVE OUTBREAKS AND 1177 PATIENTS THAT I'VE SEEN PERSONALLY THAT THIS EPIDEMIC TOOK US BY SURPRISE AND WE HAVE A LOT MORE HUMILITY THAN WE DID IT IN ZERO AND GULU AND WEEJ, AND SHOULD WHAT WE USED TO CALL EBOLA ZAIRE, BUT IT HAS A CLINICAL SYNDROME. SO WHILE THERE ARE LESSONS LEARNED, FROM THE MODELS THERE ARE SYNDROMES THAT HAVEN'T BEEN REPLICATED AND THIS IS A CAUTIONARY NOTE THAT WE NEED TO KEEP IN MIND. SO THERE'S AN EIGHT YEAR-OLD CHILD THAT CAN HELP ME ADVANCE THE SLIDES, I'M IN GOOD SHAPE. >> OKAY, THERE ARE DISCLAIMERS HERE, THE TOP ONE IS MASS GENERAL HOSPITAL, I ALSO HAVE A COMMERCIAL CONNECTION TO NEVERROLOGY, NO OTHER COMMERCIAL CONFLICTS BUT I AM GOING TO TALK ABOUT COMMERCIALLY AVAILABLE PRODUCTS. OMINOUSLY I WILL TALK ABOUT NONFDA APPROVED PRODUCTS, NOT IN THE OFFLABEL USE INDICATION BUT THE FACT OF THE MATTER IS THAT IN THE CLINICAL TRIAL MANAGEMENT SITES, IN THOSE ETUs, THERE AREAZIAN MANUFACTURED RAPID DIAGNOSTIC TESTS TO HELP AND DETAILS DIFFERENTIAL DIAGNOSIS TO GET THOSE MALARIA PATIENTS OUT OF ETU BEFORE THEY BECOME INFECTED AND LASTLY, THE OPINIONS HERE DO NOT INCLUDE THE OPINIONS OF THE U.S. DEPARTMENT OF DEFENSE, THE U.S. GOVERNMENT, AND MY NG Os AND PH O COLLEAGUE WHO IS CONTRIBUTED TO THE DATA SETS. OKAY. SO, MOVING ON. GOING TO POINT THIS AT SOMEBODY. >> OKAY, NOT GOING TO TOUCH IT. OUR FOCUS WILL BE CLINICAL BUT IN ORDER TO EXPAND OUR THINKING WE REALLY NEED TO UNDERSTAND A LITTLE BIT MORE ABOUT THE OBSERVATIONS THAT ARE COMING FROM THE COMMUNITY AND TO RECONCILE THE EXPERIENCES OF PRIOR OUTBREAKS WITH THE CURRENT OUTBREAK. SO WE WILL SPEND THREE OR FOUR MENUTES ON THE TOP BULLET FOCUING ON ON FEATURES OBSERVATIONS RELEVANT TO THE ACQUISITION OF CONVALESCENT IMMUNITY IN HUMANS AND THE IMPLICATIONS FOR CONDUCTION OF PROSPECTIVE ELECTRIC BEING TRIAL AND EFFICACY TRIAL FOR A VACCINE. WITH THAT, JUMP RIGHT INTO IT, THERE'S OBVIOUSLY A SLIDE AND THIS IS THE TWO DAY OLD SLIDE, IT IS INTERESTINGLY REPORTED BY THE LIBERIAN MINISTRY OF HEALTH, BY THE SIERRA LEON GOVERNMENT AND FROM THE REPORTS THAT SAY WE DON'T HAVE A PROBLEM TODAY. I WANT TO EMPHASIZE A COUPLE POINTS WHICH WE'RE GOING TO BE HAUNTING US AS WE CONSIDER OUR WE CONDUCT OUR TRIALS AND DELIVER CARE. YOU KNOW THE OUTBREAK WHICH YOU MIGHT NOT APPRECIATE THOUGH IS THAT IT'S THREE WEEKS IN MONITOR ROVIA BETWEEN APRIL AND JUNE WE AMASSED THE GREATER COLLECTIVE EXPERIENCE IN ALL PRIOR OUTBREAKS, IT IS URBAN AND RURAL, THE CO-LOCATION OF PATIENTS SEEKING HEALTHCARE AND URBAN HEALTH CENTERS AND WE'RE PROTECTED, THE GOOD NEWS FOR THIS IS WE'RE PROTECTED BY ALMOST THREE MONTHS BY THE RAINS, PREVENTING TRAVEL TO EPIY CENTERS IN GINA AND LIBERIA PREVENTED THE CRUSHING OF THE PUBLIC HEALTH SYSTEM UNTIL THE END OF JULY AND AUGUST. SO SEASONALITY IS IMPORTANT MITIGATING FACTOR IN REDUCING THE [INDISCERNIBLE] OF THIS OUTBREAK. THE CO LOCATION OF ESTATES WITH ONE MILLION WITH DIRECT FLIGHTS TO EUROPE AND ASIA IS AN IMPORTANT POINT TO REEMPHASIZE HERE NOT JUST BECAUSE OF THE AIR TRAVEL BUT BECAUSE OF THE 36, 36,000 FILIPINOS AND THE INDOTHESIAN, THAT WENT HOME TO JAKARTA, AND THEN THE SEVERAL THOUSANDS OF ASIANS THAT WENT TO LIBERIA WITH THAT WE DODGED ONE BECAUSE THEY RESILIENCE TURNED TO LARGE CITIES WITH A GOOD PUBLIC HEALTH INFRASTRUCTURE IN WHICH IT WOULD HAVE BEEN DIFFICULT TO MOUNT A RESPONSE, IT'S INTERCONTINENTAL, THAT BRINGS US TO BULLET NUMBER TOIRE. YOU HEAR ABOUT THE PATIENTS THAT ARE GET ACROSS THE BORDERS AND ARE IDENTIFIED YOU DON'T HEAR THE PATIENTS THAT ARE TURNED BACK AT THE BORDERS, THIS CALCULATION TELLS US ABOUT THE NEWLY SOPHISTICATED iPHONE EXPECTATIONS QUIPPED INTERNET SAVVY INDIVIDUALS THAT ARE DESPERATELY SEEKING HEALTH CARE FOR A CHILD LOVED ONE. CASE FATALITY RATE IS WOBBLING. THE TRAGEDY IS THAT IN OCTOBER AND DECEMBER OUR CASE FATALITY RATE VARIED AS MUCH AS 19% AND SIMILARLY EQUIPPED ETUs. SO WHAT WE'RE TRYING TO DO WITH THE HOST AND W. H. O. PARTNERS AND IS TO PRODUCE A CASE FATALITY RATE THAT IS CONSISTENT AND LOW. TO USE THE WORDS OF AUTONOMY AND FOULERS DOING THE SIMPLE STUFF SUPERBLY, THE AGGRESSIVE USE OF THE SIMPLE THERAPIES TO PRODUCE TREATMENT AND INCENTIVIZE SEEKING CARE IN ETUs, THAT GETS TO YOU TO THE BASELINE TO CONDUCT STUDIES. AND THIS IS THE STUFF AS LISA POINTED OUT AND INDICATES. THE SURVIVAL COHORT IS THE SURVIVING EBOLA IMMUNITY. SO MAPPING THESE PATIENTS FORENSICALLY AND UNDERSTANDING HOW THEY GOT THERE WITH THE INDUCTION OF NAIVE IMMUNE RESPONSE, LET'S CALL IT THE INTERFERONS AND THE INDUCTION OF EDJ RECOMBINATION AND IDJ AND SWITCHING AND LOOKING AT THAT HOW THEY ARE RESPONDING IN OUR ETUs REQUIRES THAT WE INVEST IN RESEARCH CAPACITY THERE. EBOLA LIGHT, A TERM COINED BY THE LIBERIAN COLLEAGUES REFERS TO THE EBOLA INFECTED PC R CONFIRMED PEOPLE WITH VIRAL LOADS RUNNING TO THE THIRD AND FOURTH POWER. SO WHY DID THEY GET OFF THE HOOK? WHY DID THEY GET OFF LIGHT? SO MAPPING THESE PATIENTS CAN BE VERY REVEALING FOR US AND WE ARE COMPELLED TO TAKE A CLOSE LOOK AT. THIS THIS DISEASE IS HIGHLY REGUARDED AS BECOMING ENDEMIC BECAUSE OF THE PIRCYST ENSEL IN THE BRUSH FIRES IN THE COMMUNITY, THE LONG INCUBATION PERIODS BETWEEN EXPOSURE BUT ALSO BECAUSE OF THE PRESENCE OF VIABLE VIRUS, NOT JUST PC R POSITIVE BUT VIRUS IN SEMEN IN THE BREAST MILK AND VAGINAL SECRETIONS PUBLICATIONS ARE IMPRESSED ON THOSE ISSUES AND ALL ACCOUNTED FOR SPOUSAL EBOLA PATIENTS WHO ARE INFECTED BY OUR CONVALESCE ENSEL LEAVING THE ETU. AND LASTLY OVER THE GATES DONATIONS OVER THE YEARS JUST TO ACKNOWLEDGE THE GOOD WORK IN EBOLA AND HIV PREVENTION, EBOLA KILLS TWICE, IT KILLS HEALTHCARE WORKERS AND DESTRUCTS THE COMMUNITIES BUT IT IS A SMART BOMB FOR THE HEALTHCARE INFRASTRUCTURE SO ALL THE ROUTINE THINGS THAT CAN BE SAVED OVER THE YEARS DISAPPEAR UNTIL YOU REPOPULATE THOSE CENTERS. THIS IS A DISCUSSION OF HUMAN IMMUNITY SO WHY THE BAT? AND IT HAS TO DO WITH WE SHOULD LEAVE NO OPTION IMMUNOLOGICAL SPEAKING ON THE TABLE. BATS ARE ACTUALLY MODELED AS THE NUMBER ONE ANIMAL FOR LATERAL VACCINATION. BY STANDARD VACCINATION BECAUSE THEY DO KACCT RUES, SOCIAL GROOMING, USE OF ANTIFUNGALS, WHITE SYNDROMES SET UP THE PROSPECT WE COULD ERADICATE THE DISEASE IN THE CELL RESERVOIR ISSUE, AS WE HAVE DONE WITH OTHER WILDLIFE DISEASES, RABIES AND DISTEMPER, THE MED TERRAINION AREAS DO NOT HAVE THIS, VERY INTERESTING. THIS IS CHICKLET AND THIS IS ALSO ACROSS THE BORDER IN CHOCOLATE CITY KH-RBGS IS ACROSS THE SWAMP FROM GFK HOSPITAL, YOU'RE LOOKING AT THE EARLIER IMPROVIDE ETURBGSS FROM SPRING AND USING THIS TO DEMONSTRATE THAT THESE ARE HIGHLY CONTAGIOUS ENVIRONMENTS AS YOU KNOW AND I UNDERSTAND THIS GROUP IS VERY, QUANTED WITH THE KNOWLEDGE OF WHERE THE VIRUS IS IN HIGH AND LOW CONCENTRATIONS AND AT THE END OF THE SLIDE THERE'S A REFERENCE FOR YOU ABOUT THAT, WHAT I NEED TO POINT OUT THOUGH IS THE FINE PATHWAY GIVES TINA OF EBOLA THAT IS THROUGH THE ETU AND THE FACT THAT THIS THAT DOESN'T MEAN IT'S INFECTIOUS VIRUS, WHEN YOU SWAP THE WALL AND THE RAILINGS AND YOU GET A POSITIVE PC R THAT DOES NOT MEAN VIABLE VIRUS SO SOMEWHERE IN OUR CALCULATION WE SHOULD CONSIDER VIABLE VIRUS QUANTITATION AS AN INDICATOR OF THE MULTIPLICITY OF INFECTION. THAT BRINGS ME TO THE BOTTOM POINT IS I LOST PERSONALLY NINE HEALTH CARE WORKERS IN THE OUTBREAKS, FIVE OUTBREAKS GOING BACK TO 2003. MANY OF THEM EARLY ON WE WERE PROTECTING OURSELVES IN TRASH BAGS AND GOGGLES AND FLASH GUARDS WE ACKNOWLEDGE THAT THE INTPEBLGT UGZ DOCUMENTED HAVE SHORTER INCUBATION PERIOD THAN THOSE IN THE COMMUNITY. THIS NEEDS TO BE SCIENTIFICALLY MONITORS WITH GOOD INCIDENT MANAGEMENT OF THOSE EXPOOED POSURES AND LONGITUDINAL PC R TESTING SO IT'S IMPORTANT ACKNOWLEDGMENT OF THE MULTIPLICITY OF INFECTION OR INFECTIOUS DOSE. TO THE MORE DEEPLY SEEDED ISSUES REGARDING CLINICAL DISEASE, IS WE ACCEPT THE TWO-21 DAY INDUE BATION PERIOD PRACTICES EXPOSEDDURE, WE FIND IT DISQUIETING THAT A NUMBER OF THOSE PATIENTS 12% ARE CLOSER TO ON 22 DAYS OR CLOSER TO 21 DAYS SO THIS MIGHT LEAD TO AN EXPANSION EVER THIS WINDOW OF THE PREINCUBATION PERIOD. QUITE MAGNIFICENTLY OUR SYMPTOMS STILL APPEAR BEFORE WE GET A VIRAL LOAD. IT'S INTERESTING AND HELPFUL FOR US WHEN WE'RE MANAGING OUR ETU POPULATION AND OUR HEALTH CARE WORKERS USING MONITORING AND THEN WE PUT THEM INTO THE PC RQ FOR HEALTHCARE WORKERS TO GET INFECTED. WE KNOW THAT PATIENTS BECOME INCREASINGLY MORE CONTAGIOUS AS THE VIRAL LOAD ESCALATES, AND WE HAL LOAD BTUs AND 10-THE EIGHTH, IT IS ASSOCIATE WIDE HIGHER MORBIDITY AND MORTALITY AND SHORTER TIMELINES TO DEATH AND WE REFER TO THE EBOLA LIKE PATIENTS. THIS NEEDS TO BE REPEATED WITH HUNDREDS OF PATIENTS WITH ETUs, WITHSTAND ARDIZEED PC R PROTOCOLS NORMALIZED ACROSS THE NG Os AND THE ACADEMIC MEDICAL TEAMS. FOR YOUR REFERENCE BECAUSE THIS IS AN IMMUNOLOGY CENTERED TALK, YOU NEED TONED THE DIAGNOSTIC DILEMMAS WE HAVE IN THE FIELD. WHEN THESE PATIENTS COME IN AND HAVE PEB RILE SYNDROMES THEY INCLUDE FEBRILE SYNDROMES THAT WILL STYMIE YOUR SURVEILLANCE DATA. YOUR IMMUNOLOGIC DATA. ON THIS LIST ARE THE THREE BIGGEST OFFENDERS THAT WRECK YOUR LIFE AND USE DENGUE THE LITERATURE NS-ONE, AND THIS IS SPORADIC IN OUR WEST AFRICA, CHIK, MALARIA AND THEN DOWN THE LIST RICKETTSIA, AND HIV, AND BOTH OF THOSE ELITE OFFENDERS IN DEGRADING THE QUALITY OF YOUR SURVEILLANCE DATA WE NEED TO ACCOUNT FOR THAT, BUT AGAIN THESE NUMBERS, 4 PERCENT IN MONITOR ROVIA, THEY PRODUCE BIG MEDICAL MANAGEMENT ISSUES BECAUSE THEY'RE ON THE METABOLIC ACIDOSEIS IS THAT EBOLA OR COMPA VIR, DO I RESCIND HIV THERAPY. T'S NO PLAY BOOK FOR THIS. SO WE ARE OPERATING OFF OUR POINT OF CARE DEVICES IN OUR CLINICAL JUDGMENT AND WE'RE GETTING SOME OF THIS WRONG FOR SURE. WE HAVE A LOT OF HUMILITY ABOUT THIS ISSUE. DATA COMING OUT AS YOU KNOW. MANY FOLKS SHARED THEIR DATA WITH US BECAUSE THEY UNDERSTAND WHAT WE'RE PRESENTING TO YOU. JUST A COUPLE REAFFIRMATIONS FROM LIBERIA OVER TO SIERRA LEON, IF TWO OF THE HIGH THREE PROGNOSTIC VARIABLES FOR DEATH IN HUMANS ARE ADVANCED AGE WHICH NOW IN WEST AFRICA IS 38 YEARS OF AGE IS ONE OF OUR CUT OFFS. IT'S INDICATED 45 HERE ON THE LEFT SIDE OF THE CHART AND THE INCREASED VIRAL LOAD WHICH HAS BEEN REPLICATE INDEED MULTIPLE STUDIES AND HAPPILY THE ANIMAL MODELS. IN OUR CLINICAL PRESENTATION, I JUST NEED TO REAFFIRM A COUPLE KEY POINTS AND THAT'S THAT THIS SCIENCE AND SYMPTOMS APPEAR BETWEEN FIVE AND 10 DAYS, WE HAVE PNEUMONIC WE TEACH TRADITIONAL HEALERS, THE EBOLA FIVE BY FIVE WAS REWRITTEN AFTER THREE OUTBREAKS FOR THIS ONE, WE HAVE VOMITING AND DIARRHEA BY THE FIFTH DAY AS A DOM NAT NATURE WHICH CORRELATES TIGHTLY WITH THE PC R. THEY COME WITH FIVE SYMPTOMS IN FIVE DAYS WE'RE IN THE 90 PERCENTILE OF CORRELATION, PRETTY GOOD IF YOU'RE TALKING TO A PRODITIONAL HEALER WHO IS REFERRING CASES TO YOU. BUT THE VOMITING AND DIARRHE IS SOMETHING I WANT TO FOCUS ON. YOU HEARD OF THE GENERAL EBOLA STUFF, IT'S LIKE THE GENERAL PARTICLE BURG STUFF BUT THE GENERAL GI IS 2.75 TIMES GREATER THAN THE LAST EBOLA WE SAW. AND IN SUDAN IT'S COPIOUS AND MAJ OR INFECTIOUS DISEASE, SOILED LINENS AND LARGE ORGANIC HYDRATED Ph NEUTRAL MEDIA THAT IS ALLOWED THE VIRUS TO BE RECOVERED AND AS PROVEN FROM SHELL VILE ASSAYS, THE BIGGEST ISSUE FOR US. THE ISSUES THAT I JUST WANT TO EMPHASIZE IS THERE ARE OTHER POINTS TO BE MADE. ONE IS THE VOMITING AT THE FRONT END, AND THE WATERY DIARRHEA AT THE REAR END IS SPARING THE SMALL BOWEL. THE PROXIMAL SMALL BOWEL IS ABSORBING NUTRIENTS, IS ABSORBING ELECTROLYTES SO WE'RE REPLETING ORALLY WITH KCL, SO IT'S NOT END TOENT, WE CAN MAINTAIN ALBUMIN THREE, WHEN WE FEED THESE PATIENTS THAT'S IMPOSSIBLE TO DO OTHERWISE, OTHER ANOMALIES, HICK UPS AND BAD PROGNOSTIC INDICATOR, IS THAT AND LASTLY THE CO AG LOPATHY. ENDS UP HERE IS THE FACT THAT WE FOR THE FIRST TIME HAVE GENERATED COLONOSCOPY OR ADENOOSCOPY OF THESE ENTHUSIASMER O PATH EIGHT HOURS PATIENTS AND INDICATED AT THE BOTTOM IS THE COLLEAGUE'S WORK AT THE ETU, THAT IS NOT A CHOLERA BOWEL, SO ANYBODY WHO IS PUTTING THEM ON LOMODDAL, THEY'RE DOING THEM A DISSERVICE, IT'S HEMORRHAGIC INFLAMMATORY BOWEL DISEASE, SO LAST POINT, YOU CAN'T IMAGINE CLINICALLY WHAT THE POETIC IT SAYSIUM DEFICIT, AND THEY'RE HYPER OS MOLAR, THEY'RE Ph AND YOU CAN GET ROUGH APPROXIMATIONS THE WAY WE HAVE DONE FOR YEARS AND WE'VE SHOWN EIGHT HOURS SIGNIFICANT REDUCTIONS BY BRINGING THE RIGHT STUFF INTO THE UNIT AT THE RIGHT TIME. WITHOUT ENDORSING A COMMERCIAL PRODUCT, THE WAY WE HAVE SIGNIFICANTLY INDUCED FATALITY RATE SYSTEM BACK UP WITH POINT OF CARE DEVICES, SO WHETHER YOU USE A PICELLA, IS ALLOWS TO YOU REDIRECT THESE PATIENTS WHY AM I EMPHATIC ABOUT THIS POINT. BECAUSE WE'RE AT THE CUSP OF THINKING ABOUT PHASE TWO STUDIES, TO THINK YOU CAN DO THAT CLINICALLY AND MYSTERIOUS, YOU CAN BE THE. AND YOU CAN'T DO YO-LACTIC ACIDOSEISATE LEVELS YOUR RESUSCITATION, YOUR ANTI MICROBIAL THERAPY, DEPENDING ON THESE FROM ASCHEMIC BOWELS IN 18% OF OUR DYING PATIENTS OVER THERE THESE ARE THINGS THAT US WARRANT DOING MORE IN THE UNIT. THAT WAS MY LAST KEY POINT BUT I'LL END WITH THE POINT THAT THESE TECHNOLOGIES THAT WE'RE THINKING OF BRINGING INTO THE ETU, NEED TO BE SET UP TO DO MULTLE STUDIES AND WE STILL HAVE WORK TO DO TO CORRELATE AND COORDINATE ACROSS THE DIFFERENT CARE DELIVERY GROUPS THERE. EVERYBODY KNOWS ABOUT THE CYTOKINE KASP A RICATE SO MY LAST SLIDE IS THE NONFATAL CASES VERSES NATAL CASES ARE LEADING LIST OF WINNERS IN THIS PUBLICATION WILL BE IN ABOUT SEVEN-NINE WEEKS NOW, FINAL REVIEW IS THAT TIKITNIA IF THEY HAVE A METABOLIC ACIDOSEIS AND THEY'RE TACHYPNEA, YOU'RE LIABLE TO LOSE THEM BECAUSE THEY'RE NOT FIXING THE Ph. SO YOU NEED TO KNOW THE Ph IS A VERSES ACIDOSEIS. THIS DUE TO SECONDARY PNEUMONIA, GI WE TALKED ABOUT, IF THEY'RE LOSING SEVEN LITERS OVER SIX DAYS THERE'S 96% CORRELATION OF DEATH AMONG 409 FATALITY SO THERE'S A QUANTITATIVE NUMBER TO THROW IN THERE. WE DIDN'T TALK ABOUT THAT MANY WEST AFRICANS HAVE HYPERTENSION AND ARE ON LOOP DIURETICS. AND THEN THEY BECOME ACIDOSEIS. SO WOO A FICTITIOUS NUMBER, AND WE DO THIS DURING BLOOD DRAWS AND WE REPLETE THESE PATIENTS AND WHY DID THEY DIE THE NEXT MORNING OVERNIGHT BECAUSE OF ARITHMETRICSAS, AND REMEMBER THEY SELF-TREAT 18% OF THE TIME BEFORE THEY SHOW UP. AND THEY MIGHT BE COUNTERFEIT MALARIAL OR RDT TEST AND LASTLY THE VAC REAMIA WE TALKED ABOUT AND METABOLIC ACIDOSEIS. ALL RIGHT, SO WHAT HAVE WE DONE, MULTIPLE--66 EBOLA CLINICIANS FROM 19 COUNTRIES AS WELL AS THE W. H. O., EMS, HOST NATIONS OF LIBERIA, CONGO AND SIERRA LEON TO CONDUCT TRIALS FOR THE TROPICAL MEDICINE AND ETHICAL REVIEW GROUPS ISSUE, THE FDA RECENTLY PUBLISHED AND BOB PUBLISHED WE NEED BASIC SUPPORTIVE CARE. EVERYBODY'S COME TO THE SAME CONCLUSION THAT WE NEED TO PRODUCE A STABLE NONWOBLING CFR THAT DRIVES DOWN FACAS TAILITY RATES BEFORE YOU ENTER THE PROSPECT OF RANDOMIZATION FOR PLACEBO CONTROLLED STUDIES. OT RIGHT IS THE LIBERIA PROTOCOL AND YOU CAN SEE THAT WE'RE NOW INTO THE LOW 50S AND HIGH 49%. THAT WAS MY LAST SLIDE. AND IN THE BACK UP SLIDES YOU WILL SEE--OKAY. IN THE BACK UP SLIDES YOU WILL SEE A BUNCH OF REFERENCES SO PLEASE IF YOU HAVE ANY QUESTIONS, THESE SLIDES WILL BE MADE AVAILABLE FOR THE ORGANIZERS, THANK YOU FOR YOUR TIME AND SORRY FOR THE BREVITY. [ APPLAUSE ] >> SORRY FOR THE TIME BUT WE NEED TO KEEP MOVING BUT THE NEXT SPEAKER IS PETER JAHR LING FROM NIAID FROM ANIMAL MODELS OF DISEASE AND NATURAL HISTORY STUDIES. >> GOOD MORNING, SO WE'RE SHOOTING FOR WHO WAS INVITED TO GIVE THIS TALK BUT SHE WAS DEPLOYED TO MONITOR ROVIA MONROVIA FOR THE LAST TIME--IT JUST STRIKES ME LISTENING TO THE THEME OF THIS SYMPOSIUM TODAY GOING BACK ABOUT 40 YEARS IN MY FORMATIVE DAYS LISTENING TO MAURICE, IS THAT THE ONLY WAY TO ROUGH ATOM TEBGZ IS PROTECTION AND SOMETIMES I BEING WE HAVEN'T GOT MUCH FURTHER THAN THAT. SO ANIMAL MODELS FOR EBOLA ARE BEING STUDIED IN ALL OF THE BSL-FOUR TAKEN--THEY SILLITIES IN COUNTRY AND ABROAD NOW. MOST OF THE WORK IS DONE IN NONHUMAN PRIMATES SIN CYNOMOLGUS MA CABBINGS OR RHESUS MACAQUES. ALSO THERE'S A NUMBER OF MOUSE MODELS, RABIDS, RATS GUINEA PIGS, STRAIN 13 AND OUTBRED HARTLEYS AND RECENTLY WORK AT THE ROCKY MOUNTAIN LABS IN HAMSTERS AND FERRETS. SO I THINK WE ALL HAVE A VISUAL FEEL THAT THE NONHUMAN PRIMATE MODELS ARE PROBABLY THE BEST, PROBABLY GIVE US THE MOST FAITHFUL REPRESENTATION OF THE HUMAN DISEASE AND WE ALSO RECOGNIZE THAT YOU CAN'T REALLY EXTRAP O LIGHT FROM INVITRO TO RODENTS AND NONHUMAN PRIMATES AND HUMANS BUT WE TRY TO MAKE THOSE CORRELATES ALL THE TIME AND WHAT I'M GOING TO TRY TO SHOW TODAY IS THAT THE NONHUMAN PRIMATES RECAPITULATE AT LEAST SOME OF THE MAJOR FEATURES OF WHAT MICHAEL AND OTHER VS TOLD US ABOUT THE HUMAN DISEASE. I THINK WE KNOW A WHOLE LOT MORE ABOUT THE PATHOGENESIS OF THESE DISEASES IN PRIMATES THAN WE DO IN HUMANS WHICH MAKE ITS HARD TO COMPLIGHT WITH THE ANIMAL EFFICACY RULE WHERE YOU HAVE TO SHOW THAT IT'S FAITHFUL TO THE HUMAN DISEASE BUT I FOR BETTER OR WORSE, I THINK WE'RE BEGINNING TO GET THAT INFORMATION OUT FOR THE FIRST TIME. IN LOOKING AT VARIOUS ANIMAL MODELS YOU HAVE TO RECOGNIZE THAT IF YOU TARGET HOST FUNCTIONS THIS COULD BE IMPACT BIDE SEVERAL SPECIES DIFFERENCES SO THINGS THAT EFFECT ON AGULATION KASP A RICATES FOR INSTANCE AND WHAT HAVE YOU MAY NOT BE TRANSLATABLE FROM ONE ANIMAL TO THE OTHER. AND ALSO DRUG METABOLISM CAN COMPLICATE EFFECTIVE DOSING. WE LEARN THAT NOT WITH EBOLA BUT WITH [INDISCERNIBLE] FOR A COUNTER MEASURE FOR SMALLPOX OR MONKEYPOX, IT HAS A SHORT PK IN NONHUMAN PRIMATES AND YOU CAN'T DO ALL THE STUDIES IN PRIMATES FOR THAT REASON AND THERE ARE SUBTLE DIFFERENCES LIKE THAT THAT WE'RE NOW BEGINNING TO FULLY APPRECIATE. ALSO ESPECIALLY NOW THERE'S A LOT OF EMPHASIS ON REPURPOSES DRUGS THAT HAVE BEEN DEVELOPED FOR OTHER PURPOSES. YOU KNOW? WE'RE LOOKING RIGHT NOW IF YOU CAN BELIEVE IT AT ZOLOFT AS A COUNTER MEASUR, IF IT DOESN'T CURE EBOLA IT MAKES YOU FEEL BETTER AND THERE MAY BE OTHER OFFTARGET EFFECTS BUT WE TRY TO MODEL THE ANIMAL MODAGAINST THE HUMAN CONDITION. THERE'S A LOT OF VARIABLES, IT'S VERY COMPLICATED. THE TABLE IN THE BOX THERE SHOWS VARIOUS THERAPIES IN THREFB PATIENTS HOSPITALIZED RECENTLY. YOU SEE ALL KINDS OF HYDRATION, WHAT HAVE YOU, ANTIBIOTICS ALL KINDS OF TREATMENT WHICH COMPLICATES THE UNDERSTANDING OF THE DISEASE, WE HEARD ABOUT FLUIDS AND WHAT HAVE YOU, AND IF WE'RE DOING--IF WE'RE DOING ANIMAL STUDIES, THERE'S A REAL DIFFERENCE BETWEEN AN INTERVENTIONAL STUDY AND ONE WHICH YOU HAVE SEQUENTIAL SACRIFICE. SO LET'S TALK A LITTLE BIT ABOUT THE ANIMAL MODELS FOR EBOLA ZAIRE, MOST WORK HAS BEEN DONE WITH RECESS OR CYNOs AND WE ARGUE WHETHER IT'S A APPROPRIATE DOSE OR NOT. USUALLY IT'S AN INTRA MUSCULAR CHALLENGE BUT ON THE EXPOSE PURE EYE AEROSOL. EBOLA ZAIRE, BY THE ARROW SOUL ROOT IS INFECTIOUS DOWN TO BASICALLY EXTINCTION, CAN YOU TITRATE DOWN TO PFU AND GET UNIFORM INFECTION WHICH IS QUITE SCARY. CNOMOLUS, AND MACAQUES IS ABOUT THE SAME. THE GUINEA PIG MODEL, WE DID MOST OF THE DEVELOPMENT WORK IN STRAIN 13S BUT RECENTLY SINCE THEY'RE BECOMING HARD TO FIND ADAPTED IT TO HARTLES. AND GUINEA PIG MODEL REQUIRES USE OF A GUINEA PIG ADAPTIVE SEED WHICH WHICH IS NOTHING MORE SEQUENTIAL THAN FOUR TO EIGHT TIMES IN GUINEA PIG SPLEEN. IT'S UNDOUBTEDLY A PHENOTYPIC SWARM, DIFFERENT GUINEA PIG SEAT VS DIFFERENT VIRULENCES AND DIFFERENT--VERY DIFFICULT TO COMPARE DATA ACROSS DIFFERENT PLATFORMS AND DIFFERENT LABS. THE MOUSE MODEL AGAIN IS A MOUSE ADAPTED, EBOLA, AGAIN, SEQUENTIAL PASSAGE TO WARM IT UP WHEN IT GETS COLD TO WARM IT UP AGAIN, AND IT'S MOST AUFB DONE IN BALB-C MICE. AND AS I MENTIONED AT THE ROCKY MOUNTAIN LAB THEY'RE BEGINNING TO UTILIZE HAMSTERS FOR THIS PURPOSE. NOW THIS IS A VERY BUSY SLIDE HERE. BUT IT SHOWS, YOU KNOW A NUMBER OF FEATURS IN ALL THE VARIOUS DIFFERENT ANIMALS. THEY ALL GET FEVER. THEY ALL GET I HAVE REAMIC, ALTHOUGH VIREMIA IN GUINEA PIGS IS SOMEWHAT LESS THAN IN THE MACAQUES. ALL HAVE ELEVATIONS IN LIVER ENZYMES. LIP O PENIA, NEWT ROW PENIA, NOT SO MUCH IN MYSELF. RASHES ARE SEEN IN THE MACAQUES BUT NOT IN RODENTS. LEVELS OF D-DIMER VS NOT BEEN TESTED BUT ARE SEEN IN CYNOS, AND NOT IN RECESS AND IN ALL CASES THE IN VIVO TARGET CELLS SEEM TO BE MONOCYTES MACROPHAGES, DENDRITIC CELLS AND THE LIKE AND MASSIVE INCREASES IN CIRCULATING CYTOKINES AS MICHAEL MENTIONED, THE FAMOUS CYTOKINE STORM THAT WE ALL THINK HAS SOMETHING TO DO WITH THE PATHOGENESIS OF THE DISEASE. THESE ARE THE THINGS THAT CAN JUST BE MEASURED AND I DON'T NEED TO DWELL ON THAT. WHAT DO WE KNOW ABOUT EBOLA IN R-MACAQUES? IT'S A SEVERE DISEASE, IT'S CHARACTERIZED BY HOST IMMUNE RESPONSE, MAJOR FEATURE IS BI STANDER LYMPHOCYTE APOPTOSIS, PRO INFLAMMATORY CYTOKINES AND D IC, YOU SEE THIS IN MACAQUE BUT NOT IN THE MICE. BUT THE QUESTION IS, WHAT TRIGGERS THESE CLINICAL MANIFESTATIONS HOW MUCH IS DUE TO REPLICATION OF THE VIRUS AND HOW MUCH IS THE HOST RESPONSE TO THE VIRUS AND ONCE YOU UNDERSTAND THAT, WHAT CAN YOU DO ABOUT IT. IF YOU LOOK AT THE DEVELOPMENT OF DISEASE AND PRIMATES, IT'S FIRST OF OFF A VERY RAPID DISEASE, MOST ANIMALS ARE DEAD BY DAY EIGHT OR NINE WHICH MAKE ITS TRUNCATED FOR THE HUMAN CONDITION AND YOUR WIND O OF OPPORTUNITY FOR INTERVENTION IS SOMEWHAT DELAYED. FAIRLY EARLY ON, DAY OR TWO OR THREE DAYS OUT THEY BEGIN TO DEVELOP FEVER, SOON THEREAFTER YOU GET DEVELOPMENT OF VIREMIA, AGAIN WHAT MICHAEL TOLD US ABOUT THE HUMAN CONDITION. OOPS. AND--OKAY AND VIREMIA GOES UP TO ABOUT SEVEN LOGS BY THE TIME THE ANIMALS ARE DEAD. I DON'T HAVE TIME REALLY TO SHOW THE DATA BUT IF YOU CAN KEEP THE VIREMIA BELOW ABOUT SIX LOGS BY WHATEVER INTERVENTION, YOU'RE PROBABLY GOING TO EFFECT SURVIVAL. GO ABOVE SIX LOGS AND IT'S PROBABLY GOING TO END IN DEATH AT LEAST IN THE MONKEYS. DEVELOPMENT OF DISEASE CAN BE MONITORS EARLY ON BY MICROARRAY ANALYSIS AND INTERFERON ALPHA COMES UP FAIRLY EARLY. AND AGAIN, D-DIMERS CORRELATES WITH THE SEVERITY OF DISEAS. YOU KNOW THAT THE CELLS TARGETED ARE THE IMMUNE CELLS, THERE'S LYMPHOCYTE APOPTOSIS, DRASTIC DEPLETION OF NK-CELLS AND CDEIGHTS, APOPTOSIS IS VISIBLE IN CIRCULATING CELLS AND TISSUE SECTIONS, THIS SHOWS THE DIFFERENT POPULATIONS OF PBMCs THAT ARE INFECTED BY EBOLA, COUR CELLS BEING THE MOST PROMINENT. AND IT'S THE SAME DATA. >> SO EARLY INFECTION OF MONOCYTES AND MACROPHAGES AND SUBSEQUENT FEEDING OF THE SPLEEN AND LYMPHNODES YOU CAN DETECT THE VIRUS PRESENCE IN ITS--IT'S THE RED ANTIGEN IN THE GREEN AND YOU CAN SEE THE EFFECTED SIDE IN THE MACROPHAGE ON THE RIGHT. YOU CAN CONFIRM THIS BY ELECTRON MICROSCOPY SHOWING INFECTION OF MACROPHAGES LOADED WITH NUCLEIC ACIDS AND CONFIRM THAT THESE CELLS ARE INFECT WIDE EBOLA BY IMMUNO GOLD. NOW IF WE GO LOOK A LITTLE BIT LATER AT THE TIME WHEN THE ANIMALS ARE NO SYMPTOM ATATTIC AND THIS IS COMPARABLE TO WHEN PATIENTS COME TO THE ETU, YOU HAVE VIREMIA, SEEDING OF MAJOR ORGANS, CHANGES IN CHEMICAL HISTORIES AND HEMEATOLOGY, CYTOKINES AND THE DEVELOPMENT OF SOME CO AG LOP CATHY AND I AGAIN I THINK THIS IS PROBABLY FAIRLY SIMILAR TO WHAT'S BEING SEEN WHEN THE PATIENTS SHOW UP A LITTLE BIT LATE AT THE ETU. THE DISEASE OFTEN PROGRESSES TO [INDISCERNIBLE] AND SHOCK AND I WAS ACTUALLY SURPRISED IN MICHAEL'S DAT A WAS UNDER THE IMPRESSION THERE WAS A SIGNIFICANT AMOUNT OF VACCOREMMIA ASSOCIATED WITH LATE STAGES WE DO SEE THAT IN OUR MONKEYS, WE USED TO THINK WE HAVE LOUSY TECHNIQUE AND NOW WE UNDERSTAND THAT IN THE FINAL STAGES MANY OF THESE ANIMALS ARE VAC REAMIC AND CONTRIBUTES TO THEIR SHOCK. AND JUST THE--YOU KNOW THE COAGULOPATHY WITH ALL THE BUSINESS [INDISCERNIBLE]. SO, OKAY, HERE'S JUST HISTOPATHOLOGY SHOWING LYMPHOID DEPLETION AND FOLLICULARINOSE ESTIMATE THAD AND WHITE PULL'M IN MACROPHAGES MARGINAL SIGN USS ARE CONGESTED ANDIFIABLE RIN IN RED. PROGRESSION OF VIRAL ANTIGEN IN THE LIVER, LIVER IS MAJOR SITE OF REPLICATION, PROBABLY SEEDS SECONDARY VIREMIA AND LARGE CONCENTRATIONS OF ANTIGEN IN THE LIVER WITH THE ACCOMPANYING HISTOPATHOLOGIC CHANGES YOU WOULD EXPECT TO SEE. THERE IS A DUODENAL LESION AND WE SEE IT WITH THE HEMORRHAGIC FEVERS BUT IN SOMEWHAT DIFFERENT FROM WHAT'S BEING SEEN IN THE HUMANS. WE'VE DONE A NUMBER OF TELEMETRY STUDIES, THIS IS [INDISCERNIBLE] STUDIES WHERE YOU SEE TRACING OUT OVER THE EIGHT DAYS THAT YOU KNOW FEVER GOES UP, RESPIRATORY RATE GOES UP, EVENTUALLY THEY GO INTO SHOCK AND AGAIN THIS--PATIENTS WERE MONITORED BY TELEMETRY WOULD SEE SOMETHING SIMILAR TO. THIS SO EVERYTHING I'VE SHOWN YOU UP TILL NOW HAS BEEN WITH EBOLA, PROBABLY [INDISCERNIBLE], OR VERY RECENTLY, GARY COKEINGER GOT THE WEST AFRICAN STRAIN IN GUINEA IN THE INITIAL OBSERVATION WAS THAT THE ANIMALS DIED VERY RAPIDLY WITH LESIONS THAT WERE SOMEWHAT DIFFERENT FROM THE WHAT WE WERE USED TO SEEING. SO WE--WE FINALLY GOT OUR CDC [INDISCERNIBLE] WE ATTEMPTED TO REPEAT THE STUDY. AND HERE'S YOUR CAP LANMEYER, SHOWS THE ANIMALS ARE ALL DEAD, SIX ANIMALS MEDIAN TIME TO DATE 8.3 DAYS AND REALLY THIS IS NO DIFFERENT FROM EBOLA ZAIRE, IN OUR HANDS. IF YOU LOOK AT CONVENTIONAL STUFF, BUNs ARE SKY ROCKETING AT THE LATE STAGES, SAME WITH KRE TINSA TYPES, AND ASD ALL UP VERY SIMILAR TO WHAT WE'VE SEEN BEFORE--YEAH. AND I'M NOT GOING TO BELABOR THE COAGULATION CASCADE. WE ALL UNDERSTAND THE CENTRAL ROLE IN PATHOGENESIS. AND OKAY, I'LL JUST THAT IN GOING BACK NOW TO THE CONVENTIONAL MODEL WE HAVE USED IT TO TEST A NUMBER OF STRATEGIES WE USE THE ACTIVATED PROTEIN C OR ZYGERS WAS DEVELOPED FOR PERACCEPT SUSAND IT DID HAVE A BENEFICIAL EFFECT AND IT WAS INTERESTING WE SAVED ABOUT A THIRD OF THE ANIMALS, A THIRD OF THE ANIMALS WERE--DIED AS REGULAR AND THEN THERE WERE A NUMBER OF ANIMALS THAT DIED LATE AND THESE LONG-TERM SURVIVALS WITH ULTIMATE DEATH, I THINK IS SOMETHING WE REALLY NEED TO BE CONSCIOUS OF WHEN WE START THESE INTERVENTIONS, THE MORE EFFECTIVE WE ARE IN TREATING THE EARLY STAGES OF DISEASE, THE MORE SEQUELY WE'RE BEGINNING TO SEE IN THE HAN MALS AND I SUSPECT THAT WILL BE THE CASE IN HUMANS AS WELL. OKAY, IMMUNE CORRELATES TO SURVIVABLE, YOU KNOW WE ALL RECOGNIZE TOTAL ANTIBODY LEVELS MATTER, NEUTRALIZING ANTIBODIES MATTER, AD CCs MATTERS, I DON'T HAVE A WHOLE LOT MORE INFORMATION ON THAT. YOU KNOW WHAT MAKES--WHAT CORRELATES OF SURVIVAL ARE YOU KNOW LOW VIRAL LOAD, LOW PROTEIN C, D-DIMERS, IL-SIX, MCP, ALL DOWN. YOU KNOW I RESURRECTED THIS FROM A PAPER I WROTE 16 YEARS AGO BUT I PUT IN HERE TO ILLUSTRATE A POINT. WE DO GET OCCASIONALLY SURVIVE OARS AND THIS IS ONE RECESS MONKEY THAT SURVIVED AND THAL IS CURVE HERE IS THE IF-EIGHT T-ASPECT BODY THAT COMES UP EARLY AS YOU SEE BUT NEUTRALIZING ANTIBODY COMES UP VERY LATE AND I DON'T KNOW IF THIS IS TYPICAL OR NOT, BUT THIS IS VERY SIMILAR TO LASA BY THE WAY, BUT WHEN WE COLLECT PLASMA FOR CONVALESCENT THERAPY AND WHAT HAVE YOU YOU, I WONDFER GETTING THESE GUYS WHEN THEY'RE DISCHARGED FRIDAY THE HOSPITAL OUT HERE IF WE'RE FOOLING OURSELVES. WE'LL KNOW WHEN THE STUDIES ARE DONE. BUT IF I WERE COLLECTING THE PLASMA I WOULD COLLECT IT LATER THAN TWO WEEKS. THIS SHOWS, I PUT THIS IN TO SHOW, THE RUSSIANS MADE THIS STUFF IN THEIR BSL-HORSE BARN AND WHAT IT SHOWS S&P THAT WE COULD SUPPRESS VIREMIA FOR FIVE DAYS, THERE WAS NO VIREMIA, BUT THEN VIREMIA TOOK OFF AND THIS WAS A CONSEQUENCE OF IMMUNE--SERUM SICKNESS ASSOCIATED WITH THE EQUINE SERUM. THIS JUST SHOWS THE PASSIVE TIGHTERS OF THE EQUINE IGG, FIRST INFECTION, FIRST INJECTION AND THEN CAME BACK 45 DAYS LATER IN THE IMMUNOLOGICALLY CLEARED AND WE PUT ONE OF THOSE MONKEYS INTO ANAPHYLAXIS WITH THAT ONE. AND THIS SHOWS THAT THAT WE GAVE THE MONKEYS A SECOND DOSE OF EQUINE IGG ON DAY FIVE AND YOU SEE IT SUPPRESS VIREMIA FOR TWO DAYS BUT THEN IT TOOK OFF, SO WE HAVE TO BE CONSCIENCE OF THAT EFFECT WHEN WE LOOK AT ALL THE PASSIVE IMMUNIZATION STRATEGIES, FINALLY THIS IS EFFECTIVE THIS, IS GARY [INDISCERNIBLE], ONE OF THE MONOCLONAL COCKTAILS AND IT SHOWS THAT THE OPEN CIRCLES ARE THE ANIMALS THAT LIVED AND YOU SEE AGAIN IF YOU GET VIREMIA UP AROUND FIVE OR SIX LOGS, THE ANIMALS DIE AND IF YOU KEEP IT BELOW THAT, THE ANIMALS LIVE SO AND I'LL JUST SAY THAT THE NATURE OF YOU KNOW OF THAT ANTIBODY COCKTAIL IS VERY SIMILAR TO WHAT'S NOW BEING USED CALLED C-MAP AND TWO OF THOSE ANTIBODIES ARE NEUTRALIZING BUT ONE IS NOT AND HAS ADCC ACTIVITY AND HAO HIGHLIGHTS THAT IT'S PHENOMINALLY AS WELL AS KD--SALLY WHAD WE TALKED ABOUT IV FLUIDS AND JAMES AND OTHERS DID AGGRESSIVE FLUID MANAGEMENT YEARS AGO AND WE'RE SEEING THAT BEING REPEATED NOW IN THE ETUs AND WHAT HAVE YOU AND IT'S KIND OF A MIXED BAG. IN ANIMALS THAT ARE GETTING AGGRESSIVE FLUID MANAGEMT HAVE THESE DISTENDED BOWELS AS YOU SEE HERE, AND SO THIS KIND OF INTERVENTION REALLY MAKE ITS DIFFICULT TO INFORM EFFICACY STUDIES. [INDISCERNIBLE]. I DID MENTION PATHOLOGIC TPAOEUBDING WITH THE DEATH, WE'VE SEEN THIS WITH MODERATELY EFFECTIVE INTERVENTIONS. I'M JUST GOING TO CONCLUDE WITH AN INFOMERCIAL, THIS IS THE IMAGING SUITES AT THE IRF CONTROL ROOMS AND BASICALLY THE TUBE EXTENDS DOWN INTO THE BORE OF THE INSTRUMENT SO WE CAN DO MEDICAL IMAGING AND I PUT THIS IN HERE, THIS IS--THIS IS A PREAND POST EXPOSURE OF GARY COKE I THINKERS MONKEYS SHOWING THIS DISTENDED BOWEL. THIS LOOKS LIKE THE CASE SEEN IN DUNCAN IN--WHEREVER IT WAS IN HOUSTON. AND THESE ARE MRIsOT BRAIN AND I SHOWED, YOU CAN GET DIFFERENT PICTURES WITH T-1, T-TWO AND YOU CAN MIX AND MATCH AND WHAT WE'RE FINDING HERE IN THESE ANIMALS THAT ARE DIEING ON DAY EIGHT OR NINE, ALL THIS AREA HERE HAS BEEN CONFIRMED AS HEMORRHAGE WHICH WE CAN SEE HERE GROSSLY AND WITH THAT I WILL STOP. THANK YOU. [ APPLAUSE ] >> THANK YOU, I WILL LET YOU ASK ONE QUESTION, BARNY. YOU HAVE TO USE THE MICROPHONE. WE HAVE PEOPLE LISTEN NOTHING DISTANT PLACES. >> AS WE TRY TO TAKE THE ANIMAL DATA AND TRANSLATE IT INTO THE HUMAN IMMUNO GENERATEDISSITY WE'RE SEE NOTHING EARLY PHASE TRIALS. TING TO UNDERSTAND WHAT THE CORRELATES MEAN IN THE ANIMAL MODEL WHEN THEY GET A THOUSAND PSU CHALLENGE DOSE WHICH IS A HUNDRED TIMES OVER THE LD99 THE CORRELATES MAY BE DIFFERENT WITH THAT HIGH OF AN MLI, DO YOU SAY ANYTHING ABOUT WHY WE'RE USING A THOUSAND LD-PFUs OR WHAT THE CONSEQUENCES WOULD BE OR THE TEMPORAL COURSE OF THE DISEASE WOULD BE IF YOU USE THESE. >> WELL, YOU COULD ARGUE THAT IF YOU WANT TO SET THE BAR LOW, CAN YOU PROBABLY GIVE A VERY LOW DOSE, I THINK THE ASSUMPTION, YOU GO WAY BACK, YOU KNOW 15 YEARS WHEN WE FIRST STARTED DOING THESE THINGS, I THINK IF THERE WAS ANY THOUGHT GIVEN TO IT AT ALL, IT WAS THAT IF VIREMIA IN A PATIENT WAS ON THE ORDER OF SIX LOGS AND YOU HAVE A NEEDLE STICK AND THE VOLUME OF BLOOD IN THAT NEEDLE IS PROBABLY ABOUT A MICROLITER IN THAT TRANSLATES TO 10 TO THE THREE. AND I MEAN, CAN YOU ACCEPT THAT OR NOT. BUT I MEAN IF YOU'RE LOOKING TO PROTECT AGAINST INFECTION, I MEAN, YES, YOU CAN DELETE DOWN TO EXTINCTION AND KILL A MONKEY. BUT I THINK A REASONABLY DOSE, I DON'T THINK A THOUSAND PFUs IS AN OVERWHELMING DOSE. >> I WILL ADD IN OUR FIELD IN HIV, WE HAVE THE SAME DISCUSSION, AND USING THESE WHOPPING AMOUNTS OF VIRUS WAS PROBABLY A MISTAKE AND WE'RE DIALING THAT BACK BUT OBVIOUSLY PROTECTING AGAINST NATURAL EXPOSURE, UNNATURAL EXPOSURE OF THIS PROBABLY SETS THE PACE FOR QUESTIONS YOU WOULD ASK IN MHP STUDIES. OKAY WE HAVE TO MOVE ON TO OUR LAST SPEAKER. THIS IS ERICA SAPPHIRE WHO WILL TALK ABOUT VIRUS STRUCTURE NEUTRALIZATION, EVOLUTION AND EMUNE O PATHOGENESIS. >> THANKS FOR HAVING ME TODAY. SO THIS FIELD AS A WEALTH OF STRUCTURES, IT'S BECAUSE OF THE STRONG SUPPORT WE GOT FROM NIAID OVERALL STRATEGY THE LAST 10 YEARS AND IN CASE THERE MIGHT BE AN OUTBREAK. WE ALSO HAVE MAP MUTATIONS, IN IS NOT MY WORK BUT THE WORK OF OTHERS. IF YOU MAP THE MUTATION SCENE IN 2014 IN THE VIRUS. THEY MAP TWO PLACES YOU MIGHT EXPECT. THEY MAP TO THE POLYMORPHIC LOCI, AND THE MAP TO THE DISORDERED REGIONS THIS IS AS WE MIGHT EXPECT. THIS IS A VIABLE EBOLA VIRUS, IF THE MUTATIONS UNFOLD THE PROTEINS IT WOULD NOT BE A VIABLE EBOLA VIRUS, BUT THEY MAP TO PLACES THAT ARE FLEXIBILITY IN DISORDERS THAT WE'RE NOT VISUALIZING OR THEY MAP TO PLACES THAT ARE ALREADY DIFFERENT AMINO ACIDS ACROSS THE EBOLA VIRUSES SO WE CAN'T SUBJECT FUNCTIONS OR CHANGES IN THE PROTEINS OF THESE LOCATION. THIS IS GOING TO HAVE TO BE DETERMINED IMPERICALLY, ONE BY ONE OR IN COMBINATION BUT THERE THIS CAN DEFINITELY EFFECT HOW THE PROTEINS INTERFERON-GAMMA T-CELL ACT WITH EACH OTHER AND HOW THEY INTERACT WITH THE RISK FACTORS. WHAT THE FIELD IS MISSING ARE STRUCTURES IN THE PROTEIN, SO THOSE WILL HELP US THERE, MANY OF THESE AS WELL. BUT WHAT WE CAN DO IS USE THAT GENETIC INFORMATION TO SELECT AND REVISE THE TREATMENT. SO PART OF MY LARGE ANTIBODY PROGRAM IS WHEN WE KNOW THEIR EPITOPES WE CAN MAP CHANGES IN THE RIHAVE YOU SEEN TO WHAT'S GOING TO KNOCK OUT EACH ANTIBO AND INSTEAD OF THE VIRUS CHANGES WE CAN COME UP TO THE MAP IN REALTIME THIS IS THE ONLY PROTEIN EXPRESSED IN THE VIRUS AND IT'S WHAT IT USES TO ATTACH AND ENTER TO TARGET CELLS. THIS IS THE FIRST STRUCTURE WE SAW WITH THE SELECTOR PROTEINS, SHAPED LIKE A POLE, THE VIEW IN HERE IS THE VIRAL MEMBRANE TOWARD THE BOTTOM AND TARGET CELLS TOWARDS THE TOP. BUT THE BLUE AND GREEN SUBUNITS ARE WHAT ATTACH TO THE TARPGET CELLS AND THE WHITE MATERIAL IS THE FUSION MACHINERY, THAT UNCOILS AND DRIVES ITSELF INTO THE TARGET CELL IN INFECT, SO THE BLUE AND GREEN ARE THE GP ONE AND WHITE IS GPTWO. AND THE UPPER AND OUTER PARTS OF THE ONE IS WE CALL THE GLYCAN CAPS AND HAS FOUR GLYCOSYLATION ON A CLUSTER, ATTACHED TO THE GLYCAN CAP, ARE DO MAINS THAT CALL THE MUSIN DOMAIN. AND UNIQUE TO A EBOLA VIRUS AND IMPORTANT HO HOW IT'S FUNCTIONED. THESE ARE PRIMARILY UNSTRUCTURED DOMAINS AND CARBOHYDRATE AND 75 DILL O DALTON WITH THE SECONDARY STRUCTURE. WE CANNOT CRYSTALLIZE A GPP CONTAINING THOSE DOMAINS BUT WE CAN TRY TO UNDERSTAND THE STRUCTURE OF THE COMPLETE VIRAL SURFACE PROTEIN THAT DOES CONTAIN THEM USING OTHER TECHNIQUES, LIKE SMALL ANGLE SCATTERING AND FINDING THEM TUMBLING AROUND IN SOLUTIONS SO WHAT YOU SEE IN THE RIBBON MODEL IS THE CRYSTAL STRUCTURE OF THE ORDER CORE, THE BLUE CLOUD IS THE ADDITION OF THE VOLUME OCCUPIED BY THE FLEXIBILITY MUSIN LIKE DEMAND. NOW SMALL ANGLE SCATTERING OVER EMPHASIZES GLYCAN AND IT TAKES INTO ACCOUNT SOME OF THE IDTH OF USING [INDISCERNIBLE] AND EFFECTIVELY ACLUED THIS IS MUCH SPACE BUT PROBABLY ABOUT HALF THAT. BUT THIS IS MORE OR LESS WHAT THE PROTEIN LOOKS LIKEOT SURFACE OF THE VIRUS. NOW THIS IS IMPORTANT. THIS IS NOT THE VERSION OF THE PROTEIN THAT BINDS THE RECEPTOR, WHAT HAPPEN SYSTEM THAT IT ENTERS A CELL BY THE MACROPENE O SIGNIFYITOSEIS LIKE MECHANISM. ONCE GET INTO THE ENDOSOME, IT IS CLEAVED BY HUMAN ENZYME CALLED EFFECTIN, THE ROLE OF THAT CLEAVAGE IS TO DELETE THOSE COTTON CANDY LIKE CLOUDS OF CARBOHYDRATE. THIS IS BEFORE CLEAVAGE, THIS IS WHAT IT LOOKS LIKE AFTER CLEAVAGE. IT'S JUST THE CORE WITH THE MUSEIN IN THE [INDISCERNIBLE] PATH. YOU'RE LOOKING AT THE CRISTICAL STRUCTURE. WHAT IT DOES IS LOB OFF ALL THAT. THE CARBOHYDRATE STOP LEAVING A RECEPTOR BINDING, RECEPTOR COMPETENT CORE UNDERNEATH. SO WE HAVE TWO VERY DIFFERENT MANIFESTATIONS OF THE SAME PRODUCT. WE HAVE THIS VERSIONOT SURFACE OF THE VIRUS AND THIS IS SUBJECT TO ANTIBODY SURVEILLANCE. WE HAVE THIS VERSION OF THE PROTEIN WHICH IS WHAT IS COMPETENT FOR RECEPTOR BINDING AND IT ONLY APPEARS IN THE ENDOSOME, INSIDE THE CELL, AN EBOLA VIRUS IS WE HAVE AN ABUNDANT SECRETED VERSION, 80% OF THE TRANSCRIPTS OF THAT, NOT THAT. SO THAT COMPLICATES THE IMMUNE RESPONSE AND THE INTERPRETATION OF THE RESPONSE AND A LOT OF ANTIBODIES ARE CLIPPED OFF, CAN YOU RAISE A LOT OF ANTIBODIES AGAINST PIECES OF POLYPEPTIDE BETWEEN THOSE GLYCANS AND THE GLYCAN CAPS. BUT THOSE EPITEMS AND ANTIBODIES BOUND TO THEM ARE CUT OFF THE GP ONCE THEY'RE IN THE ENDO STUDIES OF MULTIPLE ENDOCRINES. WHAT YOU MIGHT REALLY WANT TO HIT WHICH IS THAT CONSERVED ESSENTIAL BINDING SITE IS NOT EXPOSED ON THE SURFACE OF EBOLA VIRUS SO IF YOU COULD ENGINEER AN ANTIBODY AGAINST THAT SEAT, IT DOESN'T RECOGNIZE THE INTACT VIRUS. ALSO ANTIBODIES COULD CROSS REACT TO THAT MUCH MORE ABUNDANT SUP AND WE DON'T FINISH THAT'S GOOD OR BAD OR EITHER. SO WHAT WORKS? ONE WAY YOU CAN ASK WHAT WORK SYSTEM WHAT NEUTRALIZES. THIS IS THE HUMAN ANTIBODY, THE SURVIVEAR OF THE 1995 OUTBREAK CALLED KZ52 IT'S BEEN CLEVER, IT BYPASSED EVERYTHINGOT BOP AND CLIMBED TO THE TOP AND AGE ANCHORED ITSELF, THIS IS AN ANTIBODY AGAINST THE SUDAN EBOLA VIRUS, IT BINDS IN THE SAME PLACE, ALSO ANCHORING TO THE BASE. IT HAS PROBABLY THE SAME FUNCTIONAL EFFECT. SO WAS TWO OUT OF TWO NEUTRAL STRUCTURES OUT OF THE ANTIBODIES AND THAT WAS THE GENESIS OF THE IDEA AND THAT SPOT IS BASED COULD BE A HOT SPOT FOR EBOLA VIRUS NEUTRALIZATION, NOW THIS HASN'T YET BEEN TRY INDEED PRIMATES BUT THE K52 WOULD, THIS IS PROTECTED AGAINST RODENTS BUT NOT PROTECTED AGAINST PRIMATES. PRIMATES DIED. THAT WAS DATA WE HAD IN 2007. AND IN 2007 THIS WAS THE BEST ANTIBODY WE KNEW AGAINST EBOLA VIRUS, THE BEST WE HAVE DOESN'T WORK. DOES THAT MEAN THE ANTIBODIES WILL BE EFFECTED? THAT WAS THE STATE OF OUR KNOWLEDGE. IN 2011-12, THEPOLOGYY KNOWNAL MIXTURE OF ANTIBODIES COULD CONFER PROTECTION. WHAT ARE THESE ANTIBODIES THAT USE THEM WE HAD STRUCTURES OF ONE OF THE COCKTAILS OF THE EPITELOMERE, THE ONE BY THIS, AND THAT BIOME, IT'S THREE ANTIBODIES, WITH THE STPRUBGTURES ARE LOOKING AT EXTRA CRYSTAL STRUCTURES AND ANTIBODIES FOUND TO THE MUSEIN LIKE PEPTIDE IN YELLOW AND THE OTHER ONE IS THE MICROSCOPY AND LIGHT BLUE GLYCAN AND THIS PROTREK EVALUATION PROCESS COCKTAIL BINDS MUSEIN, MUSEIN AND GLYCAN CAPS. IT BINDS ALL THE PARTS THAT ARE CLEAVED OFF IN THE OWNED O STUDIES OF MULTIPLE ENDOCRINE. HERE'S FUNNY THING, THESE ANTIBODIES DON'T NEUTRALIZE INVITRO WHEN YOU NEUTRALIZE A BIT WITH COMPLEMENTS BUT ON THEIR OWN THEY'RE NOT NEUTRALIZING SO IF YOU'RE SCRING ANTIBODIES AND TESTED ALONE YOU WOULD NOT SELECT THESE. BUT UTR PUT THEM TOGETHER AND THEY'RE PROTECTED AND PRIMATES. SO WE'RE LEFT WITH THIS OBSERVATION A COUPLE YEARS AGO, THIS ANTIBODY OFFERS NEUTRALIZATION BUT NO PROTECTION. THIS SET OFFERS PROTECTION IN THE ABSENCE OF NEUTRALIZATION. SO IS IT THAT THIS WAS WRONG AND THIS IS RIGHT OR IS IT THIS WAS DELIVERED BY ITSELF AND THIS IS A MIX TOUR OF THREE? THE IDEA THAT MAYBE YOU NEED A MIXTURE WAS SUPPORTED BY THE MONOCLONAL ANTIBODIES AT THE TIME. THE ANTIBODY BY ITSELF, NO PROTECTION, TWO ANTICOCKTAIL FROM THE ROCKY MOUNTAIN LAB GIVE PARTIAL PROTECTION, TWO DIFFERENT COCKTAILS WOULD BOTH PROTECT. SO YOU CAN'T QUITE COMPARE THESE STUDIES BECAUSE THEY'RE ALL DIFFERENT DOSAGES ON DIFFERENT SCALE OR TIMES BUT ONE PROBLEM WE HAD IS THAT THE TESTS WEREN'T STANDARDIZED SO THIS IS WHAT WE THOUGHT TWO YEARS AGO. DO WE JUST NEED A COCKTAIL? IF WE NEED A COCKTAIL HOW MANY ANTIBODIES GO IN THE COCKTAIL? IS THE MAGIC NUMBER THREE? WHICH ANTIBODIES ARE BEST IN AND MORE IMPORTANTLY HOW WOULD WE KNOW? YOU CANNOT BEGIN IN PRIMATES, RIGHT? YOU WOULD HAVE TO DOWN SELECT WHEN WERE ELSE, BY WHAT ASSAY WOULD WE FIGURE OUT WHAT WOULD WORK? AND WE'RE PUTTING THINGS TOGETHER IN A COCKTAIL WHAT WE REALLY LIKE FOR ANTIBODIES THAT HAVE AN ADDITIVE EFFECT EVEN BETTER SINNER GESTIC EFFECT WE DON'T WANT ONES THAT COMPLETE WITH EACH OTHER. SO THIS IS A COMPLEX PROBLEM WITH NESTED NESTED SETS OF QUESTIONS AND WE NEED A SAMPLE SIZE TO LOOK AT THIS AND WE HAD A GENESIS OF A BETTER IDEA, WE FORM THE VIRAL HEMORRHAGIC FEVER FOR THE CONSORTIUM AND NIAID FUNDED IT THROUGH THEIR CDER MECHANISM. NEARLY EVERY LAB IN THE FIELD WITH ANTIBODIES AGAINST EBOLA, SEND THEM AND SENT OUT IDENTICAL BOXES TO DO A BATTERY OF IN VIVO AND INVITRO TESTS WITHOUT KNOW WAG THEY'RE GETTING AND BRING ALL THE DATA BACK TOGETHER. THE GOAL OF THIS ARE ANSWER THE BASIC RESEARCH QUESTIONS, WHAT EPITOPES WORK? CAN WE PREDICT WHAT WOULD WORK, CAN WE PUT TOGETHER A BETTER COCKTAIL USING THE FIELDS ANTIBODIES RATHER THAN WHAT'S AVAILABLE IN SINGLE LABS IN ISOLATION. MAYBE WE CAN MAKE A GOOD COCKTAIL FOR THERAPEUTIC USE. AND MAYBE WE CAN COME UP WITH A BENCHMARK GOING FORWARD. WE THOUGHT WE WOULD GO ABOUT THIS TWO DIFFERENT WAYS, SORT OF A TORT AND I GUESS HAIR STRATEGY. THE SORTIS STRATEGY WAS TO DO THIS PROPERLY. GET AS MANY ANTIBODIES AS WE CAN, SEND US THE BEST, DO ALL THE INVITRO AND IN VIVO ASSAYS AND FIGURE OUT WHAT WORKS AND WHY, AND THE HAIR STRATEGY WAS MORE OF A RAPID RESPONSE. IF THERE'S AN OUTBREAK OR EXPOSURE, WE NEED SOMETHING FAST. THE HAIR STRATEGY TO TAKE THE STRANDS THAT DID WORK AND MIX AND MATCH TO SEE IF WE CAN COME UP WITH SOMETHING BETTER FROM THE TWO COCKTAILS FROM WHAT THIS LAB AND THAT LAB HAD IN ISOLATION. THAT HAIR STRATEGY RESULTED IN ZMAB, AND THAT WAS DATA THAT WAS COLLECTED THAT WILL BE TALKED ABOUT LATER. WHAT IS CMAB, THIS IS ZMAP, THIS IS DONE BETWEEN MY LAB AND MY COLLEAGUE. ZMAPP, CONTAIN THREES ANTIBODIES, BLUE AND 13 CSIX, IT BINDS THE GLYCAN CAP, NOT NEUTRALIZING THE COMPLEMENT, THE JOB IS TO RECRUIT THE EFFECTOR FUNCTION. YELLOW AND GREEN ANTIBODIES ARE 472 D FOUR, THEY BIND THE BASE, THEY LOOK JUST LIKE CZ52 AND NET SIX, THEIR JOB IS TO NEUTRALIZE. SO NEUTRALIZATION IS IMPORTANT. THIS IS WHAT WE LEARN FROM ZMAPP, SO WHY DIDN'T KZ52 WORK, WELL THE PROBLEM WITH KZ52 AND THESE GREEN AND YELLOW ANTIBODIES OR IS THAT IT WAS DELIVERED BY ITSELF IN ABSENCE OF THE BLUE ANTIBODY THAT CONFER FRIDAY IMMUNE EFFECT OFFER FUNCTION. NOW DRAWING THE STRUCTURE THIS WAY, BUT I COULD DRAW IT THIS WAY AS WELL BECAUSE TWO GFOUR AND G4G SEVEN OVERLAP AND NOW THE IDEA IS THAT THEY WOULD BIND EACH OTHER AND BIND DIFFERENT MONOMERS BUT THEY DO COMPETE WITH EACH OTHER SO IT'S A GOOD QUESTION WHETHER THESE ARE THE SAME ANTIBODY THAT THERE'S FUNCTIONAL REDUNDANCY HERE OR ARE THEY DIFFERENT. THIS IS LOW RESOLUTION SINGLE PARTICLE E. N. BECAUSE WE'RE WORKING FAST, THERE'S AN OUTBREAK. WHAT WE NEED IS THE HIGH RESOLUTION TO SEE IF THERE IS A DIFFERENCE BETWEEN THESE TWO ANTIBODIES. MAYBE THEY RECOGNIZE SUBTLY VARIATION, OR MAYBE ONE'S REDUNDANT. IF ONE'S REDUN ANT IS THIS AN OPPORTUNITY FOR IMPROVEMENT AND WE FIGURE OUT WHICH OF GREEN AND YELLOW IS BEST AND USE THAT ONE AND COME UP WITH A THIRD ANTIBODY AGAINST ANOTHER SITE OR SIMPLIFY AND MANUFACTURING. WHAT ELSE IS THERE. THIS IS WAWE MAPPED STRUCTURALLY SO FAR. WE HAVE FOUR THAT NEUTRALIZE AND THE SPOT AT THE BASE. WE HAVE TWO AGAINST THE GLYCAN CAP, WE HAVE TWO AGAINST THE STRUCTURES, BUT WE HAVE THIS SORTIS STRATEGY. NOW THIS IS GOING ON FOR THE LAST FOUR MONTHS AND I CAN TELL YOU THE DATA THAT WAS GENERATED SO FAR AND HOW REMARKABLE IT WAS WHEN ALL THESE DIFFERENT LABS CAME BACK TOGETHER IN NOVEMBER TO COMPARE WHAT WE LEARNED. AND OUR FIRST COLLECTED 81 ANTIBODIES AND STANDARDIZE AND DEIDENTIFY THEM AND GAVE THEM CODE NAMES AND SENT THEM ALL OUT. SO THE FIRST THING WE DID IN MY LAB, MAPPED WHERE THEY BIND BY EALIZA, WE FOUND 16 SETS OF IN THE BIND THE DOMAIN, 17 TAK-THEY BIND THE CAP, EIGHT THAT BIND THE BASE, AND THEN ANOTHER SET OF 15 THAT BIND THE CORE. THOSE ARE THE BLUE AND GREEN AREAS, HALF OF THOSE CROSS REACT WITH FGP AND HALF DO NOT. AND THEN THERE ARE MORE THAT WE BIND WITH THE CORE, AND MAYBE THEY'RE SUBTLE. BUT WHAT NEUTRALIZES? WE'VE DID NEUTRALIZATION TESTS LOOKING AT PSEUDOVIRUSES AND DELTA RIHAVE YOU SEENS. THE NEWS THAT NEUTRALIZE ARE THE ONES THAT ARE IN EBOLA THAT ARE UNDERLINED. IF YOU LOOK AT THE RED EPITOPE IN THE BASE, THEY UNIVERSALLY NEUTRALIZE WHERE NONE OF THE PHAOUT ANTS NEUTRALIZE AND NONE OF THE GLYCANS NEUTRALIZE SO IT'S ABILITY TO NEUTRALIZE DEPENDS ON THE EPITOPE THAT IT BINDS. SO THAT'S WHAT WORK WE HAVE TO DO AND WHAT WORKS IN ANIMALS. THIS IS IN. VIVO PROTECTION, TWO DAYS EXPOSURE, ONE DAY EXPOSURE AND IT'S IN MICE. THERE'S QUITE A RANGE. IF YOU LOOK AT THE BASE, YOU UNIVERSALLY HAVE SOME SURVIVAL. SO THE NEUTRALIZATION DOES CORRELATION THERE, BUT THE OPTAUPE IS RANK FROM 50 OR 60%. SO IF WE SYNTHESIZE THIS DATA, HERE'S WAWE SEE, MOST POTENT NEUTRALIZATION AND MOST IMPORTANTLY SUCCESSFUL PROTECTION BUT IF YOU WANT TO MAKE A COCKTAIL HOW MANY BASE RUNNERS CAN YOU PUT TOGETHER, THEY'RE GOING TO COMPETE WITH EACH OTHER, AND YOU WANT TO RECRUIT FUNCTIONS, WE CAN FIND PARTIAL PROTECTION OF ANTIBODIES AGAINST OTHER SITES. SO THOSE ARE OUR CHOICE FOR PUTTING TOGETHER A COCKITATE EMPLOY WHAT ELSE HAVE YOU LEARNED. OFTEN IT'S AN ANTIBODY NEUTRALIZE IT WILL NOT PROTECT. WE FIND 24 OUT OF 48 EXAMPLES LIKE THAT. BUT SOMETIMES IT DOESN'T. THESE ARE ANTIBODIES THAT DO NOT NEUTRALIZE THAT DO CONFER PARTIAL PROTECTION. AND THESE ARE THE BEST IN THEIR CLASSES. HERE'S ANOTHER OPEN QUESTION, THIS SDP, IT'S A DECOY IS IT HELPFUL, HARMFUL OR NEITHER? THIS IS CROSS REACTIVE AND IT'S NOT THE BEST. SO BINDING OF SGP DOES NOT SEEM TO HAVE ADVANTAGES. OKAY, THE BASE FINDERS LOOK TERRIFIC WE NEED ONE OF THESE IN THE COCKTAIL BUT DO WE NEED MORE THAN ONE. IT'S MORE THAN ONE BASE FINDER REDUNDANT OR PICK IN OUR FAVORITE A COUPLE OF OUT THESE AND WORK BEST WITH PRIMATES AND GO WITH THAT. FOR COMPLEMENTING THE COCKTAIL AND THE BEST, THE BEST ANTIBODIES IN THE POOL SO FAR, THIS IS TOP PRIORITY FOR SOLVING STRUCTURES AND FIGURE OUT WHERE THEY BIND AND WHY. BUT LOOK AT THESE THREE, THESE ARE THE BEST IN CLASS FOR THE OTHER EPITOPE GROUPS FOR A COMPLIMENTARY COCKTAIL, SO PROTECTION IN THE NEUTRALIZATION, AND WE DON'T KNOW EXACTLY WHAT. THIS IS STUDIES WE NEED TO DO SO WENEY NEED TO UNDERSTAND WHAT MAKES THE BEST IN CLASS, WHAT DOES THAT ONE CONFER 50% SURVIVA AND THE REST ARE NONE. OKAY OTHER OPEN QUESTIONS WE FIND, WE'VE DONE IN VIVO AND OTHR REMAINING TO GO AND WE MY FEIGNED NEW THINGS. THIS IS THE INRESULTS IN THE LARGE STUDY AND WE HAVE MORE DATA IN COMING MONTHS. SO I WOULD LIKE TO THANK ALL THE PEOPLE IN THE FIELD THAT CONTRIBUTED ANTIBODIES TO THIS BLINDED STUDY, WE HAVE ANOTHER PATH, ANOTHER COLLECTION OF ANTIBODY FEBRUARY 1, PEOPLE THAT THE PEOPLE THAT DID EXPERIMENTS ARE INDICATE BIDE AN ASTERISK AND I WANT TO THANK JOHN FOR HIS LEADERSHIP IN GETTING THE ORGANIZATION SET UP, BRINGING ALL THE PEOPLE IN THE FIELD ON TO THE STUDY. I DON'T THINK ANY OTHER FIELD HAS DONE THIS. I DON'T THINK ANY OTHER DISEASE HAS BEEN PUTTING ONE POOL TOGETHER AND BLIND THEM SO I WOULD LIKE TO THANK NIAIDFOR THEIR STRONG SUPPORT OF THIS PROGRM, AND ALL THE PEOPLE IN MY LAB AND COLLEAGUES ARE ALL LISTED AT THE BOTTOM. THANK YOU. [ APPLAUSE ] >> I THINK WE SHOULD HOLD QUESTIONS BECAUSE WE'RE ALREADY FIVE MINUTES INTO THE 25 MINUTE BREAK. BUT THIS DOCTOR WILL BE IN THE PANEL LATER SO LET'S COME BACK, IN 20, TWO-ZERO MINUTES AND WE WILL START AT 25 AFTER THE HOUR, THANK YOU. >> ALL RIGHT DUE TO OUR TIME CONSTRAINTS TODAY WE WILL GO AHEAD AND START. THIS NEXT SESSION WILL DEAL WITH THE IMMUNE RESPONSE TO EBOWL ASAY WOULD BE --EBOLA AS WE KNOW IT AND AS YOU HEARD FROM THE LAST SESSION, WE DON'T KNOW A LOT ABOUT THE RESPONSE TO EBOLA AND THE STAFF WILL TALK ABOUT THE IT IN MONKEYS THAT HAVE BEEN USED IF ARE DIFFERENT VACCINE STUDIES. SO THE FIRST COUPLE TALKS WILL TALK ABOUT THE PROTECTIVE IMMUNE RESPONSE THEY SAY WITH PARTICULAR VACCINES TO HELP DETERMINE THE ROLE OF SEALULAR AND HUMORAL OVERALL PROTECTION AND OUR FIRST SPEAKER WILL BE GARY WONG WHO WILL TALK ABOUT LIVE ATTENUATE VECTORS FOR IMMUNE RESPONSES. >> HI, EVERYONE I FORGOT TO MAKE AN AACKNOWLEDGMENT SLIDE SO I WOULD LIKE TO THANK THE ORGANIZERS FOR GIVING ME THE CHANCE TO SPEAK. SO I WILL GET STARTED WITH THE STUFF. THIS IS A QUICK BACKGROUND OF GSP, IT AFFECTS CATTLE, HORSES, PIGS AND INSECTS, CAUSING LIKE A DISEASE AND CAUSES MUCOSAL ULCERS IN THE MOUTH AND RESOLVES COMPLETELY WITHIN TWO WEEKS. MOST OF THOSE ARE ASYMPTOMATIC WITH ASC, BUT IT MAY CAUSE A MILD, FLU-LIKE ILLNESS. SO THE VSV VECTORED VACCINES, THE CANDIDATE VS TAKEN UTR THE WILD-TYPE GLYCOPROTEIN AND REPLACED IT WITH EBOLA GLYCOPROTEIN AND THEN ARRESTED THE RECOMBINANT VIRUS. SO WHAT HAPPEN IS WE RECOMBIN EIGHTED THE VIRUS, AND THE WILD-TYPE PROTEINOT SURFACE. AND SETHE PROS AND CONS OF THE VACCINES, SOME OF THOSE ARE VERY HIGH TITERS. AND INDUCES STRONG B AND T-CELL IMMUNE RESPONSES IN VIVO. IT ELICITS BOTH MUCOSAL ASK SYSTEMIC IMMUNITY AND LOW LEVELS OF PREEXISTING IMMUNITY TO THE VSV IN THE GENERAL POPULATION. SO IT'S NOT LIKEEE A SIGNIFICANT CONCERN. BUT SOME OF THE CONCEPTS THAT ONE STUDY FOUND THE INTRA THALAMIC INNOC KHRAOUGZ OF WILD-TYPE VSV, AND SETS OF THIS THERE'S BEEN ASTUMBLING BLOCK TO THE VSV VACCINES TOWARDS LICENSURE. SO AMONG THE GROUPS THEY TESTED WILD-TYPE, SO IN INNER THALAMIC, WILD-TYPE, ASK THE TWO IN CYNOs, AND THEY THOUGHT LESIONS IN THE NEW TISSUES OF THE WILD-TYPE VSV, BUT THE NOT THE EBOLA VACCINE. SO BASED ON THIS IT CONCLUDED THAT THAT THE NEAR VIRULENT CONCERNS WITH THE WILD-TYPE IS PROBABLY NOT AN ISSUE WITH GSP EBOLA VACCINES. SO, I'LL TRY TO FOCUS MORE ON THE NHP DATA BUT I DO HAVE NEW DATA TO PRESENT. SO THESE ARE SOME OF THE VACCINES THAT HAVE BEN DONE AVENUE THE LAST 10 OR 15 YEARS OR SO. SO A MOUSE STUDY, FIRST THEY WERE GIVEN VEV, IM, 20 DAYS BEFORE LETHAL CHALLENGE, AND WAWE SEE IS THAT MICE SURVIVE AG AND THE INDUCTION OF THE AUTOIMMUNITY AND THEN WE ALSO SAW THAT THIS VACCINE WAS FULLY EFFICACIOUS IN MICE IF THEY WERE GIVEN I. M., I. N. OR ORALLY. AND THIS IS SUPPLIED IN THE IMMUNE RESPONSES THAT WERE DONE ON THIS STUDY. SO THEY SAID CD-EIGHT T-CELL DEPLETION, BEFORE, DURING AND AFTER THE CHALLENGE AND THEY SHOW TODAY DID NOT NEGATIVELY IMPACT THE EFFICACY. THEY ALSO TRANSFERRED THE SERUM FROM THE VACINATED MICE TO NAIVE MICE AT 24 HOURS BEFORE CHALLENGE AND SHOWED THAT IT PUT IT PROTECTED FOUR OUR FIVE MICE FROM THE EBOLA CHALLENGE. SO THIS SUGGESTS THE ANTIBODY RESPONSES ARE REQUIRED FOR POETIC PROTECTION. ANOTHER RODENT STUDY, THIS IS A LONG-TERM VSV STUDY IN MICE AND GUINEA PIGS. SO MICE WERE GIVEN THE CHALLENGE AND AT VARIOUS TIME POINTS POST VACINATION. SO THEY WOULD CHARGE PSYCHES .5 MONTHS AND THEN GUINEA PIGS ARE CHALLENGED AT SEVEN, 12 AND 18 MONTHS VACCINATION. SO ALL THE MICE SURVIVE AT 6.5 MONTHS AND NINE MONTHS AND ONLY 15 ANIMALS SURF VIE FOR 12 MONTHS. IN GUINEA PIGS WE HAD ONE DEATH AT SEVEN MONTHS BUT VSV WAS ABLE TO CONFIRM LONG-TERM PROTECTION AT WELFARE-18 MONTHS. AND IN THE STUDY, ONLY THE ANTIBODY RESPONSES FOR WERE ANALYZED SO IN MICE, THERE WAS ACTUALLY QUITE HARD TO GET DETECTABLE LEVEL OF NEUTRALIZING ANTIBODIES AND WE DIDN'T GET IT IN EVERY MOUSE, AND SO,--AND BASED ON OUR STUDYS IT DOES NOT THINK THEY'RE RELIABLE MEASURE OF PROTECTION, HOWEVER, IF YOU LOOK AT THE EBOLA IGG LEVELS, AND WHEN WE--WHEN WE DEVELOP THEM, WE MEASURE THEM INDEEDLY BEFORE THE EBOLA CHALLENGE, THEY APPEAR TO CORRELATE FOR PROTECTION, SO AND YOU SEE IN BLUE HERE, SO, YOU REMEMBER WHAT I SAID ABOUT THE MICE WITH THE 15 SURVIVE ALGORITHMS AND THE--IN THE 12 MONTH GROUP, THE THREE NONSURVIVORS SO WE THOUGHT THESE MICE, INDIVIDUALLY, THESE THREE MICE ACTUALLY DECREASED IN IGG, BEFORE THE CHALLENGE. SO THIS SUGGESTS THAT ANTIBODY RESPONSES SO THEY FIND ANTIBODY RESPONSES MIGHT BE THE REASON WHY THIS MIGHT DO NOT SURVIVE. SO WE DIDN'T DO T-CELL RESPONSES FOR THIS STUDY, FOR THE GUINEA PIG, AS GUINEA PIGS WE ARE--WE DO RECEIVE ANTIBODIES AND MOST AND ALL OF THE SURVIVING ANIMALS. WHERE IF AN UPPER IGG AS WELL AND WE SEE THE NON--THE SOLE NONSURVIVING GUINEA PIG, WE SLEEP APNEA AND OBESITY THAT FOR SOME REASON HAD A POOR RESPONSE TO THE VSV, IT HAD APPROXIMATELY THREE-FOUR BLAST IGG, AND NEUTRALIZING ANTIBODIES AS WELL, SO IT'S NOT STATISTICALLY SIGNIFICANT BUT IT IS FOLLOWING THE INDIVIDUAL ANTIBODY, THE INDIVIDUAL ANIMALS WE CAN SEE THE BETTER ANTIBODY DOES TELL US ABOUT WHETHER THE VSV ACSEEN IS EFFECTIVE OR NOT. SO MOVING ON TO SOME NONHUMAN PRIMATE DATA SO THIS IS--THIS IS STUDIES WITH THE VSV FACTIN SO WE GET MONKEYS, VACCINE ARE 28 DAYS BEFORE CHALLENGE AND SO WE'RE ONLY ABLE TO DETECT VSV VIREMIA IN THESE MONKEYS TWO DAYS MOST IMMUNIZATION BUT THIS WAS GONE BY FOUR DAYS. SO IT WAS VERY WELL TOLERATED IN HP AT LEAST AND WHEN WE CHALLENGED THESE MONKEYS WITH EBOLA 28 DAYS LATER WE SAW THE IMMUNITY AND FULL PROTECTION RIGHT HERE. IF WE LOOK AT IMMUNE RESPONSES BEHIND THESE INDIVIDUAL NHPs, ALL THESE NHPs DEVELOP EBOLA SPECIFIC ANTIBODY RESPONSE AFTER VACCINATION BUT ONLY AFTER CHALLENGE. SO IF WE TAKE THE ANTIBODY RESPONSE AT CHALLENGE WE ONLY SAW EBOLA SPECIFIC IGG. ALSO WITH THE CELL MEDIATED RESPONSES WERE ALSO DONE AND YOU CAN--CAN YOU SEE THAT THEY WERE DETECTED AT DIFFERENT LEVELS, IN EACH HP, SO THE READ OUT OF THE T-CELL RESPONSE WITH THE STUDY, AND THE ALPHA GREEN TEA CELLS. AND IN ANOTHER NHP STUDY, THIS ONE AGAINST AN AEROSOL EBOLA CHALLENGE SO NHPs WERE GIVEN, 28 DAYS BEFORE CHALLENGE AND SO ALL--EBOLA MONKEYS SURVIVED, THE CONTROL ANIMALS WERE GIVEN AN EXPRESSING MARBURGS SO THEY DID THE CHALLENGE AS YOU CAN SEE HERE, AGAIN, THE EBOLA AGAIN THIS PROTECTION WAS SEROAHEWNITY SO EBOWL APPROVAL FROM SBA NOT DETECT INDEED ANY OF THE SURVIVING ANIMALS SO IF WE LOOK AT IMMUNE RESPONSES SO THIS IS IGG AND POLLUTION TITERS, YOU SEE ALL THESE VSV, AND ANIMALS DEVELOPED AN IGG RESPONSE, AND AT A ALSO LOOKED AT CD4 AND CDEIGHT T-CELLS IN THE PAPER. THEY DIDN'T SHOW IT IN THE GRAPH OR ANYTHING BUT IT'S IN THE PAPER THAT THEY DID FOCUS ON THE DETECT ANY INTERFERON-GAMMA OR TNF ALPHA POSITIVE T-CELLS IN ANY OF THE SURVIVING ANIMALS. SO AT THIS ONE, AT LEAST FROM THIS STUDY, IT SEEMS THAT THE T-CELL RESPONSE DID NOT PLAY A GREATER ROLE IN THE PROTECON. SO THEN ANOTHER STUDY LOOKED AT THE VSV VACCINE AND NHP, AND MUCOSAL IMMUNIZATION, SO THEY LOOK AT IT INTRA NASAL AND ORAL FACTIN AND YOU CAN SEE THAT, IT'S GIVEN THE VACCINE, FOR THESE ROUTES, 28 DAYS BEFORE CHALLENGE, THEY WERE ALSO 100% PROTECTED. AND ALL THIS OF CLINICAL SCIENCE OF THE DISEASE AND THE CONTROL ANIMALS THAT WERE GIVEN, GSP MARBURG DID NOT SURVIVE THE CHALLENGE. IF YOU LOOK AT THE IMMUNE RESPONSES YOU SEE THAT ALL THE ANIMALS DEVELOP A ROBUST, SPECIFIC IGM AND IGG RESPONSE BEFORE CHALLENGE AND THE IGA RESPONSE WAS ALSO OBSERVED IN MUCOSAL VACINATED ANIMALS BEFORE CHALLENGE. NEUTRALIZING ANTIBODIES WERE ONLY--THEY WERE ONLY DETECTED IN MUSEUM KOEZAL IMMUNIZED HP BUT NOT PROTECTED IN INTRA MUSCULAR NHP BEFORE CHALLENGE SO IT SUGGESTS THAT THE ROUTE OF GSP ADMINISTRATION MIGHT ALSO--YOU MAY ALSO GET A DIFFERENT TYPE OF ANTIBODY RESPONSE. SO THIS GROUP ALSO CELL MEDIATED ANALYZED IMMUNE RESPONSES AND THEY THOUGHT THAT THE ANIMALS THAT WERE VACCINATED IM, AND T-CERESPONSE INCREASE MARKEDLY FOR EBOLA CHALLENGE AND IF THE EBOLA ANIMALS USED THE INTRA NAISAL RESPONSE AFTER CHALLENGE. SO, BUT HOWEVER IN THE STUDY ALL THE ANIMALS SURVIVED SO IT'S UNCLEAR, YOU KNOW LIKE WHAT THE ROLE OF THESE CELL--WHAT THE ROLE OF THIS IMMUNE RESPONSE PLAYED IN SURVIVAL OR NOT. IT'S HARD TO COMPARE, THERE'S NOTHING TO COMPARE IT TO. NOW WE LOOK AT A SCENARIO, SO ON THE UNIQUE PROPERTIES IT'S ALSO ABLE TO PRODUCE POST EXPOSURE PROTECTION AGAINST EBOLA AND NHP. IF WE GAVE THE VACCINE, 20-30 MINUTES AFTER THE CHALLENGE. YOU GET 50% SURVIVAL SO BEFORE I TREAT THE NHP SURVIVE. SOW THE CONTROLS THAT GIVE, [INDISCERNIBLE] THEY DID NOT SURVIVE. SO FOUR OF EIGHT SURVIVE AND IF WE LOOK AT THOSE AND ALL THESE ANIMALS INDIVIDUALLY AND ACTUALLY ONE OF THE ANIMALS DID NOT DEVELOP THE DISEASE CONSISTENT WITH THE EBOLA INFECTION AND THAL IS SUPPORTED BY VIREMIA, SO WITH HAVING HIGH LEVELS OF EBOLA VIREMIA AND DIED AROUND 18 POST CHALLENGE SO IT WAS CONCLUDED THAT THE STUDY THAT THIS ANIMAL ACTUALLY WOULD SUCCUMB TO BACTERIAL INFECTION, SO IF YOU LOOK AT THE IMMUNE RESPONSES OF THESE THREE--OF THESE SURVIVORS, YOU NOTICE THAT THREE OR FOUR OF THE GFP EBOLA ACINATED SURVIVORS HAVE EBOLA IGM AND ALL FOUR SURVIVORS HAVE DETECTABLE IGG AND NEUTRALIZING ANTIBODY RESPONSE AT THE CIPE OF CHALLENGE SO THIS IS HERE AND HERE. THIS IS IGM AND IGG. SO THEY WERE ABLE TO SEE AN ANTIRESPONSE HOWEVER THIS ANIMAL DIED DIED FROM SECONDARY INFECTION, SO THERE DATA DO LOOK AT FOR THIS. SO ONE OF THE THINGS ABOUT THE PROTECTION IS AS MENTIONED BY OTHER TALKS BEFORE WAS THE STATISTICS. AND SO THERE WAS--THERE WAS A STUDY THAT WAS DONE ON THE BEST PANEL HERE, YOU SEE, THIS IS--JUST BEFORE CHALLENGE AND THE ANTIBODY RESPONSE AT THE CHALLENGE AND WHAT--WHAT HAPPENED IS THAT WE SEPARATED THESE ANIMALS BASED ON SURVIVAL OR NONSURVIVAL AND WE SEE THAT BEFORE--BEFORE CHALLENGE, SURVIVORS,--SURVIVOR VS SIGNIFICANT LEVEL OF ANTIBODY--ANTIBOD RESPONSES WHERE THE NONSURVIVORS SO THESE ARE TREATED BUT NONSURVIVING ANIMALS DID NOT HAVE DETECTABLE IGG RESPONSE. SO IF YOU LOOK AT THE CHALLENGE, IT'S THE SAME THING HERE, AND THAT SURVIVORS TEND TO HAVE A BETTER IGG RESPONSE THAT IS THOSE THAT DON'T SURVIVE. AND ONE LAST STUDY, I WANT TO PRESENT THIS, THE DEPLETION OF SELECTED IMMUNE CELLS. SO WHAT THIS GROUP DID IS THEY VACINATED NHP WITH THE VSV, EBOLA AND THEN THEY DEPLETED THE CDEIGHT-T-CELLS AND THEY SAW THE DEPLETION OF THE CD-T-CELLS DURING THE PROCESS, WAS NOT SURVIVAL UPON EXPOSURE SO THIS SUGGEST THAD THE CD-EIGHT T-CELL IS NOT NEEDED FOR VACCINATION. THEY DEPLETED CD4-DCELL CELLS IN THE MATURATION AND THIS--RESULT INDEED COMPLETE LOST OF EBOV GP SPECIFIC ANTIBODIES AND ALSO DEPLETION OF CD4 T-CELLS DURING EBOLA CHALLENGE DID NOT IMPACT SURVIVAL. SO ONE HELPED ESTABLISH IGG IMMUNE RESPONSE AGAINST EBOLA, THAT'S ALL IT TAKES, FOR PROTECTION TO OCCUR. SO THIS SUGGESTS THAT EBOLA SPECIFIC ANTIBODIES ARE ACTUALLY QUITE CRITICAL FOR PROTECTION. SO JUST A SUMMARY OF ALL THOSE STUDIES, SO, THEY SHOWED THAT A SIMILAR DOSE OF THE VSV FOR EBOLA IS WELL TOLERATE INDEED MICE, AND IF VACCINE IS PROVIDED 28 DAYS PRIOR TO EBOLA EXPOSURE IT PROVIDES 100% SURVIVAL. AND IF IN THE STUDIES IT SEEMS THAT THE EBOLA ANTIBODY LEVELS ARE A RELIABLE CORRELATE OF PROTECTION AND CRITICAL FOR PROTECTION FOR VACCINE. NEUTRALIZING ANTIBODIES AND CELL MEDIATED IMMUNITY, WE BELIEVE THEY PLAY A ROLE IN TEBGZ BUT AS OF RIGHT NOW, THE STUDIES AND ALSO--SO SOME OTHER GROUPS AND ALSO FROM OUR OWN, THEY DON'T SEEM TO BE A GOOD CORRELATE OF PROTECTION. SO AND ALSO THE EBOLA FOR THE PROTECTION AND DEVOTED UP TO--UP IN THE GUINEA PIGS SO I WANT TO LEAVE YOU WITH SOME QUESTIONS THAT I THINK--WE'VE BEEN THINKING ABOUT. SO NUMBER ONE IF THE EBOLA SIMILARITIES ARE EFFECTIVE IN NHPs AND WILL IT REQUIRE BOOSTERS? AND THEN ALSO WHAT'S THE LEVEL OF EBOLA VACCINE AFTER VACICATION CAN REQUIRED FOR CONFER PROTECTION IN HUMANS. AND I WOULD LIKE TO THANK EVERY FOR THEIR ATTENTION. [ APPLAUSE ] >> THANK YOU GARY. LET'S SAVE THE QUESTIONS FOR LATER. NEXT TALK IS BY BENOIT CALLENDRET, AND THIS WILL BE ON HUMAN ADENO VIRUS AND MVA-VECTORS VACCINES. >> THANKS, THANKS A LOT. I WILL GO STRAIGHT INTO THE PRESENTATION AS WE ARE RUNNING A BIT LATE. JUST SOME GENERAL BACKGROUND THAT CHRISLE JOHNSON HAS BEEN WORKING ON THIS FOR QUITE SOMETIME AND ALL THE WORK WE PRESENT TODAY HAS BEEN SUPPORTED BY DMID CONTRACT THAT WAS AWARDED IN 2008. AND MOST OF THE WORK THAT HERE IS REALLY BASED ON HUMAN SEROTIME, ADENO SEROTYPES WITH THE PREVALENCE AND AD26 SQUARELY FIT 35 BASED ON VECTORS AND THE CONTRACT WAS BASED ON PRODUCT FREQUENCY AND [INDISCERNIBLE] WHO WENT ON AT PREDICTION FOR THE VACCINE AND FURTHER PLATFORM SAFETY AND THE VECTOR THAT WE WILL PRESENT AND WILL USE IN THIS PLANTATION AS THE [INDISCERNIBLE] EXPRESSED THE AND THE [INDISCERNIBLE] AND THE WORK WITH THE IVORY COAST VECTOR. WE WILL FIRST GO THROUGH A LITTLE BIT OF GENE DETAILSA OF THIS STRATEGY OF AD26 AND 35 VACCINES AND THEN GO INTO PROTECTION DATA WITH EBOLA FROM THE ADDEN O VIRUS AND MVI AND THEN WE WILL HAVE A COUPLE OF SLIDES ON THE IDENTIION OF CORRELATES OF PROTECTION. THE PRIME STRATEGY WITH ADENO IS IMPORTANT TO MENTION THIS TODAY BECAUSE THERE'S MORE AND MORE DISCUSSIONS IN THE PART OF THIS OF THE NEED TO IMPLEMENT THE STRATEGY TO THE LONG-TERM PROTECTION IN HIMANS AND WE DID WORK IN THE PAST WITH [INDISCERNIBLE] VACCINES 426 IN THE PRIME BOOSTED WITH FOUR AD35 IN THE BOOST AND THEN WE STUCK WITH THE BOOST IMMUNIZATION WITH THE 03 AND FOUR WEEKS AND WE ANALYZE IMMUNE RESPONSE BY ELISSA AND THEN WHEN YOU SEE HER IS THE SHARPENING THE PRIME BOOST SCHEDULE ON IMMUNE RESPONSE AND WE DON'T SEE MUCH OF AN IMPACT ON THE RIGHT ON THE CELLULAR IMMUNE RESPONSE AT LEAST WHEN WE LOOK AT IT BY INTERFERON-GAMMA BUT ALSO LINKED TO THE SPREAD THAT WE ARE USED TO SEEING IN THE ENVIRONMENT. CLEARLY ON THE LEFT IS THE PSEUDOTYPE AND YOU SEE THE ZERO-TWO WEEKS WITH THE SCHEDULE SOOIEE NEUTRALIZING ANTIBODY BARELY AND THESE ANTIBODIES ARE HIGHER WHEN YOU EXTEND TO THE ZERO-FOUR WEEKS. AND IT'S NOT ONLY THE TIMING COMPARED TO THE PRIME BECAUSE THIS GROUPS HERE IS A SIX WEEKS FROM PRIME, SAME THING AS THIS ONE, SEE THE DIFFERENCE EVEN MORE STRIKING. SO CLEARICALLY A DETRIMENT IMPACT OF THE SHORT SCHEDULES AT LEAST WITH WE HAVE THAT ONE AND WE HAVE IT TO REMAIN TO BE SEEN FOR THE [INDISCERNIBLE] COMBINATION. THE SEVEN PARTS OF IT IS THE [INDISCERNIBLE] OF THE HUMAN PLATFORM, AND THAT'S WHERE THE FILL UP THE STUDIES FOR THE 04 WEEKS GROUP THAT WAS PRIME IN BOOST WITH THE 04 WEEKS WITH THE COMBINATION, AND THEN WE--WE HAVE THE IMMUNE RESPONSE ON THE LONG-TERM AND THEN WE ARE--WE ADMINISTERED OLAY THE 26 BOOST THAT WE HAVE 25 PLUS PRIME IMMUNIZATION, AND WHAT YOU SEE IS ON THE SIMILAR RESPONSE YOU HAVE THE POST BOOST DATA SO THIS IS TO REMIND YOU AT 26 PRIME AT CERTIFIED BOOST AND THEN THE PEEK RESPONSE AT TWO ASK THREE WEEKS PLUS THE POST BOOST THAT I JUST MENTIONED PREVIOUSLY AND THEN IT KIND OF PLATEAUED UP TO WEEK 85, THE DAY OF THE BOOST AND THEN AFTER THE BOOST, WE SEE A STRONG MECHANISTIC RESPONSE WITH A HUGE, HUGE RESPONSE TWO AND THREE WEEKS POST WITH THIS BOOST AND WE NOTICE THAT IT'S NOT ONLY INCREASING BUT YOU ALSO BROADEN THE NUMBER OF PEPTIDES THAT YOU ACTUALLY TARGET. THIS IS THE NUMBER OF PEPTIDES TARGETED BY IN THE DIFFERENT ANIMALS, FROM ONE TO FIVE PEPTIDES COULD COULD TABLED AFTER THE FIRST BOOST AND THE DAY OF BOOST WHICH THE FIVE STILL WITH THE SAME RESPONSE BUT AFTER THE BOOST, YOU GO FROM STUDY FROM FIVE TO 10 PEPTIDE THAT ARE TARGETED. SO AN INCREASE IN STRENGTH BUT ALSO INCREASED RISK OF THE RESPONSE AND WE ALSO NOTICED THE SAME THING FOR THE LONG-TERM--THE LONG-TERM BOOSTABILITY FOR THE MODEL RESPONSE WHERE WE RECEIVE THE [INDISCERNIBLE]--AFTER THE PEAK RESPONSE, THE RESPONSE COMES BACK AND PLATEAU TO WHERE WE K 85 WHEN WE HAVE THE BOOST AND EVEN HIGHER THAN THE POST BOOST LEVEL AND THIS WAS DELAYED AT 26 RESPONSE WAS EFFICIENT THAT WEARY CEIVE THE ANTIBODY AFTER THE SPRAOEUPL BUT THAT AT LEAST 48 AND WE HAVE TO ANALYZE THE DATA AT THE TIME OF BOOST. THAT SORT OF TWO WEEK 85, BUT AT LEAST WE DON'T SEE A TREND IN ANY DECREASE BETWEEN SIX AND 48. SO THE NEXT PART WILL BE UNDER PROTECTIONS AND WE ONE OF THE FIRST THINGS WE DID IS WE DID THE MONOVACCINE, WE COMBINE 26 ASK 35, AND ON WEEK FOUR AND THEN COMPARE IT TO FIVE, THE VERY SUCCESSFUL VACCINE AND SINGLE TO 10 TO THE 11 AND THEN A CHALLENGE WITH THE EBOLA VIRUS AND THE TISSUE, I. M. FOR THE LAST IMMUNIION AND WE ARE--WE ARE--WHAT WE HAVE IS IT'S MODIFIED PROTECTION WITH THIS MODEL, WITH THIS NEW CHALLENGE START THAT WE USE, WE WENT DOWN TO ONLY 33% PROTECTION, WE KNOW THIS CHALLENGE IS VERY LIKELY DOWN TO .01, AND I CONTINUING COMES BACK TO WHAT [INDISCERNIBLE] MENTIONED ON THE RELEVANCE OF THE CHALLENGE AND HOW WE CAN COMPARE IMMUNE PROTECTIONS TO ONE STUDY TO ANOTHER. NONETHELESS WE WERE THERE AND WE WORK ON THE WAY TO INCREASE THE PROTECTION AGAINST THIS WILD-TYPE VIRUS AND WE ARE--WE TESTED DIFFERENT THINGS, THE EXTENSION OF THE VACCINATION SCHEDULES FROM 04 TO EIGHT WEEKS, THE COMBINATION OF AD26 WITH MVA THAT WAS IN PARTICULAR WITH THE BAVARIAN NORDIC AND THIS STUDY HAS HERE HAS BEEN DONE WITH THE HELP OF DMID SERVICES AND THIS WAS THE PART OF THE STUDY WAS NEGATIVE CONTROLS AND THEN [INDISCERNIBLE] WITH THE VACCINE AND THEN THE PRIME WITH 26, WE HAVE 35 AT EIGHT WEEKS, 26 MVA, AND THE OTHER WAY, WE HAVE THE IMMUNIZE AT 26 AND 26 MVA. AND THAT'S THE OUTCOME OF THE CHALLENGE, WE GIVE THE TWO CONTROL VALUE EXPECTED AT AROUND THE DAY SIX OR DAY SEVEN. BUT ALL THE ANIMALS NOW, WITH A DISEASE AT THIS 26 MDA COMBINATION, OR WITH THE EXTENSION OF THE PRIME BOOST ON 26 [INDISCERNIBLE] WE FULLY PROTECTED AGAINST THE DISEASE, YOU DON'T SEE MUCH SYMPTOMS IN THE ALL THE SURVIVAL, AND WE HAD A HUNDRED PERCENT WITH THIS COMBINATION. THIS WAS ASSOCIATE WIDE A STRONG T-CELL RESPONSE THAT WE MEASURED BY [INDISCERNIBLE]. SO THIS IS THE WEEK, SO THIS IS POST [INDISCERNIBLE] RESPONSE AND THIS IS RESPONSE WHEN WE REACH QUITE HIGH LEVEL OF T-CELLS BY THE [INDISCERNIBLE] FOR ALL THE DIFFERENT COMBINATION WHETHER WE DO ANOTHER ADENO OF THE ADENO-ADENO COMBINATION, AND THIS IS FOR THE HUMAN RESPONSE WHEN WE SEE THIS IS AGAIN [INDISCERNIBLE] WEEKS AND THE HUMAN RESPONSE IS PRIMED BY THE ELISA, AND IT'S A STRONG RESPONSE AFTER THE EBOLA WAS BOOSTED AMONG THEM. WE ALSO DID THE MAYINGA COLLABORATION AND I THINK JAY WILL HAVE A NICE TALK LATER ON ON HIS ASSAY AND THE IMPORTANCE OF VNA AND YOU SEE THE PRIME RESPONSE AT 26 IS ABLE TO NOTICE AT LEVEL OF ANTIBODIES IN ALL THE ANIMALS THAT HAVE BEEN PRIMED AND THEN THE RESPONSE IS HIGH ABOVE 3.5 OF 10 IN ALL THE ANIMALS THAT RECEIVED THE BOOST IMMUNIZATION. SO THAT'S COMBINING A LOT OF DIFFERENT MULTIPLE STUDIES, ALL IN MULTIVALENT SETTINGS. WE PULLED THE SURVIVAL, NONSURVIVAL DATA AND ON THE LEFT WHAT YOU SEE, THE HUMAN RESPONSE AND THE COMPARISON BETWEEN SURVIVAL AND NONSURVIVAL AND YOU SEE SEE A TREND FOR HIGHER RESPONSE FOR THE SIGNIFICANT BUT IT'S A LOT OF OTHER BETWEEN THE TWO. AND AGAIN WHEN YOU LOOK AT THE T-CELL RESPONSE MEASURED BY THIS, TOTAL RESPONSE AGAINST THE GLYCOPROTEIN, AGAIN, TRAINED FOR HIGHER RESPONSE IN THE ANIMALS THAT ACTUALLY DO SURVIVE WILL CHALLENGE COMPARED TO THE ONE THAT'S NOT. BUT AGAIN, THE LAB BETWEEN THE TWO DIFFERENT POPULATIONS. SO WHAT WE DID, WE PLOTTED THIS IN A TWO WAY VARIABLE WHEN IS HAVE YOU THE T-CELL RESPONSEOT Y-AXIS IN [INDISCERNIBLE] AND THEN THE ELISAA RESPONSE ON THE X-AXIS AND THEN YOU HAVE THE NONSURVIVAL IN RED AND THEN THE SURVIVAL TIMES ARE THE BLACK POINTS AND YOU CAN THEN PUT PUT THE SQUARES WHICH WILL FIT DR. PERKINS WAS MENTIONING THAT IF YOU HAVE A VERY HIGH ANTIBODY RESPONSE AND ABOVE IN OUR ASSAY, WE [INDISCERNIBLE] 3.8, 2.1, 2.9, THEN ALL ANIMALS WILL ACTUALLY SURVIVE AND IF YOU ARE YOU GO, LOWER YOU SPEAK THAT INTO THE ANIMALS THAT ARE LOW T-CELL RESPONSE AND ONLY 10% SURVIVAL BUT THEN THE ANIMAL LOW ANTIBODY AND HIGH T-CELL RESPONSE WE WILL BE ABLE TO COMPENSATE THE LOWER DEVELOP OF ANTIBODY RESPONSE. AND THAT'S THE LAST TIME, AND ANNOUNCING THAT THIS WOULD BE--NOT THE CORRELATE PROTECTION, BUT AT LEAST WE ARE TRAINED FOR EX( EXEXPECTATION, AND WHAT WE NOW WILL WANT TO ADD IN THIS, IN THIS MODEL WITH THE MATURE EYIZATION DATA WE WE DID GABBING IT HISTORICAL STUDIES AND WE WILL GET DNA DATA MATCHING THAL TIME POINT. SEE THE CLUSTER THAT WE CAN SEE CAN BE REFINED AND THEN BE BETTER, ANTIBODIES AND T-CELL ASSAYS ADDED JUST TO SEE IF WE CAN REALLY DIFFERENTIATE AND SEE THE MORE DIFFERENT CLUSTERS BETWEEN THE SURVIVALS AND THE NON SURVIVALS AND I THINK WE SHOULD DO AS VACCINE DEVELOPERS IS WE SHOULD LOOK AT THE MEND SET THAT WAS MENTIONED ON THE MONOCLONE'S ANTIBODIES, WE COME TOGETHER AND PUT OUR DATA TOGETHER WITH THE NORMALIZATION OF HUMAN, SAYS AND WE DO ALL ASSAYS IN ALL ADS AND WE TRUST ON ALL SPECIFIC BIAS BUT I THINK IT WOULD BE NICE TO AAGREE ON CENTRALIZED WHERE WE HAVE NORMALIZED IMMUNE ASSAY TAC COMPARE, PUT THE DATA TOGETHER AND BE ABLE TO REALLY IDENTIFY CORRELATE PROTECTION FOR THE DISEASE. AND ONE THING WE WILL HAVE TO ALSO AGREE ON BECAUSE I'M NOT SURE WE'RE THERE YET, IS NORMALIZATION OF THE CHALLENGE MODEL, AND THE ANIMAL SPECIES, THE INOCULATION, ALL OF THAT CAN INFLUENCE THE PROTECTION SO THAT'S PART OF THE NORMALIZATION THAT NEED TO WORK ON. AND THAT WILL BE REQUIRED BY THE--BY QUALITY BY THE ANIMAL ANYWAY. I THINK I AM DONE AND I PROBABLY [INDISCERNIBLE] THANK YOU. >> [ APPLAUSE ] >> NEXT TALK IS BY NANCY SULLIVAN WITH THE VACCINE RESEARCH CENTER OF NIH AND SHE WILL TALK ABOUT SOME OF OUR STUDIES AND DISCUSS ISSUES OF IMMUNE CELLULAR CORRELATES. NANCY? >> THANK YOU. OKAY, SO WHAT I THOUGHT I WOULD DO TODAY IS JUST WALK THROUGH SOME OF THE KEY OBSERVATIONS WE'VE MADE OVER THE YEARS THAT HAVE SHAPED OUR THINKING ABOUT IMMUNE CORRELATES AND IMMUNE MECHANISMS OF PROREALLY FOCUSED ON ADVECTOR VACCINES AND THAT TKING BEGAN BEFORE WE WELL A PROTECTIVE VACCINE IN PRIMATES. AND SOME OF THE EARLY APPROACHES USING EITHER RECOMBINANT PROTEIN, VIRUS LIKE PARTICLES, THINGS THAT WERE VERY GOOD AT GENERATING ANTIBODY RESPONSES SHOWED GOOD PROTECTION IN RODENT MODELS, SOMETIS ENHANCEMENT BUT ALMOST INVARIABLY PROVIDED PROTECTION WHATSOEVER WHEN THEY WERE MOVED TO NONHUMAN PRIMATE MODELS SO THERE'S A DIFFERENCE BETWEEN THE RODENT MODELS AND NONHUMAN PRIMATE MODELS IN TERMS OF STREUFRPBLGENCY FOR PROTECTION OF WHEN'S NEEDED AND IT MADE US THINK A LITTLE BIT ABOUT THE ROLE OF ANTIBODIES AND ASKED THE QUESTION WHETHER [INDISCERNIBLE] VIRUS IS PART OF EBOLA VIRUS, SO THAT'S WHAT TRIEVE SOME OF OUR EARLY DECISIONS ALONG WITH THE FACT THAT JUST LOOKING AT THE BASIC VIROLOGY, SO EBOLA IS PLEOMORPHIC SO IT HAS HIGH DENSITY SO IT HAS CHALLENGES OF ANTIBODIES AND PROTECTIONS, AND THE VIRION IS STABLE SO AS PETE MENTIONED WHEN YOU CAN DOZE ANN OROSOLCHALLENGE WITH PFU AND GET MORTALITY, YOU REALLY HAVE QUITE A CHALLENGE FOR STERILIZING IMMUNITY. THE INFECTION IS HAS BROAD TAUPISM, MULTIORGAN INFECTION SO YOU NEED A LOT OF ANTIBODY AND YOU NEED IT EVERYWHERE. AND THEN FINALLY, THIS VIRUS IS A LOT DIFFERENT THAN SAY A SMALL SPHERICAL VIRUS LIKE HIV THAT HAS MOLECULAR CELL INTERACTIONS AT THE CELL SURFACE THAT CAN BE TARGETED AND THAT'S PARTLY BECAUSE IT'S RAPIDLY INTERNALIZED BY MACROPENE O SIGNIFYITOSEIS, SO AGAIN LIMITING THE ANTIBODY TO DO THE CLASSICAL NEUTRALIZATION THAT WE THINK ABOUT. OKAY SO THERE'S ONE MORE FEATURE OF THIS VIRUS THAT MAY PROVIDE ACHALLENGE FOR NEUTRALIZING ANTIBODIES AND THAT'S THE FACT THAT THE GLYCOPROTEIN GENE MAKES AT LEAST TWO PRODUCTS. THE PRIMARY PROD SUCK A GLYCOPROTEIN IN A ISOLATE, AND THE FORMATION THAT YOU GET THE PROTEIN THAT'S NECESSARY FOR VIRUS PREAND WHEN THE POLYMERASE DOES SLIPPING AND IT INSERTS AN ADENOSINE AND SHIFTS THE READING FRAME THAT ALLOWS FORMATION OF THAT FULL LENGTH TRIMER. SO WE APPROACHED THIS THINKING THAT A VACCINE IN PRIMATE HEAT SHOCK SYSTEM GENERATE BOTH HUMORAL AND CELLULAR IMMUNITY IS OUR APPROACH TO THAT WAS GENE BASED VACCINES EMPLOYED IT JUST SHOWS THAT YOU WITH DNA VECTORS YOU CAN GET ALMOST TRANSFECTION IN VIVO AND SO YOU MAKE THE GENE PRODUCT, YOU GET DIRECT PRESENTATION TO ANTIGEN PRESENTING CELLS, CROSS PRESENTATION TO AND BOTH OF THOSE GIVE YOU BOTH T-CELL AND HUMORAL IMMUNE RESPONSES. SO OUR FIRST VACCINE FOCUSED ON A COMBINATION OF PLASMA DNA AND REPLICATION EFFECTIVE ADENO VIRUS AND JUST TO GIVE YOU THE MODEL WHICH I DON'T THINK HAS BEEN DISCUSSED TOO MUCH IN TERMS OF HOW THESE VACCINE STUDIES ARE DONE, TYPICALLY THEIR SMALL GROUPS OF ANIMALS BECAUSE IT'S BSL FOUR, THE CHALLENGE WHICH PETE MENTIONED IS A THOUSAND PFU DELIVERED INTRA MUSCULARLY AND JUST TO TELL YOU IN THIS MODEL WE TITRATED DOWN TO 10 PSU, AND THAT'S UNIFORMLY LEATHAL SO WE'RE MUCH HIGHER THAN WHAT'S REQUIRED TO KILL THESE ANIMALS AND WE THINK ABOUT THAT NOW THAT WE'RE TRYING TO TRANSLATE INTO HUMAN IMMUNE RESPONSES AND WHAT DOES THAT MEAN, YOU KNOW? WE REALLY HAVE A HIGH BAR HERE FOR PROTECON, SO THE IMMUNE RESPONSES WE SHOW ARE NEEDED HERE MAY ACTUALLY BE LESS IN HUMANS THAT RECEIVE A LOW DOSE OF VIRUS. OKAY, SO THIS FIRST STUDY WAS A DNA PRIME AD-BOOST WEIGH MENTIONED WE CHALLENGED AT ABOUT HALF A YEAR AND WE OBSERVED THAT WE HAD FOR THE FIRST TIME UNIFORM PROTECTION OF NONHUMAN PRIMATES. OF COURSE FOR AN OUTBREAK SETTING WE WANT SOMETHING THAT WORKS MORE QUICKLY AND WE DID A SERIOUS OF EXPERIMENTS TO RATCHET THAT BACK AND SHOW THAT A SINGLE SHOT WOULD PROTECT. SO, IT DEMONSTRATED THE PROOF OF PROTECTION THAT YOU CAN PROTECT THE SINGLE SHOT MODEL, GIVES US MORE OPPORTUNITY TO SEEK IMMUNE CORRELATES IN A MORE HIGH THROUGH PUT FASHION. OKAY, AND SO, THIS IS ABOUT THE SAME TIME THAT FDA PROMULGATED THE ANIMAL RULE FOR THE LICENSURE VACCINES WHERE YOU CAN'T DO EFFICACY STUDIES AND I'M SURE YOU'RE ALL VERY FAMILIAR WITH THIS, BUT WHAT WE REALLY KEYED IN ON WAS THIS STATEMENT THAT YOU NEED TO SHOW THAT YOUR VACCINE IS REASONABLY LIKELY TO PROVIDE EYE CLINICAL BENEFIT IN HUMANS. THAT'S STILL MENTIONED EARLIER AND THE ANIMAL RULE AND DIFFERENT VACCINES AND SO WE JUST THOUGHT THE MOST STRAIGHT FORWARD WAY IS WITH AN IMMUNE CORRELATIVE PROTECTION. SO WE WANT TO DETERMINE AN IMMUNE RESPONSE RIGHT AFTER VACCINATION THAT PREDICTS PROTECTION WHETHER WE CHALLENGE SHORT-TERM OR LONG-TERM. OKAY? AND SO WE MAPPED OUT THIS FRAMEWORK FOR HOW WE WOULD GO ABOUT THIS, AND THE MAIN THING OBVIOUSLY FOR ANY VACCINE DEVELOPMENT IS OPTICAL IMAGES MYSELFING THE COMPETITION AND DOSE AND SO FORTH AND THAT HAS TAKEN US MANY YEARS TO GET TO A CANDIDATE THAT WE CAN MOVE FORWARD. WE DO THIS AND WE HAVE DONE THIS IN PARALLEL WITH PHASE ONE STUDIES. SO WE HAVE LOTS OF PHASE ONE STUDIES WITH DNA AND ADENO VIRUS ALONE AND SO FORTH. THOSE HAVE ALL BEEN VERY INFORMATIVE EVEN THOUGH THEY HAVEN'T GIVEN US A LEAD CANDIDATE BECAUSE IT'S ENABLED US TO SORT OF CALIBRATE WHAT WE GET FOR IMMUNE RESPONSES IN MONKEYS VERSES HUMANS. AND THEN ULTIMATELY, ONE HAS TO DO PIVOTAL STUDIES ONCE THE LEAD CANDIDATE IS SELECTED WITH STATISTICALLY CORRELATIVE INFORMATION TO FIND AND WE BRIDGE THESE TO THE HUMAN STUDIES AND I SHOW YOU HERE MEANING THAT THE FDA ADVISORY COMMITTEE IS A FORMAL STEP AND I'M SURE YOU KNOW THIS, THE INTERACTION WITH FDA OCCURS THROUGHOUT THIS PROCESS AND IT'S IMPORTANT TO GET THAT FEEDBACK. OKAY, SO JUST FOCUSING ON CORRELATES FOR A MOMENT, HOW DO WE DO THAT. SO I THINK SOME OF THE EARLIER TO THES HAVE SHOWN YOU THAT YOU CAN'T DO THAT WITH A FULLY PROTECTIVE VACCINE, YOU NEED TO ILLICIT PROTECTION BREAK THROUGH TO CORRELATE THE PROTECTION. SO WITH THIS CHALLENGE MODEL THAT'S A BIT DIFFICULT. WITH HIV, YOU CAN FOLLOW TITERS OVER TIME AND WITH THE VIRUSES AND SEE WHAT CORRELATES WITH INCREASING AND DECREASING FOR EBOLA BECAUSE IT KILLS SO SWIGLY WE GET A SINGLE SNAPSHOT SO WE HAVE TO BE CREATE 95 THE WAY WE LOOK FOR CORRELATES AND OUR APPROACH HAS BEEN TO USE PARTIALLY PROTECTED VACCINES AND WE CAN MAKE THEM PARTIALLY PROTECTIVE EITHER BY MODIFYING THE VECTORS, MODIFYING THE INSERTS OR MODIFYING THE DOSE. SO THE FIRST EXPERIMENT WE DID WAS A DOSE DOWN TO ELICIT INFECTION BREAK THROUGH SO FROM THE VACCINE DEVELOPMENT PE, IT WAS NICE TO SEE THAT WE COULD DOSE DOWN FROM OUR HIGHEST DOSE AND STILL GET PROTECTION AND FOR IMMUNE CORRELATES, WE REALLY WERE MOST INTERESTED IN THIS BREAK THROUGH REGION BETWEEN 10 TO THE 10 AND 10 TO THE NINTH AND SO SINCE THAT TIME I'M SHOWING YOU SURVIVORS IN YELLOW AND FATALITIES IN RED; HOWEVER, EVEN WITH SMALL ANIMAL NUMBERS WE LOOK AT ELISA IGG WE ASSOCIATION BETWEEN TITERS AND PROTECTION. SO WE WANT TO MAKE THAT A STATISTIC LIE SIGNIFICANT OBSERVATION SO THIS WAS OVER MANY YEARS WHERE WE IN RESPONSE TO CONVERSATIONS WITH FDA WHERE THEY WERE CONCERNED ABOUT CYTOPATHISSITY OF THE INSERT, WE ACTUALLY MADE A LOT OF MODEUFBDZS TO THE INSERT AND WE HAD SOME THAT WORKS AND SOME THAT DIDN'T WORK AND WE COMBINED ALL THOSE DATA AND AND WE WERE ABLE TO SHOW THAT ELISA, AND AGAIN NOT NEUTRALIZING ANTIBODY WAS A STRONG AND STATISTICALLY SIGNIFICANT IMMUNE CORRELATIVE PROTECTION AND SO FOR A HUNDRED% SURVIVAL WE HAD OUR BENCHMARK OF ONE TO 3500 AS A TITER AND FOR 85% IT WAS ONE-1500. OKAY, SO AS STAN MENTIONED THERE ARE DIFFERENT WAYS TO THINK ABOUT IMMUNE CORRELATES AND THIS IS AN OPERATIONAL DEFINITION THAT WE'VE BEEN RELYING ON MOST RECENTLY AND THAT IS THINKING ABOUT CORRELATES AS EITHER MECHANISTIC OR NONMECHANISTIC AND SO WE WANTED TO UNDERSTAND WHETHER OUR CORRELATE WAS MECHANISTIC OR NOT AND THE FIRST ATTEMPT TO ANSWER THAT QUESTION, WAS BY DOING A PASSIVE TRANSFER OF NAIVE MACAQUES. SO WHAT I'M SHOWING YOU HERE IS TITERS JUST BEFORE A CHALLENGE OF EITHER VACINATED, NAIVE PASSIVELY TRANSFERRED OR OF COURSE, IN NAIVE ANIMALS WE DON'T HAVE ANY TITER, REMEMBER THE BENCHMARK OF ONE-3500 FOR UNIFORM PROTECTION, SO OUR TRANSFERRED TIGHTERS WERE MUCH, MUCH, HIGHER THAN WHAT WE ASSOCIATE IN A WHOLE VACCINE IMMUNE RESPONSE WITH PROTECTION. IN HERE WE DID NOT SEE VERY GOOD PROTECTION SO ONE ANIMAL SURVIVED THAT. SO THAT WAS THE FIRST SUGGESTION THAT MAYBE MECHANISTICALLY SOMETHING IN ADDITION TO ANTIBODIES WAS NEEDED FOR PROTECTION. SO THE NEXT EXPERIMENT WAS THEN TO DOES WHAT IS THE ROLE OF CD-EIGHT T-CELLS AND HERE WE VEHICLEINATED PRECABBINGS AND REMOVED T-CELLS JUST PRIOR TO INFECTIOUS CHALLENGE AND WE SHOWED THAT WE LOST PROTECTION INDICATING IMPORTT ROLE OF CDEIGHT T-CELLS SO FINALLY SORT OF A NATURAL EXPERIMENT CAME ABOUT WHEN [INDISCERNIBLE] WAS DISCOVERED, AND SO WE HAD A BUNCH OF ANIMALS AND WE SAID LET'S SEE IF THERE'S CROSS PROTECTION AND WE DON'T HAVE THE CHALLENGE VIRUS, GLYCOPROTEIN IN THE VIRUS, CAN WE GET PROTECTION? AND THERE WAS A LOT OF REASONS TO BELIEVE THIS WASOT THE CASE BECAUSE IF YOU LOOK AT ANTIBODIES THEY DON'T REACT WITH DISEASE SPECIFICS. SO WE HAD A HUNDRED PERCENT SURVIVAL IN THE PRE BOOST EXPERIMENT. WE LOOKS AT T-CELLS THIS IS T-CELLS AGAINST THE VACCINE INSERT. GOOD T-CELL RESPONSES. WE ALSO HAD T-CELL RESPONSES AGAINST THE CHALLENGE VIRUS THAT WAS NOT IN THE VACCINE WHEN WE LOOKED AT ANTIBODY RESPONSES, WE HAD ANTIBODY RESPONSES ONLY AGAINST THE VACCINE INSERT BUT NOT AGAINST THE CHALLENGE. SO THIS INDICATED THAT YOU CAN NOT ONLY--NOT ONLY DO YOU LOSE PROTECTION H YOU REMOVE CDEIGHT T-CELLS BUT CAN YOU GET PROTECTION IN THE ABSENCE OF ANTIBODIES. SO THIS LED US TO A WORKING HYPOTHESIS THAT AT LEAST FOR THE ADVACCINE, ELISA NONIGG IS A PROTECTION, IT DOESN'T MEAN IT DOESN'T HAVE A ROLE BUT AS A CORRELATIVE PROTECTION IT'S REFLECTING THE OVERALL IMMUNE RESPONSE. OKAY, SO, THIS WAS ALL GREAT AND WE WERE READY TO RUN WITH THIS VACCINE MOVING FORWARD INTO--OT REGULATORY PATHWAY, JULIE LEDGER WOOD WHO HAD LED ALL OF OUR CLINICAL TRIALS FOR THE EBOLA VACCINE DID A STUDY IN HUMANS, AND IT WAS ENCOURAGING TO SEE THAT WHAT I'M SHOWING YOU HERE IS THE RESPONSE RATE IN THE INTERVAL THAT AT TWO DOSE LEVELS ALL OF THE VACCINEES HAD AN ANTIBODY RESPONSE. THE DISAPPOINTING NEWS THAT IF THIS WAS DONE IN ADFIVE SEROPOSITIVED INDIVIDUALS AND THAT IT IF PEOPLE HAD AN IMMUNITY TO THE VECTORS WE WERE USING THE RESPONSE RATE WENT WAY DOWN. SO OUR NEXT EXPERIMENT WAS TO LOOK IN MONKEYS TO SEE IF WE SAW THE SAME THING AND HERE I'M SHOWING NUCLEOTIDES NAIVE ORAD-IMMUNE ANIMALS WHERE WE LOOK AT VACCINATIONI LIZA TITERS, AD-FIVE IMMUNITY DIDN'T SEEM TO MAKE A RESPONSE AT ALL. SO WHEN WE LOOKED AT CD-EIGHT WE LOOKEDDA IMMUNE SUBJECTS. SO THAT TOLD US THAT WE COULDN'T GO FORWARD WITH AD-FIVE AND THE NEXT STEP WAS TO LOOK FOR ALTERNATIVE RARE SEROTYPE VECTORS. WE WERE--WE HAD A VERY NICE COLLABORATION WITH WHAT IS NOW J& J, WITH THE AD26 AND 35 SECTORS. THIS IS I SINGLE SHOT. THIS IS SINGLE SHOT WHEN WE DELIVER THE VACCINE AT 10 TO THE 10th WHICH IS THE ADFIVE FOES OR A LOGUE HIGHER, WE DIDN'T GET THE PROTECTION THAT WE WANTED. LIKEWISE FOR AD26, IF WE INCREASE TO THE BEST OR HIGHEST DOSE THAT WE PROBABLY CAN'T DELIVER THIS IN HUMANS WE WEREN'T GETTING A HUNDRED PERCENT PROTECTION. BUT IT GAVE US AN OPPORTUNITY TO LOOK AT CORRELATIVE PROTECTION. SO THIS TIME NOW WE'RE LOOKING AT DIFFERENCES IN VECTOR PERFORMANCE AND LOOK AT IMMUNE CORRELATES. AND WHAT WAS CURIOUS TO US WHAT WHAT I DIDN'T SHOW YOU BEFORE IS THAT WE HAVE A LOWER LIMIT CUT OFF WHICH IS A TITER OF ONE-500, ALL OF THESE ANIMALS THAT DIED HAD PRETTY RESPECTABLE ANTIBODY RESPONSES. SO WE LOOKED AT T-CELL RESPONSES AND FOR CD4, AD26 AND 35, LOOKED JUST AS TKPWTD GOOD AND AD35 WAS A BIT BETTER. AND CD-EIGHT WE EXPECTED TO SEE DIFFERENCES BUT WE DEPARTMENT SEE DIFFERENCES SO THAT WAS PUZZLING TO US UNTIL WE THOUGHT ABOUT T-CELL QUALITY. AND I'LL STEP BACK A BIT BECAUSE NOT EVERYONE IS A T-CELL OFFICKIANAD O. --THIS COMES FROM CELLS MAKING THAT, SELLS MAKING CYTOKINES, THREE CYTOKINES AND WE DIDN'T CHOOSE THESE CYTOKINES WE MEASURE ARBITRARILY, THEY HAVE SOME ASSOCIATION WITH FUNCTIONS OF DIFFERENT T-CELL SUBSETS AND SO THE BOTTOM LINE IS THAT EACH OF THESE IS DISTINCT AND THE ONLY WAY TO MEASURE THAT IS BY MEASURING COMBINATIONS OF CYTOKINES. AND THE WAY THAT WE DO THAT OR DEPICT THAT IS SHOWN HERE. SO YOU CAN MEASURE EVERY COMBINATION OF THOSE THREE CYTOKINES AND THEN ASK WHAT PROPORTION OF CELLS IN YOUR T-CELL POOL MAKE ONE CYTOKINE, HOW MANY MAKE TWO, HOW MANY MAKE THREE AND RIGHT AWAY, EVEN JUST AT THAT LEVEL, CAN YOU SEE A BIG DIFFERENCE AT 35 AND NONPROTECTIVE VACCINE, AND IT DOESN'T JUST SORT WITH THE NUMBERS OF CYTOKINES, IT SUPPORTS--IT SORTS WITH ACTUALLY WHICH CYTOKINE COMBINATIONS ARE PRODUCED SO REMEMBER THIS POPULATION IS WHAT WE THINK OF AS AN EFFECTOR TYPE FOR CD-EIGHT T-CELLS SO THAT WAS A BIG DIFFERENCE BETWEEN THESE TWO VECTORS. SO WHEN WE THOUGHT ABOUT NOW WHAT WE WILL DO FOR AN ALTERNATIVE VECTOR, WE WILL MOVE TO COMMUNISM AD BECAUSE WE PRESUME IN HUMAN WHO IS DON'T GET INFECTED WITH THE PREEXISTING IMMUNITY WILL BE LOW AND SO ONE OF THE FIRST THINGS WE ASK WAS WHAT WOULD BE MOST LIKE AD-FIVE AND CHIMP AD-THREE SORTS WITH ADFIVE AND WE ELIMINATED THE TWO GROUPS WHERE WE HADN'T SEEN PROTECTION AND WE ALSO CHOOSE CHIMP AD-63 BECAUSE IT PROBABLY USES THE SAME RECEPTOR AS AD-FIVE SO ONE OF THE IF I HAVE THING WHAT'S LOOK AT AND WAS T-CELL QUALITY AND HERE I'M SHOWING YOU AGAIN 26 AND 35 WITH VERY FEW OF THESE DOUBLE POSITIVES WHO WERE IN THIS GROUP AND AD-FIVE WHERE YOU SEE THAT BIG JUMP THERE AND THAT IMPORTANT POPULATION IN CHIMP AD-THREE, AND WE MOVED FORWARD, THIS IS ACUTE LIE LOOKING AT FOUR WEEKS AFTER VACCINATION WITH THE IMMUNE RESPONSES ARE. CHIMP AD63 IS HOVERING RIGHT AROUND THE CUT OFF FOR PROTECTION, CHIMP AD63 IS ABOVE WAWE SAW WITH FIVE. CD4 LOOKS PRETTY GOOD AND WE'VE ALSO SEEN THAT WITH THE OTHER VECTORS AND CDEIGHT IS ALSO LOWER FOR CHIMP AD63. SO WE DID THE CHALLENGE ACUTELY AND CHIMP ADTHREE GAVE US PROTECTION AND AS PROPRIETARY HAVE BEEN PREDICTED FROM THE IMMUNE RESPONSES CHIMP AD63 AGAIN CONSISTENT WITH HOW WE THINK ABOUT ANTIBODIES AND CD-EIGHTS DO NOT GIVE US THE SAME LEVEL OF PROTECTION, AND WE'RE ALSO INTERESTED IN DURABLE IMMUNITY. WHEN WE INCREASE THE DOSE OF CHIMP ADTHREE, A LOG OVER WHAT WE ARE USING FOR ACUTE PROTECTION, WE GET SOME PROTECTION BUT NOT UNIFORM. AT THE LOWER DOSE WE DON'T GET ANY PROTECTION. SO WE DIDN'T GIVE OUT ANY PROTECTION. SO WE ASK THE QUESTION WHETHER PRIME BOOST WOULD BE NEEDED FOR DURABLE PROTECTIONS. AND IMOCCUPYOLOGICALLY THERE ARE REASONS TO THINK THAT WE'RE ASKING THIS VACCINE TO DO THINGS THAT YOU KNOW AREN'T PRESENT AT THOSE SAME TIME POINTS SO WE WANT RAPID PROTECTION AND WE WANT DURABLE PROTECTION. SO WHEN YOU THINK ABOUT IMMUNE RESPONSES, IN THAT PRIMARY RESPONSE IT WOULD BE RAPID. TYPICALLY YOU HAVE HIGH CONCENTRATION OF ANTIBODY, LOW AFFINITY AND THEN AT MEMORY TIME POINTS THAT DECLINES DOWN TO LOWER CONCENTRATIONS BUT IT'S AFFINITY MATURES. T-CELLS GIVE YOU HIGH MAGNITUDE INITIALLY AND SORT OF A DYNAMIC QUALITY AND OVERTIME, THAT MAG FIELD FUNCTIONS FEUD GOES DOWN AND SRO A CONTRACTED QUALITY SO WE CHOSE MVA AS A BOOST BECAUSE IT'S GOOD AT BOOSTING CD4 AND WE THOUGHT THAT WOULD ADD THE MEMORY COMPONENT THAT NEEDED THE EFFECTOR OF QUALITY EARLY ON AND I'LL SHOW NUCLEOTIDES THE NEXT COUPLE OF SLIDES IS IMMUNE RESPONSES ASTERISKS PEAK, EITHER AFTER THE PRIME OR AFTER THE BOOST AT MEMORY, AND THEN THE CHALLENGE IS DONE RIGHT AFTER WE MEASURE THIS MEMORY RESPONSE SO THIS IS LOOKING AT PEAK AND MEMORY FOR A SINGLE SHOT COMPARED TO THE PRIME BOOST SO OBVIOUSLY MVA IS GIVING US A HUGE BOOST EFFECT IN THE ANTIBODIES AND WE SAW THE SAME TREND WITH CD4 AND EIGHT S. AND SO WHILE WE COMPARE, THEY'RE TYPICALLY AT PEAK. SO WHAT I'M SHOWING YOU HERE IS PEAK RESPONSES AND MEMORY RESPONSES AFTER THE MVA BOOST AS WE SAW WITH THE CHIMP VACCINE, AND DIDN'T GIVE US QUITE THE LEVEL WITH THE CHIMP AD-THREE, SO IMMEDIATELY AFTER THE BOOST, WE HAVE HUGE ATTENT BODY RESPONSES WHICH CONTRACTS DOWN BUT STILL ABOVE WHAT WE SEE WITH OUR SINGLE SHOT ACUTE VACCINE. CD-FOUR AGAIN NOT STRIKE DIFFERENCES BETWEEN THE VECTORS AND CD-EIGHT AS WE SAW WITH THE ACOO VACCINE HAD WE DID THE CHALLENGE AT SIX MONTHS, MVA GAVE US 63 PROTECTION AND CHIMP AD363 DID NOT. SO WHAT WE'RE REALRY INTERESTED IS HOW THE T-CELL RESPONSE DEVELOPED OVER TIME AND WHAT HAPPENS AT THE MEMORY TIME POINT AND I'M SHOWING YOU THIS AS THE FINAL SLIDE AFTER--DURING THE PEAK RIGHT AFTER THE PRIME, WE SEE THAT DOUBLE POSITIVE POPULATION WHICH IS SO IMPORTANT FOR CHIMP ADTHREE, A LITTLE BIT LESS FOR 63. MDA BOOSTING DOES IS GIVE US THIS TRIPLE POSITIVE MEMORY POPULATION. AND IT GIVES THAT FOR THREE AND 63, BUT THE DIFFERENCE THAT REMAIN SYSTEM THE PROPORTION OF TNF ALPHA INTERFERON-GAMMA AND THE PROPORTION OF THE TRIPLE POSITIVE AND AT THE DURABLE TIME POINT JUST BEFORE CHALLENGE WE SEE AGAIN THAT THE DOUBLE POSITIVES ARE HIGHER FOR THREE, TRIPLE POSITIVES ARE HIGHER AND LOWER FOR 63. SO, THESE DIFFERENCES THAT WE SEE IN IMMUNE RESPONSES IN TERMS OF MAGNITUDE OF ANTIBODIES AND QUALITY OF CDEIGHT T-CELLS TRANSLATE INTO WHAT WE NEED FOR PROTECTION LONG-TERM WITH THE ADDITION OF THAT TRIP ILLEGALS POSITIVE MEMORY POPULATION ALONG WITH THE EFFECTOR POPULATION. SO I THINK I WILL STOP THERE WITH JUST A SUMMARY TO RECAP, JUST YOU KNOW ELI SA IGGIS PROSENTED TODAY. AND WE'VE SEWN FOR THIS VACCINE WE NEED CDEIGHT T-CELLS THAT THE QUALITY OF THE T-CELLS IS IMPORTANT FOR ACUTE PROTECTION WE GET ASSOCIATION WITH BOTH THE ELISA AND THE CDEIGHT QUALITY AND LIKEWISE FOR DURABLE PROTECTION WE'RE SEEING THAT DUAL ASSOCIATION BETWEEN CDEIGHT AND ANTIBODY RESPONSES. AND I DON'T KNOW RAFI IF YOU WANT TO DEFER QUESTIONS. YES, THANK YOU. [ APPLAUSE ] >> LAST TALK OF THE SESSION IS BY ALAN SCHMALIJOHN, WHO WILL TALK ABOUT ROLE OF ANTIBODIES AND TRANSFER AND ZMAPP TRANSFER. >> THANKS. THE FIRST SLIDE IS FOR THE DISCLAIMEROT BOTTOM THAT NOBODY ELSE TAKES CREDIT FOR WHAT I SAY. THIS TALK WILL BEGIN AND END WITH THE ZMAPP STORY THAT IT REALLY STARTS WITH THE OUTSTANDING THERAPEUTIC EFFICACY IN NONHUMAN PRIMATES THAT THOSE OF US WHO WORKED WITH MONKEYS AND VIRUSES OVER THE YEARS WILL PROBABLY UNIVERSALLY ASTONISHED NOT THAT AN ANTIBODY COCKTAIL COULD PROPHYLACTICALLY PREVENT DISEASE BUT THAT IT COULD THERAPEUTICALLY NOT ONE BAY BUT HERE STARTING AT THREE, FOUR, OR FIVE DAYS AFTER INFECTION, WHICH IN MONKEYS WAS A COMPRESSED TIME SCHEDULE AS PETE DESCRIBED THAT'S FAR INTO DISEASE AND THIS IS A COCKTAIL OF ANTIBODIES AND I'LL ADDRESS SOME OF THAT AS WELL. SO, FIRST REFLEX AMONG MANY OF US IS WHEN SOMETHING LOOKS TOO GOOD TO BE TRUE, IT PROBABLY IS, SO IS THAT TO GOOD TO BE TRUE AND I LOOK BACK THROUGH THE DAT AND NO NOT IN VIEW OF THE FOUNDATIONS OF THIS AND THE LARGER SCIENTIFIC LITERATURE, BUT WHAT I'M GOING TO TALK ABOUT LESS THAN THE DETAIL SYSTEM THE OVERARCHING CONCEPTS STARTING WITH TPHAOEUFPY, I'M TRYING TO BE UNDERSTOOD ON THE WHOLE. WHAT I WILL TALK ABOUT ARE THESE BIGGER CONCEPTS AND SOME GENERALLALLITYS ABOUT ANTIBODIES IN EBOLA IMMUNITY AND THE ORIGINS OF ZMAPP. A SIDE BAROT IMPORTANCE OF FC AND THE COMPLEXITIES OF ADCC, AND THEN SOME OF THE POTENTIAL LESSONS. SO TAKING THIS BACK TO VIROLOGY 101, YOU KNOW VIRUS ENTER CELLS, DISAPPEARS, BEGINS TO FORM NEW VIRUS PARTICLES, THAT'S THE BURST SIZE THIS, IS AT THE CELLULAR LEVEL SO THE NUMBER OF VIRUS PARTICLES MADE PER CELL, OPPORTUNITY FOR INTERVENTION IS BEFORE THE VIRUS FINDS THE CELL AND WE CALL THAT NEUTRALIZATION. THAT'S ONE OF THE THINGS WE CALL NEUTRALIZATION AND ANOTHER OPPORTUNITY IS AS THE VIRUS BEGINS TO SYNTHESIZE PROTEINS EVEN BEFORE IT'S MADE INFECTIOUS VIRUS AND FOR THE INN TIRE DURATION WHILE IT DOES MAKE INFECTIOUS VIRUS, CDEIGHT POSITIVE T-CELLS AND PARTICULAR CYTOTOXIC T-CELLS AND INTERRUPT REDUCE THE BURST SIZE AND THIS IS SO WELL ACCEPTED THAT YOU ALMOST NEVER FIND IT PUBLISHED ANYMORE AND IN THE LAST 30 YEARS, AS OTHERS DID IT EARLY ON TO SHOW THAT T-CELLS DO THIS IN LCM AND VACCINA VIRUS. I DINED IF PARADOXICAL THAT THE SAME PEOPLE WOULD FIND IT DIFFICULT TO UNDERSTAND THAT ANTIBODY CANS DO THE SAME THING IN THE PRESENCE OF THE RIGHT ACCESSORY CELLS. SO TO TRY TO HARMONIZE THOSE TWO LINES OF THOUGHT, NEUTRALIZATION IS ALSO POSSIBLE DURING THIS WHOLE PROCESS AND NOT ALL NEUTRALIZATION IS PREVENTION OF ENTRY, THERE'S OTHER THINGS THAT READ OUT AS NEUTRALIZATION. SO THESE THINGS CAN REDUCE BURST SIZE AND AS PETE SAID, YOU BEND THE CURVE A BIT, A LOG OR TWO ASK THAT'S ENOUGH TO CAUSE--LEAD TO SURVIVAL. ONE OF THE EMPATHYS OF THIS WHOLE TALK IS THAT A LOT OF THESE MECHANISMS WE'RE TALKING ABOUT ARE SC RECEPTOR DEPENDENT MECHANISMS INCLUDING OPTIMIZATION AND BY THAT I MEAN, UPTAKE NOT BY SUSCEPTIBLE CELLS AND LIKE MONOCYTES AND DCs AND NOT BY NONSUSCEPTIBLE CELLS THE CENOFILLS, ET CETERA. IT'S AN IN VIVO FORM OF NEUTRALIZATION THE LEVEL WE HEARD FROM A CLINICAL PICTURE AND STUDIES WITH EBOLA AND ACUTE DISEASE WE GET THE PICTURE WHERE LETHAL INFECTION THERE ARE OTHER INDIVIDUALS AND YOU HAD MASH OUTBREAKS AND A LOT OF OTHER VIRUSS, DISEASE AND RECOVERY WHERE THE TOTAL VIRUS LOAD IS LOWER, AND THEN AN APPARENT OR UNREPORTED DISEASE WHICH WE HEARD A BIT ABOUT AS WELL AND WE DON'T KNOW HOW BIG THIS IS WITH EBOLA. IGM AND IGG, AFTER THE T-CELL RESPONSE INFLAMMATION AND RECOVERY PRETTY MUCH THE SAME WITH THIS NEW EPIDEMIC. EXPOSURE WAS SOMETIME BEFORE THAT AND WE HEARD YOU NEED TO VACINATE BEFORE EXPOSURE OR POSSIBLY VACINATE WITH THE VSV, SHORTLY AFTER EXPOSURE, NOTED THAT THE VIREMIA IS HIGHER IN THE FATAL CASES IN THE NONFATAL CASES AND THAT IMPACTS BOTH ON YOUR LIKELIHOOD OF SUCCESS IN THERAPY AS WELL AS YOUR RISK OF INFECTION TO CONTACTS. SO IN A DIAGRAM, IF WE LOOK AT UNIVERSE OF VIRAL ANTIGEN BINDING ANTIBODY AFTER VACCINATION OR INFECTION, HAVE YOU A TOTAL ANTIBODY FIELD, WHAT WE'RE REALLY INTERESTED IN AS WE'RE NOTICING IS PROTECTION, THE ONLY CORRELATE OF PROTECTION IS PROTECTION. BUT WE LOOK FOR SURROGATES AND WITH THE SIMPLE VIRUS IS THAT THE HEDRAL VIRUSES THAT CAN BE A CLOSE OVERLAP WITH NEUTRALIZING ANTIBODIES THAT ACT WITH A LIMITED VARIETY OF MECHANISMS AND MAINLY ATTACHMENT AND ENTRY. AND WE'RE PARTICULARLY INTERESTED IN BROAD PROTECTION AGAINST MULTIPLE SEROTYPES. AND ALL THOSE BROADLY NEUTRALIZING ANTIBODIES AND WE ALSO APPRECIATE TO DO NO HARM AND HARMFUL ANTIBODIES THAT CAN ACT IN A NUMBER OF WAYS. THE CELL SURFACE ARE MORE COMPLEX THAN THAT, WE'RE INTERESTED IN PROTECTIVE ANTIBODIES, AND WE'RE INTERESTED AS ALWAYS IN NEUTRALIZING ANTIBODIES TO NEUTRALIZE BY MANY MECHANISMS THAT I WAS REFERENCE IN THIS A REVIEW I WROTE, WE NOTED INCOMPLETE OVERLAP AND THEY'RE NEUTRALIZING ANTIBODIES THAT DON'T PROTECT BUT A LOT OF THEM DO. MORE INTERESTED IN BROADLY PROTECTIVE ANTIBODIES, A LOT OF WHICH ARE NEUTRALIZING, SOME OF WHICH ARE NOT. MECHANISMS INCLUDE ADCC MEDIATED SIGNIFY TOLL-LIKE RECEPTOR SIS THAT OVERLAP A LOT BUT ARE NONOVERLAPPING BECAUSE COMPLEMENT IS QUITE HAPPY WITH IGH AND ADCC, AND ADM IS NOT. THERE'S OTHER MECHANISMS DISCUSSED ELSEWHERE WHEN YOU GET INTO THE WEEDS OF HOW DIFFERENT MONOCLONAL ANTIBODIES MAY PROTECT AND AGAIN WE HAVE THE PROSPECT OF HARMFUL ASPECT BODIES WE HAVE TO LOOK OUT FOR. THERE'S AN ABUNDANCE OF LITERATURE TO SAY THESE EXIST AND ARE RELEVANT BUT TODAY, THE BINARY SPLIT BETWEEN THOSE IS NOT IMPORTANT. WHAT I'M INTERESTED IN ARE THOSE ANTIBODIES THAT TARGET INFECTED CELLS, CELL TARGETING ANTIBODIES AND THAT INCLUDES A LARGE PN OF TOTAL NEUTRALIZING ANTIBODIES AS WELL AS THOSE THAT MEDIATE ADCC, OR COMPLEMENT LICENSE, SO WE WILL LOSE THAT SPLIT AND I'M NOT SURE WHAT EVERYBODY ALWAYS MEANS BY POLYFUNCTIONAL IMMUNE RESPONSES BUT I THINK THAT THE CELL TARGETED ANTIBODIES AS BEING EMBEDDED AS PARTS OF A POLYFUNCTIONAL IMMUNE SYSTEMUNE RESPONSE. LOOKING FOR TERMINOLOGY FOR THAT. SO GENERAL PRINCIPLES IN MY OPINION, IT'S RECKLESS TO UNDERESTIMATE THE IMPORTANCE OF ANTIBODIES, THE FIELD OF IMMUNE AGO DID THIS FOR ABOUT 25 YEARS. THEY WEREN'T WRONG, T-CELLS OTHER THAN THE ALWAYS IMPORTANT ESPECIALLY IF PRIMARY EARLY T-CELL RESPONSE IN NAIVE SUBSKWREBGS AND VACINATED OR PREVIOUSLY EXPOSED SUBJECTS THEY REMAIN CRITICAL IF ONLY TO SHAPE THE ANTIBODY RESPONSE, THE CONTEXT MATTERS AND 28 DAYS AFTER VACCINATION WITH THE HIGH DOSE VACCINE MAY BE TOWARD THAT EARLY PART OF THE IMMUNE RESPONSE THAT REMAINS TO BE RESOLVED. I'M NOT AN OPPONENTS OF VIRAL NEUTRALIZATION, JAY AND I MADE SOME OF THE BEST POX VIRUS NEUTRALIZING ANTIBODIES IN THE PLANET AND THEY'RE STILL SPREAD AROUND. VIRAL NEUTRALIZATION IS GENERALLY A VERY GOOD THING, BUT VIRUS NEUTRALIZATION IS ANN ABSTRACTION RETURNING TOALIS AND WONDER LAN, AS STAN SAID, WORDS MEAN SOMETHING BUT THERE'S A QUEEN OF HEARTS ELEMENT TO NEUTRALIZATION WHERE NEUTRALIZATION MEANS EXACTLY WHAT THE INVESTIGATOR REPORTING IT SAYS IT MEANS. IT'S OPERATIONAL DEFINED BY THE PARTICULAR ASSAY USED TO DEFINE AND MEASURE FOR A GIVEN VIRUS. ANTIBODY MEDIATED NEUTRALIZATION ARE AVENUE ESSENTIAL AS DEMONSTRATED BY THE IMPORTCE OF THE SC PORTION BY NEUTRALIZING AND NONNEUTRALLIZING ANTIBODIES AND I WILL TAUPE ON THE COMPLEXITY ADCC, BECAUSE I THINK APPRECIATING COMPLEXITY OF WHAT WE FACE IF WE UNDERSTAND MECHANISMS AND APPRECIATE THE COMPLEXITY. THERE MAY BE A SIMPLICITY BEYOND THE COMPLEXITY BUT WE'RE GOING TO GO THRU THE COMPLEXITY. AND AS ALWAYS, WE WANT TO DO NO HARM OR TREAT WITH AUTOANTIBODIES AND SOMETIMES THE WRONG ANTIBODY OF THE WRONG TYPE ARRIVING AT THE WRONG TIME AND PLACE IN VIRUS INFECTION CAN BE CATASTROPHIC, NOT HELPFUL SO WE HAVE TO GUARD AGAINST THAT. AND SOME OF THIS IS DISCUSS INDEED THAT REFERENCE THERE. SO JUST SAMPLING SOME OF THE EVIDENCE I'VE SEEN MEDIATED ANTIBODY FUNCTIONS IN ANTIVIRAL IMMUNITY THERE'S AN APWUPDANCE OF LITERATURE IN MICE, PROBABLY THE MOST WELL DEVELOPED AND RECENT IS WITH WEST NILE VIRUS BUT IT'S ACROSS THE FIELD OF ENVELOPE VIRUSES. THERE'S GENERALLY POOR ANTIVIRAL EFFICACY IN VIVO WITH FABs TWO AND MURINE IGG-ONE. NONHUMAN PRIMATES ONE OF THE MORE AGGRESSIVE PROPONENTS OF NEUTRALIZATION ONLY, DENNIS BURTON PROVIDES ACTUALLY THE BEST MODEL THAT FC RECEPTOR INTERACTION MATTERS A LOT EVEN WITH THE NEUTRALIZING ANTIBODY AS REPORT INDEED A SHIV MODEL. IF YOU TRACK THE EBOLA ONE OF THE TRAILS OF THE EARLY MIXTURES OF THE MODEL OUT OF THE GENOMIC ASPECT BODY, AND THE DEVELOPMENT OF THE CMAP, THERE'S GREATER EFFICACY WITH GLYCAN-OPTIMIZED FC AND IN HUMANS THERE'S GROWING ACKNOWLEDGMENT FROM--TRIGGERED BY THE RB-1 44 STUDY THAT FC RECEPTOR, FC INTERACTIONS, FC RECEPTORS MATTER A LOT IN TERMS OF HUMAN HIV VACCINE EFFICACY, IT'S BASED--THIS IS I COMPLETE LIST OF EVIDENTS BUT THE LAST ONE IS ACTUALLY A--JUST BEING PROVOCATIVE, THERE'S A POOR CORRELATION BETWEEN NEUTRALIZATION AND PROTECTION NOT ONLY WITH HIV BUT WITH REASON DENGUE VACCINE TRIAL AND THIS COULD BE A RECEPTOR RELATED PHENOMENON TO LET YOU CHEW ON THAT A BIT OR TALK ABOUT IT IN THE HALLWAY AND RECIPROCALLY, THERE'SENTIOUS SENTIALLY TO EVIDENCE TO CONTRACT DICK THE HYPOTHESIS THAT EVIDENCE IS CCIAL IN HUMORAL IMMUNITY TO ENVELOPED VIRUSES REFERENCES. AND SKIP A ALL THE OTHER MOUSE EXAMPLES AND TURN TO ONE OF THE POOLS OF MONOCLONAL ANTIBODIES THAT LED TO ZMAPP. SO THIS WAS A 2001 STUDY. IF WE HIGHLIGHT HERE THIS IS ONE OF THEM THAT WAS ADVANCED AS A NONNEUTRALLIZING MONOCLONAL ANTIBODY AND YOU SEE PASSIVE TRANSFER ON PROPHYLACTIC MINUS ONE AND PLUS ONE AND PLUS TWO AND DIFFERENT DOSES HERE ARE TWO OF THE NONNEUTRALLIZING AND NEUTRALIZING ANTIBODIES IF THEY ADD FRESH GUINEA PIG SERUM OF WHAT WE CALL COMPLEMENT IS THE ACTIVE FACTOR. BUT THE NEUTRALIZING ANTIBODIES DEFIN PENDING ON HOW YOU DEFINE IT, SO THIS IS ONE THAT WAS ADVANCED TO ZHAPPEN SO ANOTHER THING THAT YOU WILL POTENTIALLY NOTE AND MAYBE A LITTLE NOTE HERE IS--WELL, ISOTYPE MATTERS, THE FC MATTERS SO WHEN YOU ARE SCREENING MONOCLONAL ANTIBODIES FOR PROTECTION AGAINST EBOLA, TWO THINGS MATTER A LOT. THE FC PORTION OF THE ANTIBODY, THE OTHER THING THAT MATTERS IS DOSE AND I'LL TALK ABOUT DOSE IN JUST A SECOND. SO THERE ARE CASES IN WHICH NEUTRALIZATION IS A MINOR PORTION OF THE PROTECTION, THEN YOU WILL MISS PROTECTIVE ANTIBODIES IF YOU'RE NOT ATTENTIVE TO THE FC AND THE SPECIES MATCH, ET CETERA. SO THE OTHER POOL OF MONOCLONAL ANTIBODIES FOR THE ZMAPP AROSE, FIRST THING NOTICING HERE IS THERE'S THIS DISCORDANCE OF THESE ANTIBODIES GIVEN PROPHYLACTICALLY WERE INEFFECTIVE, WHEREAS THE SAME ONE GIVEN ON DAY ONE OR TWO WERE PROTECTIVE AND YOU SEE THE PATHWAY GIVES PATTERN WITH THOSE ANTIBODIES BUT WITH THE OTHER ANTIBODIES AND THIS IS UNEXPLAINED. FASCINATING, IT LETS ME AT LEAST SPEAK TO THE OBSERVATION THAT UNLIKE NEUTRALIZATION WHEN YOU PASSIVELY NEUTRALIZING ANTIBODIES AND THERE'S TOO MUCH OF A GOOD THING, YOU COULD TRANSFER 50-MILLIGRAMS PER KILOGRAM, ALL OF THE FC RECEPTOR MEDIATED INTERACTIONS ARE SENSITIVE TO CONCENTRATION AND THERE'S A HIGH DOSE PROZONE, THAT'S ROUTINELY SEEN INVITRO, AND I ONLY KNOW OF EXPERIMENTS ONGOING NOW THAT ARE INTENTIONAL DESIGNED TO LOOK AT THIS IN VIVO BUT I MIGHT MISS PROTECTIVE ANTIBODIES BY GIVING A HIGH DOSE THINKING THAT HIGH IS ALWAYS BETTER. IT MAY NOT BE WITH DEPENDING ON THE EKOR MECHANISM. SO THESE WENT INTO ZMACK AND TWO OF THESE WENT INTO ZMAPP. SO THIS IS ADDITIONAL DISCERNMENT AND THIS IS PUBLISHED AND I EXPECT EVERYBODY WHO CARES DEEPLY ABOUT THIS HAS ALREADY READ THESE PAPERS. SO WHY A MIXTURE OF MONOCLONAL ANTIBODIES. FOR ONE THING THE MONOCLONES AS A WHOLE AND FAR HIGHER CONCENTRATIONS OF QUOTE THE RIGHT ANTIBODIES UNQUOTE TAYLORED ISOTAPES AND TKPWHRAOEUB O FORMS, THE CONSISTENCY OF PRODUCT AND USING BLOOD-BORN AGENTS AND I'M NOT AT ALL OPTIMISTIC WITH PASSIVE TRANSMITTAL OF PLASMA, NOT THAT THERE'S NOT ANTIBODIES IN THERE BUT NOT ENOUGH IN THERE TO BE AS EFFECTIVE AS YOU WISH IT TO BE BUT THE DATA WILL SHOW WHETHER IT WORKS. ANOTHER REASON IS THE DIFFERENT MIXTURE OF SPECIFICITIES AND MINIMIZE APPEARANCE OF THE ESCAPE MUTE ANTS FOR THE NEUTRALIZING ANTIBODIES. AND THE MIXTURE OF THE POSSIBILITY OF ADDITIVE OR SINNER GESTIC EFFECTS THE THAT THE PINING OF ONE MAY FACILITATE THE BINDING OF LITTLERS OR SOME WAYS CHANGE THE SHAPE TO MAKE THE FC MORE RECEPTIBLE TO EFFECTOR CELLS AND THERE ARE SOME INVITRO PRECEDENCE FOR THIS ALREADY WITH HIV AND IT'S NOT ASSERTED OR KNOWN WITH ZMAPP BUT IT'S NOT BEEN CLOSELY LOOKED AT. THIS IS ANOTHER WAY OF LOOKING AT THIS TRAIL OF ORIGINS, I WON'T TAKE THE TIME ON THAT. SO IN ADDITION TO VIRAL NEUTRALIZATION, AND OBVIOUS POSSIBILITY BY WHICH CELL TARGETS ANTIBODIES MAY WORK IS ADCC. WHAT DO WE REALLY MEAN BY ADCC. THESE ARE THE OTHER POSSIBILITIES AND I WILL FOCUS ON ADCC, BUT YOU CAN GO TO REVIEW ARTICLE AND THERE'S LOTS OF DIFFERENT WAYS THAT NONNEUTRALLIZING ANTIBODIES CAN INFER PROTECTION. WAWE AUFB PORTRAY IS A SIMPLE DIAGRAM OF EFFECTOR CELL WITH RED FC RECEPTORS AND THE ANTIBODY BOUND TO ANTIGENOT CELL SURFACE. BUT IT'S FAR MORE COMPLICATED THAN THAT. THE--THERE ARE MANY DIFFERENT POTENTIAL TYPES OF CELL TYPE EFFECTORS, MONOCYTES, MA ROUGH ATOM PHAGES, NKs, MATTERS WHETHER YOU DO A PRIMARY OR FROZEN LINE, MATTERS WHAT SPECIES THE EFFECTOR CELL IS, THERE ARE ALOE TYPES AND VARIANTS AND SPECIES DIFFERENCES BETWEEN THE FC RECEPTORS, ET CETERA, THE TARGET CELL CAN BE HARD TO FIND A UNIVERSAL TARGET CELL, THERE'S DIFFERENT SUSCEPTIBLE TO WHATEVER YOU MEASURE IN TERMS OF LEAKINESS OR OTHER FACTORS. THE ASPECT BODY TARGET EURBT ACTION MATTERS A LOT, AS SEEN FROM THE CRYSTALLOGRAPHY AND THE OTHER STRUCTURAL DATA THAT THE FC MAY BE POINTING DIFFERENT DIRECTIONS AND THERE ARE DATA OUT THERE THAT SHOW WHERE YOU BIND AND HOW THE FC IS EXPOSED MATTERS A LOT IN TERMS OF WHETHER THE FC RECEPTOROT EFFECTOR CELL CAN ENGAGE, THE ANTIBODY ITSELF HAS ALL KINDS OF SYNAPSE IN THERE, THIS IS A COORDINATE BINDING PHENOMENON, THE PHAGOCYTOSIS IS SOMETHING THAT TURNS OUT THE ADCC ASSAYS DON'T MEASURE LYSIS, THEY MEASURE SIGNIFYITOSEIS AND THE FLOW CYTOMETRY ASSAY, THAT'S MEASURED AND THAT'S NOT BAD BECAUSE IT'S A CORRELATE OF PROTECTION, ONE OF THE BEST ONES FOR HIV, BUT NOT MEASURING KILLING. SO THERE ARE A NUMBER OF ASSAYS FOR ADCC, AND IT'S LARGELY BEEN ABANDONED, PROBABLY MAINLY BECAUSE OF THE PAPERWORK AND THEN THERE'S ALL THESE--ALL THESE--AND IT'S THOT A PERFECT ASSAY BECAUSE IT WAS REALLY HARD TO GET A CHROMIUM RELEASE ARK SAY OF AN ADCC BASED ASSAY TO WORK IN MICE SO YOU COULDN'T GET THAT CORRELATE THERE, BUT THERE THE LICENSES PROBABLY, IT'S LESS LYSIS THAN THE MEDIATE THE ADCC. WE'RE DOWN TO THE LAST MINUTE. SO I'LL TAKE THE MINNITE FOR MY PANEL PART. SO THE ZMAPP STORY BEGINS AND ENDS HERE. DOES IT WORK IN HUMANS? WE DON'T KNOW. WHAT DO WE KNOW IN? A MIXTURE OF MONOCLONAL ANTIBODIES THAT EXTRAORDINARILY NONEFFECTIVE IN NONHUMAN PRIMATES, THE PRINCIPLES, THE PATHWAY DEVELOPMENT FOR ZMAPP HAS BEEN IMPERICAL GUIDED BY WHAT WORKS AND NOT WHAT WE THINK SHOULD WORK IN PROTECTING ANIMALS AGAINST EBOLA VIRUS DISEASE. SO RED LINE, THERE'S NO--NOT YET AN INVITRO SURROGATE TO PREDICT WHETHER GIVEN MONOCLONALANDY BODY OR ZMACK WILL BE EFFECTIVE AGAINST EBOLA VIRUS DEC UNLESS THIS CHANGES, NEW REPLACEMENT AND PROVEN ZMAPP WILL LIKELY REQUIRE SIMILARLY ARTUOUS TESTING AND NONHUMAN PRIMATES AT BSL-FOUR. SO THAT'S ONE OF THE MANY REASONS THAT WE ACTUALLY UNDERSTAND HOW THESE WORK BECAUSE IF WE'RE GOING TO IMPROVE UPON IT AND MAKE BETTER COMBINATIONS AND WE CAN'T BE RUNNING THESE ENTIRELY THROUGH THE BL-FOUR LABS AND FINDING OUT IMPERICALLY. AND FINALLY LAST SLIDE WHAT CAN WE LEARN. SO BY UNDERSTANDING ZMAPP AND ITS COMPONENTS WE MIGHT GET BENCHMARK REAGENTS AND PROPER ASSAYS THAT RELATE TO ALL THESE OTHER STUDIES WE TALKED ABOUT WE MIGHT LEARN WHETHER HAVING OPTIMIZED MONOCLONAL ANTIBODIES FOR MONKEY EFFICACY WHETHER THAT'S CO INCIDENT WAS HUMAN EFFICACY BECAUSE IT WON'T BE SO, THERE ARE DIFFERENCES, SO MANY PW-FRPBT DIFFERENCES BETWEEN MONKEYS AND HUMANS IN THEIR ADCC EFFECTOR MECHANISMS AND EFFECTOR CELL TYPES AND THROUGH THIS WE MIGHT ALSO DISCOVER HOW TO GET THROUGHS ON HOW TO MAKE FILOVIRUS VACCINES BETTER THROUGH ANTIGEN DESIGN. WE'RE LOOKING AT FIRST LEVEL UNIMPROVED STRAIGHT GP ANTIGEN WHICH I'LL BET IS NOT THE BEST ANTIGEN, BUT WE'RE--WE'RE CHOOSING THE GOOD ANTIGEN BUT WE MAY, IF WE UNDERSTAND MORE WE MAY BE ABLE TO GET BETTER IMMUNE RESPONSES WITH FUTURE VACCINES. THANK YOU. [ APPLAUSE ] OKAY SO NOW WE NOW HAVE A PANEL AUD? >>: YES, SIR DISCUSSION, SO IF ALL THE SPEAKERS, CAN I READ THE NAMES PETER JAHRLING, NANCY SULLIVAN, GARY WONG, I THINK THE NAME WAS LEFT OUT BUT WE ARE GET EGG CHAIR FOR YOU. SO BENOIT SHAEUZ SHOULD ALSO JOIN US HERE. >> IS BENOIT IN THE AUDIENCE? SOME SOMEBODY FINDS HIM OUTSIDE, MAYBE THEY CAN GRAB HIM. HIS NAME WAS LET OUT SO HE PROWL THOUGHT HE WASN'T GOING TO BE UP HERE. LET'S START WITH QUESTIONS. MARK? >> FIRST WANT TO START BY THANKING THE ORGANIZERS FOR PUTTING TOGETHER THIS GREAT MEETING AND FOR ALL THE SPEAKERS. I AM MARK FINEBERG, I WORK AT MERCK AND THE TALKS WERE GREAT, I WANT TO FOCUS ON THINGS EMERGING FROM WHAT DR. SAPPHIRE AND LOOKING AT THE WAY IN THE THERAPEUTIC CONTEXT AND VERY IMPORTANT BUT I THINK ALL OF US HERE WHO ARE INTERESTED IN VACCINES ARE WONDERING HOW THOSE FINDINGS WOULD TRANSLATE INTO OUR UNDERSTANDING OF WHAT MIGHT BE THE PROPER CHARACTERISTICS OF ANTIBODIES INDUCED BY VACCINATION AND MOW WE MIGHT BEST ASSESS THAT AND HOW THAT COULD INFORMAUR UNDERSTANDING OF [INDISCERNIBLE] >> I GUESS I CAN START AND YOU SAY SOMETHING MORE SAGE. WHAT WE COULD--ONE THING IS WE COULD TAKE THE SERRA FROM YOUR SUCCESSFUL AND UNSUCCESSFUL ANIMALS AND RUN IT THROUGH THE SAME KIND OF STUDY, TAKE MY ELISAs WITH THE 12 DIFFERENT VERSIONS OF THE TKPWHRAOEUBGA PROTEINS AND FIND OUT WHO LIVES AND VERSES ANIMALS THAT DIED OR UNSUCCESSFUL VACCINES AND THEN YOU COULD TINKER WITH TRYING TO ENHANCE EXPOSURE OF CERTAIN EPITOPES AT THE EXPENSE OF OTHERS. BUT THE VACCINES SEEM TO FUNDAMENTALLY WORK WITH A WILD-TYPE GP SO I DON'T KNOW HOW MUCH YOU WANT TO MESS WITH IT. >> COULD YOU DEFINE WHAT YOU MEAN BY BASELINE KD--SALLIERS? >> SO THOSE ARE THE TWO GTWO AND FOUR AND WE FIND THAT 10% OF THEM REWE RECEIVE ALL BIND AND COMPETE WITH EACH OTHER AND THERE'S A SICKLE SICK--SINGLE POINT MUTE ANT THAT WILL KNOCK THEM OUT. IT'S SOMETHING YOU WOULD LOOK FOR IN THE WILD. SO THAT ONE SITE SEEMS TO GIVE UNIVERSALLY THE BEST NEUTRALIZATION AND THE BEST PROTECTION. SO I THINK A COCKTAIL SHOULD CONTAIN ONE OF THOSE. DO WE NEED MORE THAN ONE OF THOSE, I DON'T KNOW. I THINK WE NEED MORE TO KNOW IF THEY'RE FUNCTIONALLY EQUIVALENT OR NOT. IF THEY'RE A FRAMEWORK, YOU MIGHT GET TWO DIFFERENT USES FROM THE SAME SITE. >> AS YOU KNOW THE FIELD OF IMMUNOLOGY HAS NOT ANSWERED THE QUESTIN OF ONCE YOU KNOW WHAT ADY RESPONSE, WHAT ANTIBODY RESPONSE YOU WANT, HOW DO WE ELICIT WHAT THE VACCINE SO WE KNOW THAT THERE'S PROBABLY A LOT OF THE ANTIBODY RESPONSES NOT HELPFUL EITHER BECAUSE IT'S THE WRONG ISOTYPE OR WRONG SPECIFICITY, YOU GET THE MUTANT DOMAIN OR REGIONS, ONE THING I WAS TRYING TO ACHIEVE WAS ACHIEVE THE LEVEL OF COGNITIVE DISO NANOG, YOU MAY HEAR THINGS THAT APPEAR TO DISAGREE WITH EACH OTHER BUT THEY REALLY DON'T ONCE YOU GET INTO THE WEEDS, AND THEN OF COURSE ALL THE DISPROPORTIONATE PARTS OF THE ASPECT BODY MOLECULE. >> ANY OTHER PANEL MEMBERS WANT TO MAKE A COMMENT ON THIS? >ON AT THE BACK. >> YEAH, MIKE BRAVE FROM NIAID AND THIS--I HAVE TWO RELATED QUESTIONS FOR MIKE AND PETE, THIS RELATES TO THE CLINICAL SYNDROME MIKE IN YOUR PAPERS, VOMITING AND DIARRHEA ARE COMPONENT COMPONENTS OF THE DISEASE IN WEST AFRICK AMASSIVE VOLUME LOSS AND THE VOLUME REPLACEMENT AND CRITICAL AND PR-FIOUS OUTBREAKS ALWAYS MENTION NAUSEA AND VOMITING BUT NEVER HIGHLIGHT IT AS A--BITS IMPORTANT COMPONENT OF THE DISEASE. IS THIS NEW OR NOT WELL DESCRIBED IN PREVIOUS OUTBREAKS AND THE OTHER QUESTION FOR PETE IS DO WE SLEEP APNEA AND OBESITY ANY OF THIS IN ANIMAL MODELS. I DON'T RECALL SEEING IT IN THE NONHUMAN PRIMATES THAT YOU SAMPLED. >> THANK YOU FOR THE QUESTION AND WE CAN TELL YOU THE WE CAN QUANTITATE THE RELATIVE IMPACT BASED ON THE EYES AND NOSE OF THESE PATIENTS. SO WE HAVE THE BMI OF THE WEST RFRIC AN IS DIFFERENT THAN MANY OF OUR CONGO PATIENTS SO WE HAVE TO CALCULATE FOR THAT SO YOU DON'T COUNT INS AND OUTS AS A CLINICAL MEASURE OF VOLUME STATUS AND TO JUSTIFY REPLETION ALGORITHMS. THE CHEMISTRY MONITORING THAT WE HAVE INCREASINGLY AVAILABLE HAS HELPED US TO NOW KNOW [INDISCERNIBLE] THE HYPER OS MOLAR GAP IS, OR ORGANIC ACIDOSEIS, SPECIFICALLY TO YOUR QUESTION, NOW, THE EARLIEST INDICATOR WAS CLINICAL OBSERVTION AND REPORTING BUT FOR PHYSICIAN WHO IS HAD BEEN TO MULTIPLE OUTBREAKS AND PRIOR EBOLA OUTBREAKS BY THE STRAIN DOES NOT PRODUCE THIS AMOUNT OF DIARRHE AS MEASURED BY THREE VARIABLES. THE BMI RATIOS FOR SKIN CHROME COMPLEXES SO WE DON'T HAVE VIRAL LOAD IN THERE BUT IT'S BMI, AND THEIR ADMISSION WEIGH TO THE ETU. THE SECOND ONES IS DIDN'T PUT ENOUGH POTASSIUMOT AIRCRAFT. THE POTASSIUM THAT WE'RE GOING THROUGH IS 2.6 TO 3.5 TIMES MORE THAT ARE BEEN SO OUR DEPLETION FORMULAS ARE RUNNING FROM 80 TO 120 MILLI EQUIVALENTS IV EVERY EIGHT HOURS AND THAT'S KEEPING US WITH K-ABOUT THREE. SO YOU'RE APPROPRIATELY FOCUSED ON K AND BUT WE MADE MISTAKES AND THAT'S WHEN THE MAG. WE'VE BEEN BEHIND SOPHISTICATED THE MAG AND OUR PERIPHERAL VISION NEEDS TO ACCOUNT FOR THEM AS WELL. WE WERE DOING IT FOR THE SERVICE THERE. >> IN TERMS OF THE BASIC NATURE OF THE DISEASE, IT IS DIFFERENT THAN WHAT'S BEEN SEEN IN DRC FOR EXAMPLE? >> THANK YOU FORICKING THAT COUNTRY BECAUSE THAT'S WHERE WE'RE MOST ADOPTED, ABSOLUTELY OUR NUMBERS IN TERMS OF IV CONSUFRPLGZ PER PATIENT ARE MUCH HIGHER, I CAN GIVE YOU THE CALCULATIONS IT'S AN INVENTORY ISSUE. IT'S ALSO HELPFUL BECAUSE WE PROCURE NOW INCREASINGLY LOCALLY FOR ANTIBIOTICS, ANTIMALARIALS AND IT GOT EXHAUSTED AND WOO HAD DONE A CALCULATION AND WE PICKED AN EBOLA OUTBREAK AND THE ETU AND WAY OUF IN OUR CALCULATIONS, IT'S MORE SUBJECTIVE BUT HELPFUL I THINK. PETER MIGHT HAVE MORE TO ADD FOR THE MONKEYS. >> IT'S A SIMPLE ANSWER, WE HAD NOT SEEN THIS PREVIOUSLY IN ANY OF THE ANIMAL MODELS. IT'S REALLY TOO SOON TO SAY WITH THE WEST AFRICAN STRAIN. IT SHOWS YOU ONE CT OF AN DISTENDED BOWEL AND OF COURSE WE NEVER DID CT BEFORE SO I DON'T FINISH WE WOULD HAVE SEEN THAT OR NOT. BUT IT WAS REMARKABLY SIMILAR TO YOU KNOW WHAT'S BEEN SEEN CLINICALLY IN THIS COUNTRY. SO IT MIGHT BE THAT THE STRAIN IS SOMEWHAT DIFFERENT. BUT YOU KNOW, I WOULD SAY THAT THE INENTIAL SUSPICIOUS IS THAT THE STRAIN WAS DIFFERENT. IT WAS HOTTER AND ALL THAT DOESN'T SEEM TO BE BEARING OUT. BUT THERE COULD ABE DIFFERENCE IN THE PREDOMINANTLY HREBGZ TO CAUSE DIARRHE A. >> ONE FINAL POINT BECAUSE WE DIDN'T CATCH THIS, I THINK IT WAS PRECISELY IS WHAT ARE THE OTHER DIFFERENCES? AND I DIDN'T--MANY OF US ARE EMPHATIC ABOUT THE DELERIUM WHICH IS NOT ASSOCIATE WIDE ELECTROLYTE ABNORMALITIES IN HYPOGLYCEMIA AND A APPARENT SECONDARY INFECTION, THEY WOULD REQUIRE THAT I TALK ABOUT THE ARTHMAGGIAS AND PROBABLY DAN BASHSPAY WOULD REQUIRE THAT I MENTIONED HICK UPS WHICH IS AGAIN SOMETHING THAT APPRECIATED MUCH GREATER IN THIS OUTBREAK THAN PREVIOUSLY BUT THAT ONE MAYBE WE'RE JUST LOOKING MORE. >> HELLO GREG GLEN, NOVAX, AND THANK YOU FOR FORM THANKSGIVING MEETING IT'S BEEN TREMENDOUSLY INFORMATIVE. I WOULD LIKE TO SCROLL BACK ABOUT THE TERRIFIC WORK DONE AT SCRIBES AND SO ON. ONE USE OF THE MONOCLONAL ANTIBODIES WOULD BE BY TREATMENT BUT ANOTHER USE OF MONOCLONAL ANTIBODIES ARE DEVINING THE EPITOPES IN THE VACCINE ARE CRITICAL AND I THINK THAT THERE'S' ANOTHER DISEASE OF THIS PARADIGM AS BEEN USEFUL SO, YOU KNOW THERE'S BEEN A GROUP UNDER BARNY GRAM'S WORK AT THAT'S CHARACTERIZED THE RTFOR OF THE STRUCTURE AND AS YOU MAY KNOW. THERE ARE MONOCLONAL ANTIBODIES HAVE BEEN LICENSED FOR THESE PROPHYLACTIC USE OF PREVENTION FOR THE DISEASE IN PREMATURE INFANTS AND THAT HAVE BEEN EVALUATED IN FIVE RANDOMIZED CLINICAL TRIALS AND SO IN OUR CASE WHEN WE USE A RECOMBINANT VACCINE, WE LOOKED TO SEE THAT THOSE EPITOPES ARE BOUND BY THOSE MONOCLONAL ANTIBODIES WHICH ARE QUITE EASY TO DO, AND YOU CAN USE BEA-CORPS OR USE PASSIVE STUDIES AND THEN SHOW WHEN YOU HAVE THAT VACCINE MADE AND USE THE POTENCY ASIGNIFY WHEN YOU UMPIRESUNIZE ANIMALS OR HUMANS, YOU DEVELOP THOSE SPECIFICITIES. I THINK THIS IS A AN EXTREMELY USEFUL SET OF TOOLS IN MY VIEW FOR ALLOWING US TO PREDICT WHAT VACCINES AND CONSTRUCTS MAY BE USED FOR THAT AND IF YOU CAN HOLD IT FOR A SECOND. SO ANOTHER AS I LISTEN DOES THE STRAIN MATTER, SO IT JUST SO HAPPENS FRANKLY THAT IT BINDS TO A PORTION OF THE F-PROTEIN THAT'S HIGHLY, HIGHLY CONSERED SO EVEN OVER TIME THERE'S BEEN EVOLUTION OF ESCAPING BUT FOR THE MOST PART THAT HASN'T HAPPENED. BUT YOU KNOW THERE'S RCA AND RCB, AND RCA, IT HAS LIMITED PROTECTION FOR RCB, SO NOW WE'RE LOOKING AT A GUINEA STRAIN AND I HAVEN'T HEARD MUCH DISCUSSION OF THE MASCULINIZED BETWEEN CHALLENGES AND VACCINE SPECIALIZATION OF SPECIFIC ENDOTHELIAL THESE ARE RELATED QUESTIONS. >> WHAT'S BEEN ENTHUSIASTICALLY EMBRACED IS THE [INDISCERNIBLE] I WOULD SAY MORE IS LIKE RATIONALLY INSPIRED IMPERRICISM BECAUSE THEY RELATIVELY PREDICTED WHAT THEY THOUGHT WOULD WORK AND THEN TRIED ONES TO SEE WHAT WOULD WORK AND JUST RELATED TO RSV AND FC, THERE'S A PAPER BYULARY ZIGLAND SHOWN THAT IN THE [INDISCERNIBLE] RAT MODEL WE CAN IMPROVE THE [INDISCERNIBLE] BY FIDDLING WITH THE FC, AND HE CAN ALMOST APLATE IT IN A WAY TO [INDISCERNIBLE]. SO THE ANTIBODY THAT'S DESCRIBED AS A NEUTRALIZING ANTIBODY, IT MATTERS A LOT HOW THE FC IS CONSTRUCTED. DO YOU WANT TO MAKE A COMMENT ON THOSE QUESTIONS? >> SO IT WOULD BE INTERESTING TO SEE WHAT KINDS OF ANTIBODIES ARE ELICITED BY THE VACCINES AND NAY FOLLOW THE SAME PROPORTION AS THE POOL OF MONOCLONALS. THE POOL OF MONOCLONES IS BIASED IN THE FACT THAT WE ASKED FOR MONOCLONALS THAT WERE GOOD, WE DIDN'T WANT MONOCLONALS THAT WERE NO GOOD. SO WE'RE DOING A SET OF SELECTION FROM TOTAL POOLED IGG. SO THAT WOULD BE AN INTERESTING COMPARISON TO SEE IF THE VACCINES ARE ELICITING THE SAME KINDS OF ANTIBODIES WE FIND TO BE EFFECTIVE OR NOT SO IF YOU MUCK AROUND WITH THE GP DOES THAT CHAIRMAN THE ANTIBODIES OR NOT AND CAN YOU CHANGE THEM FOR THE BETTER OR NOT. >> THE OTHER QUESTION RAISED REALLY WAS ABOUT SEQUENCE VARIATION IF SOMEBODY COULD COMMENT ON IT. >> SO THOSE ARE THE SEQUENCE VARIATION BETWEEN GUINEA AND EARLIER FORMATIONS, THERE'S ONE TOWARD THE BASE BUT IT'S A CHANGE OF A SINGLE CARBON ATOM AND IT'S NOT AS FAR AS WE KNOW IN ANY OF THE BASE FINDING EPITOPES AND - DOESN'T LIKE LIKE IT KNOCKS THEM OUT. IN THE MUSEIN DOMAIN IT LOOKS MIKE A MUTATION IN THE FSIX EPITOPE PEE DO HAVE A CRYSTAL STRUCTURE OF THAT FAB COMLEX AND THE THREE ALANINE DOES LOSE THE HYDROGEN BOND SO THAT MIGHT BE IMPORTANT. SO THE VARIABILITY THAT NATURALLY EXISTS IS ONE REASON WHY YOU MAY OR MAY NOT WANT TO INCLUDE A DOMAIN OF THE COCKTAIL. AND PUTTING TOGETHER A COCKTAIL, YOU DO NEED ANTIBODIES AGAINST DIFFERENT SITES SO YOU DO HAVE ONE DOMAIN ANTIBODY THAT DOES MUCH MORE EFFECTIVE THAN THE OTHERS. SO WE'LL HAVE TO--WE UNBLIND THEM FIND OUT WHAT THE EPITELOMERE TAUPE IS AND WHAT THE VARIABLE IS, IF IT IS VARIABLE, YOU HAVE TO KEEP AN EYE ON WHAT THE SEQUENCE OUT IN THE FIELD IS IF YOU REFORMULATE YOUR COCKTAIL BY ONE THAT'S BEEN ESCAPED WITH ANOTHER ONE YOU MIGHT HAVE ON DECK. >> JUST A GENERAL QUESTION FOR ANYONE WHO KNOWS ABOUT IT: IS THERE ANY OTHER PIECE OF EVOLUTION OF VIRUS DURING ACUTE INFECTION? >> OKAY, I THINK THE REAL ANSWER IS NO, BUT [INDISCERNIBLE] AT THE BROOD INSTITUTION DOES SOMETHING LIKE 99 SEQUENCE? PARTING 99 ISOLATES THAT SPANNED PERHAPS SIX MONTHS AND THERE WAS A LOT OF VARIATION ALLOWED TO THERE WAS PROBABLY IRRELEVANT CHANGES AND THERE WAS NO REAL PATTERN. THERE WAS NO DISCERNIBLE PATTERN BUT YOU KNOW PART OF THAT IS THAT THOSE WERE GRAB SAMPLES WITH YOU KNOW REALLY NO DEMOGRAPHIC DATA OR ANYTHING TO INDICATE THE NATURE OF THE DISEASE FROM WHICH IT CAME OR ANYTHING ELSE YOU KNOW. I THINK THOSE KINDS OF ANSWERS WILL COME FROM A RIGOROUS EPIDEMIOLOGIC INVESTIGATION WHERE ISOLATES ARE COMPARED YOU KNOW ON THE BASIS OF THEIR SEQUENCE AND CALIBRATED WITH THE PRESENTATION OF THE DISEASE BUT THAT'S NOT BEEN DONE. >> [INDISCERNIBLE] FROM FDA, I WANT TO THANK THE PANEL FOR A REALLY ENLIGHTEN DISCUSSION THIS MORNING AND I HAVE JUST ONE QUESTION ON THE NEUTRALIZATION OF THE NEUROECTODERMAL NATIONAL LIBRARY OF MEDICINE NONE NEUTRALIZATION. SO AS WE TRY TO FIGURE OUT WHAT IS THE BEST READ OUT TO INFER CLINICAL EFFECTIVENESS OF THE VACCINE, BESIDES THE END POINT STUDY, IT SOUNDS LIKE MEASURING NEUTRALIZING ANTIBODIES BOTH IN MONKEYS AND IN MAN, THERE ARE SITUATIONS WHERE CLEARLY THERE CAN BE PROTECTION WITHOUT MEASURABLE NEUTRALIZING ANTIBODY. SO I'M WONDERING WITH THE CONVERSE IS NEUTRALIZATION HOWEVER YOU MEASURED IT SOMETHING THAT'S PERHAPS NOT NECESSARY BUT SUFFICIENT TO PREDICT PROTECTION. IN OTHER WORDS HAS THERE BEEN EVER A SITUATION WHERE YOU IN A MONKEY FOR EXAMPLE WHERE YOU HAVE NEUTRALIZATION ANTIBODY AND YET IT FAILED TO PROTECT. I UNDERSTAND THAT THERE'S--CAN YOU HAVE PROTECTION WITHOUT NEUTRALIZING ANTIBODIES BUT IF YOU HAVE IT IN NEUTRALIZING ANTIBODIES DO YOU HAVE THAT ALWAYS? >> THE BEST PERSON TO ANSWER THAT QUESTION MIGHT BE THE PERSON STANDING BEHIND YOU IN LINE BUT I'LL TAKE A STAB AT IT. CAN HAVE YOU NEUTRALIZATION THAT DOESN'T GIVE PROTECTION, THAT WAS A SINGLE QUESTION WAS WHETHER THEY HIINE ANOTHER DOSE, I DON'T KNOW SO ONE THING WE'RE TRY TO DO WITH THE CONSORTIUM IS TO STANDARDIZE THE STUDIES SO THAT EVERYTHING IS GIVEN ON COMPARATIVE DOSES AND SCHEDULE SO FIND OUT IF THE DIFFERENCE BETWEEN THE COCKTAIL SYSTEM DIFFERENT IN DOSAGE OR DIFFERENT IN CONTENT OF THE COCKTAIL. >> GO AHEAD. >> YOU ARE BEING PUT ON THE SPOT. >> [LAUGHTER] >> NO PROBLEM. >> SO, IN OUR VACCINE STUDIES WITH MONKEYS THAT WE DO, WE NORMALLY SEE NEUTRALIZING ANTIBODY. HOWEVER, ARE WE LOOKING AT THE RIGHT TIME POINT? ACTUALLY DETERMINE IF THAT NEUTRALIZING ANTIBODY IS DOING SOMETHING OR HAS DONE SOMETHING, HAS IT BEEN USED UP BY THE TIME THAT WE ARE, SAYING THIS, WE DON'T KNOW. SO THEREYA A LOT OF QUESTIONS THAT REMAIN FOR NEUTRALIZING ANTIBODY AND IMPORTANCE IN A VACCINE AND I WILL USE THIS AS AN OPPORTUNITY TO--THIS WONDERFUL PANEL, I JUST HAVE ONE POINT. I THINK YOU NEED TO BE CAREFUL ABOUT WHAT THE DIFFERENCES BETWEEN A PROPHYLACTIC TREATMENT, POST EXPOSURE TREATMENT AND A VACCINE AND THE ANTIBODY RESPONSES YOU MAY WANT FOR THOSE TWO MAY BE VERY DIFFERENT. YOU HAVE VIRUS ON BOARD ALREADY IN MOST CASE WHEN IS YOU ARE GIVING IT POST EXPOSURE, AND YOU MAY WANT A NEUTRALIZING AS OPPOSE TO WHO THAT INDUCE THE PATHOLOGY, ADCC, OTHER EFFECTOR FUNCTIONS SO I DON'T KNOW IF YOU WANT TO USE THE Z-MAP COCKTAIL TO DRIVE WHAT YOU WANT FROM A VACCINE. I THINK THAT'S AN EXCELLENT POINT YOU MAY BE LOOKING FOR EXPOSURE. >> WELL I'M SURE? I AGREE WE NEED TO HOLD THAT QUESTION OPEN AND UNDERSTAND A LOT MORE ABOUT THE ANTIBODY RESPONSE AND PORTIONS OF THAT AND PARATHETICLY SAY THAT I THINK JOHN WOULD AFFIRM THIS, VACINATING AGAINST MG A SIMILAR VIRUS, IT'S DIFFICULT TO RAISE THE NEUTRALIZING ANTIBODIES YOU CAN GET ELI SA TITER AND YOU CAN SHOW THAT ANTIBODIES ARE NECESSARY AND SUFFICIENT FOR PROTECTION, SO IT'S NOT NECESSARILY THE TGS THAT WE MEASURE IN OUR CURRENT CONSTRUCTED AND THEY'RE VERY MANY DIFFERENT VARIATIONS OF THE NEUTRALIZATION ASSAY, SEVERAL DIFFERENT KINDS OF NEUTRALIZATION ASSAY AND NOT EVERYBODY'S SPEAKING THE SAME LANGUAGE. >> EXACTLY AND WE SEE THE SAME THING IN THE MARBURG PATIENTS AND UGANDA THAT WE'RE COLLECTING FROM AFTER THEY'RE LONGITUDINALLY LOOKING AT RESPONSE AND NEUTRALIZE ANTIBODY AIMED OVER TIME SO MARBURG IS A DIFFERENT VIRUS, BUT IT REALLY NEED TAOS BE TREATED IF A DIFFERENT CATEGORY IN THE EBOLA VIRUS AND YOU CAN'T LUMP THEM ALTOGETHER. >> YES, THANK YOU. >> [INDISCERNIBLE] FROM SWITZERLAND. I LEARNED A LOT ANDIME VERY MUCH IN THE LEARNING PROCESS AND TRYING TO DEFINE EXACTLY HOW BIG THE CHALLENGE IS IN FRONT OF US TALKING ABOUT DEVELOPING PROPHYLACTIC VACCINES AGAINST THE GP PROTEIN OF EBOLA. WHAT I HEARD THIS MORNING IS BASED ON THE STRUCTURE THIS MAY NOT BE A VERY EASY THING. THIS AFTERNOON WE ARE GOING TO HEAR THE FIRST RESULTS MEASURED IN HUMANS WITH DIFFERENT VACCINES AND ALSO DIFFERENT ASSAYS AND I WANT WONDER BEFORE GOING TO THAT WE COULD LEARN A BIT MORE FROM THE ANIMAL EXPERIMENTS ON THE RELATIVE IMMUNO GENERATEDISSITY OF GP WHEN ENCLUEDED OR CARRIED BY VARIOUS VECTOR FIRST AND THEN VICE VERSA WHAT IS INFLUENCE OF THE VITAL PROTEIN IN THE VECTOR IN CONTROLLING THE MAGNITUDE BUT THE KINE ETICSICS AND THE ISOTYPE WITH THE ANTIBODY RESPONSES. I THINK THIS PROBABLY NANCY, GARY, YOU COULD HELP US AND THAT IS BETTER. YOU GET LOWER OR DIFFERENT RESPONSES TO G, THAN TO AN INFLUENZA PROTEIN FOR EXAMPLE IN THE ADEN O OR VSV VECTOR AND THE SECOND QUESTION HE DID FOR EXAMPLE, VSV IS KNOWN TO INDUCE HAPPILY AND STRONG ANTIBODIES RESPONSE AND I UNDERSTAND THAT THIS IS ESSENTIALLY TO ITS OWN ENVELOPE, WHICH IS VERY SPECIFIC, HOW MUCH DO YOU KEEP THAT WHEN YOU CHANGE IT FOR THE BOTH PROTEIN, YOU STAY IN THE YOUTH [INDISCERNIBLE] OR AS LOW AS [INDISCERNIBLE]. >> EXCELLENT POINT. I THINK--THAT'S A KEY QUESTION FOR THIS SESSION. SO WHY DON'T WE HAVE SAM, THEN NANCY THEN GARY AND BENOIT? THERE ARE A FEW QUESTIONS IN THERE I WANT TO MAKE SURE I UNDERSTAND WHAT WE'RE TRYING TO-- >> I THINK ONE OF THE KEY QUESTIONS AND WHAT IS THE LEVEL OF ANTIBODY YOU GET WITH OUR ADVECTOR, AND WHAT GARY GETS FOR THE VSV, AND THE GROUP WITH THE DIFFERENT ADVECTORS. >> SO I THINK ONE OF THE POINTS THAT WAS MADE EARLIER IS WORTH KEEPING IN MIND IS THAT IS THE IMMUNE CORRELATE MAY NOT BE THE SAME FOR DIFFERENT VACCINE PLATFORMS EITHER QUANTITATIVELY OR QUALITATIVELY. SO I APPRECIATE WANTS TO COMPARE THINGS IN YOUR MIND BASED ON A AN ANTIBODY TITER BUT I DON'T KNOW THAT OPERATIONALLY THAT WILL BE TRULY HELPFUL. WHAT YOU NEED TO DO IS WORK BACK TO THE NONHUMAN PRIMATE MODEL, AND TRY TO EVALUATE WHAT YOU SEE IN HUMANS BASED ON WHAT HAS BEEN DETERMINED TO ASSOCIATE WITH PROTECTION IN MACAQUES AND THAT MAY VERY WELL DIFFER BETWEEN THE DIFFERNT VACCINE PLATFORMS SO I THINK A FEW PEOPLE SHOWED NICE GRAPHS WHERE I THINK FOR THE J& J AD VECTORS YOU CAN SEE HAVE YOU A LOT OF ANTIBODY OR T-CELLS OR MAYBE THE AMOUNT OF ANTIBODY IS LESS, SO I DON'T KNOW THAT IT'S GOING TO BE A SATISFYING VALUE THAT YOU NEED AND ONE VACCINE DOES IT AND THE OTHER DOESN'T. >> SO SORRY, MAYBE IT'S DIFFICULT FOR ME TO EXPRESS THIS COMPLEX CONCEPT IN ENGLISH, MAYBE AN EASIER OF FORMULATING THE QUESTION THEN WOULD BE WHEN YOU USE ONE GIVEN VECTOR, ONE OR THE OTHER, AND YOU WOULD EXPRESSING OR ANOTHER PROTEIN, IS IT CORRECT THAT [INDISCERNIBLE] IS MUCH LESS IMMUNOGENIC THAN OTHER EXPRESSED BY SREBGT OR OR IS THAT NOT THE CASE WHICH WOULD BE GOOD? >> I DON'T KNOW YOU CAN GENERALIZE THAT PARTLY BECAUSE OF THE DIFFICULTY IN QUANTIFYING THE RESPONSE BECAUSE OF THE DIFFERENT ASSAYS USED TO MEASURE THE RESPONSE TO DIFFERENT PROTEINS SO WHAT YOU MEASURE IS A ARE THE OUT IN OUR ASSAY WILL BE INFLUENCED BITE THE ANTIBODY FORMS. >> THE SOLUTIONS? >> WE DON'T USE END POINT TITERS WE HAVE A DIFFERENT WAY OF CALCULATING TITERS SOY EPT KNOW THAT I CAN ANSWER THAT QUESTION FOR YOU. >> BENOIT, I WILL COMPLETELY GO IN--NANCY'S DIRECTION, THAT'S THE ASSAYS WILL BE--MAKE THE COMPARISON VERY EXTREMELY DIFFICULT. FOR WHAT WE'VE SEEN, IT'S NOT THE MOST IMMUNO GENIC PROTEIN, THAT'S FOR SURE. BUT IT'S NOT LIKE WE HAVE A--IT'S ALSO WITH MONKEY IN IT. I WILL RELY THAT THE ASSAY MAINLY MAKE THE [INDISCERNIBLE]. >> I'LL JUST ADD THAT BI DEFINITION IT'S IMMUNO GENIC BECAUSE IT ELICITS PROTECTION AT VERY HIGH CHALLENGE DOSE. SO YOU KNOW I DON'T KNOW IF THAT HELPS BUT, YOU KNOW THE ASSAYS THAT WE USE ARE SOMEWHAT ARTIFACTUAL BECAUSE WE'RE TRYING TO USE THEM AS A SURROGATE FOR WHAT'S ACTUALLY HAPPENING IN VIVO, BUT YOU KNOW WE DON'T REALLY KNOW THAT. >> SO WITH A NUMBER OF ANIMAL MODELS AT LEAST, CERTAIN OTHER PLATFORMS HAVE BEEN TESTED WITH MULTIPLE DNA ACSEENS WHICH ARE NOT ELEVATED INTO THIS FIRST LEVEL AND REPLICA BASED VACCINES, ET CETERA, DOESN'T LOOK LIKE THE GLYCOPROTEIN IS UNIQUELY, POORLY IMMUNO GENIC AND IT MAY BE SOMEWHAT UNIQUELY DECEPTIVE IN THE WAY THAT IT ENCOUNTERS THE IMMUNE SYSTEM, MAYBE NOT ANYMORE UNIQUELY SO THAN HIV, BUT--BUT, IT'S NOT EXSEATINGLY POTENT AND IT MAY MISDIRECT A LOT OF IMMUNE RESPONSE THAT DOES ARISE TO UNIMPORTANT SITES. >> CAN YOU CAN TELL US ABOUT YOUR VSV IN PARTICULAR BECAUSE YOUR VSV IS VERY IMMUNO GENIC AS ANTIBODY RESPONSE TO THE POINT THAT WAS BROUGHT UP? >> SO IT'S A VERY INTERESTING QUESTION. AT LEAST FROM THE VSV POINT OF VIEW, SO I THINK ONE WAY TO LOOK AT IT IS THAT SO WHEN WE DO OUR VACCINES IN OUR LAB WE DO END POINT TITER SO IT'S A DIFFERENT MEASUREMENT. ASK ONE THING THAT I THINK WILL BE VERY INTERESTING TO LOOK AT, I MEAN ACROSS THE PLATFORMS IS YOU KNOW MAYBE THE STANDARDIZED ASSAY AND SEE IF IT'S ONE OF THE THINGS THAT CAME OUT FROM THIS MORNING'S TALK IS IT WAS INTERESTING TO PEE IS THAT IF YOU HAVE YOU KNOW LIKE EXTREMELY HIGH LEVEL OF ANTIBODIES YOU GET--MAYBE THE CELL MEDIATOR IMMUNE RESPONSE MAY NOT BE AS IMPORTANT. WHERE IF YOU HAVE A LOWER LEVEL OF ANTIBODIES THEN YOU KNOW, YOU KNOW YOU HAVE THE CELL MEDIATED IMMUNE RESPONSE IS GOOD. SO IT MIGHT JUST BE THAT, YOU KNOW LIKE THE GSP, VERSES THE ADENO VIRUS OR SOME LITTLER PLATFORMS AND THAT'S GOOD AT SIMULATING ROBUST TUMORAL IMMUNE RESPONSE SO IT'S A STUDY SHOWED THAT, YOU KNOW LIKE NOT AS MUCH CELL MEDIA IMMUNE RESPONSES SO MAYBE WE'RE NOT SEEING AS MUCH CORRELATION WITH OUR ADENO VIRUS, YOU KNOW, THIS MAY BE PERHAPS, YOU KNOW A LOWER LEVEL OF ANTIBODY THEREFORE, YOU SEE IN CORRELATION WAS CELL MEDIATED IMMUNE RESPONSES. >> [INDISCERNIBLE]-- REG ARDING THESE ISSUES? >> KNOWING HOW THE ANIMAL MODEL WORK SYSTEM ONE THING BUT WE'RE SOON GOING TO HAVE A CHANCE TO DEFINE CORRELATES IN INICAL TRIALS AS SOME OF THE EFFICACY TRIALS GET STARTED. AND I WANT TO GO BACK TO ERIC AND NANCY'S POINT THAT THERE'S SO MANY DIFFERENT FORMS OF THE GP. THE CURRENT ASSAYS ARE REALLY ASSESSING ALL THE MIX ALL AT THE SAME TIME. ERIC SIDES THERE'S GP FORMS BUT THERE'S AT LEAST THE ONE ON THE VIRUS THE ONE IN THE SIGNIFY TO THETIC VESSEL AND THEN THE SECRETED SOLUBLE FORM SO THERE'S THREE OR MAYBE NOT 12, BUT THERE'S AT LEAST FOUR OR FIVE. >> THE 12 WE CAN FIDDLE AROUND AND ENGINEER THEM TO PICK OUT DIFFERENT SITES. SO THERE'S THREE NATURALLY. >> SO THE POINT IS THAT MANY OF THOSE HAVE SHARED SURFACE AREAS SO IF YOU JUST DO A SIMPLE ELISA LOOKING AT BINDING TO ANY OF THOSE, YOU WILL SEE A LOT OF BINDING TO ALL OF THOSE AND IT'S EASIER AT LEAST IN POLYCLONAL, THAT WORKS OKAY FOR MONOCLONAL BUT THE MONOCLONAL SERRA GET A MORE INCISIVE CELL BY ABSORBING SO IF THERE WAS A CLEARLY DEFINED SET OF ANTIGENS, MAYBE YOUR 12 DIFFERENT FORMS OF GP TO BE USED TO ABSORB THE HUMAN SERRA ON STUDIES THAT ARE COMING UP WITH HUMAN EFFICACYS YOU COULD DEFINE WHAT PARTS OF THE SURFACE AREA, WHICH WOBS OF THOSE FORMS ARE CORRELATED WITH PROTECTION AND I THINK THAT IS IT IS KIND OF LEVEL OF DETAIL WE'RE GOING TO HAVE TO GET TO IF WE WANT A SIMPLE BINDING ASSAY INSTEAD OF A COMPLEX NEUTRAL OOH SAY THAT IS DIFFICULT FOR THEM AND NOT REALLY WELL. GETTING TO A BINDING ASSAY, OR A SIMPLE ABSORPTION ASSAY MAY BE A BETTER STRUCTURALLY DEFINED REAGENT. >> I THINK YOU'RE DESCRIBING IN PART WHAT'S BEEN DONE RECENTLY IN THE HIV, FOLLOWING THE RB-144 STUDIES EXPRESSING DIFFERENT FRAGMENTS AS ERICA HAS DONE TESTING SERRA AGAINST THOSE AND THAT'S WHERE SOME OF THE INTELLECTUAL LEADS CAME FROM BUT THAT HAS STILL NOT LED TO A CORRELATE THAT ANYBODY REALLY BELIEVES IN. BUT IT'S A GOOD PATHWAY TO DISSECT THE IMMUNE RESPONSE IN TERMS OF ESPECIALLY CONFIRMATIONAL PRESERVED LOOPS AND FRAGMENTS AND JUST ASK IS THERE AIAN PARTICULAR PART OF THE RESPONSE THAT CORRELATES. >> YEAH, I THINK THE MAIN THING WE'RE GETTING AT TELL BE SIMPLE AND TRAIT FORWARD, AND YOU MAKE MUSA DEPLETED AND THEN YOU BIND THEM AND THEN CAN YOU TAKE CLEAVE AND UNCLEAVED AND SUBTRACT THE PORTION, WHICH PORTION BLINDS THEIBLY GANNA AND THEN YOU START LOOKING AT MONOMERIC VERSES TRI MERRIC GP AND YOU CAN FIGURE OUT YOUR QUANTINARY EPITOPES AND THEN YOU LOOK AT WHAT'S CONTAINS THE MEMBRANE PROXIMAL REGIONS OR NOT AND YOU CAN MAP THOSE, SO THIS IS STRAIGHT FORWARD AND EASE TO DO IN EALIZA BUT IT WILL NOT TELL YOU IS IF THE SAME ANTIBODIES AT THE SAME SITE WITH THE DIFFERENT ISOTYPE AS A DINNER FUNCTION IN VIVO BUT CAN YOU CERTAINLY DO A SUPER STRAIGHT FORWARD BINDING ASSAY DISEASE TO SEE WHAT IT SAID. >> PHIL KRAUSE, AT FDA, IT SEEMED THAT MOST DATA PRESENTED SO FAR HAS LEANED IN FAVOR OF ANTIBODY TESTS BY SOME KIND OF ELIZA OR WHATEVER IS BEING RELATIVE CORRELATIVE PROTECTION. AT LEAST FOR ANY INDIVIDUAL VACCINE P, IT SEEMED WHEN HIGHER ANTIBODY LEVELS WERE MEASURED THERE WAS SOME CORRELATION WITH SUBSEQUENT PROTECTION BUT OF COURSE FOR THE INDIVIDUAL PLATFORMS THE LEVELS MIGHT BE DIFFERENT IN THE EXACT OTHER FACTORS MAY BE DIFFERENT AS WELL, AS NANCY POINTED OUT. NANCY DID HOWEVER ALSO PRESENT WHAT I THOUGHT WAS REALLY INTERESTING DATA FROM HER PASSIVE TRANSFER STUDY SUGGESTING THAT THE ANTIBODY WAS IN NONMECHANISTIC CORRELATIVE PROTECTION AND YET, IF WE THINK ABOUT THE DATA FROM THE ZMAPP WHICH AS WELL AS OTHER ASSUMPTIONS THAT WE MAY LIKE TO MAKE SUGGESTING THAT ANTIBODIES MADE BY THEMSELVES ACTUALLY BE PROTECTIVE. AND SO, I'D BE INTERESTED IN HEARING FROM ANYONE WHO HAS AN OPINION ON THIS, OF WHY--WHY THAT DIFFERS, WHY THOSE PASSIV TRANSFER STUDIES FOR THE ANTIIS NOD PROTECTIVE AND WHY, WHY DO WE THINK IN OTHER CASES ANTIBODIES MIGHT BE. >> SO, HAIR KETALK TO THIS A LITTLE BIT BECAUSE HE'S MORE CLOSELY ASSOCIATED WITH SOME OF THE EARLY PASSIVE--SOME OF THE EARLY PASSIVE TRANSFER STUDYING BUT WHAT YOU HAVE TO REMEMBER IS THAT IN MOST OF THOSE STUDIES, T-CELLS WEREN'T MEASURED. SO YOU KNOW WE VIEW THIS AS ANTIBODIES HAVING A VERY EARLY ROLE AND CONTAINING VIRAL LOAD GIVING SUFFICIENT OPPORTUNITY FOR A T-CELL RESPONSE TO DEVELOP IN THE HOST. AND SO IN THE FIRST STUDY FROM GARY COPINGER, THEY DID MEASURE T-CELLS AND SO WHEN THEY HAD ANIMALS THAT HAD EQUIVALENT PASSIVELY TRANSFERRED ANTIBODIES WHERE ONE LIVED AND ONE DIED, THE ONE THAT LIVED HAD A T-CELL RESPONSE. SO I THINK WE HAVE TO BE CAREFUL IN CONCLUDE TAG ANTIB ARE DOING EVERYTHING IN THE PASS OF TRANSFER--PATH OF TRANSFER AND LOOK AND SEE THE IMMUNE RESPONSE THE HOST DEVELOPS. >> SO THE JOB MIGHT BE TO KNOCK DOWN THE VIRAL LOAD ENOUGH TO GIVE THE IMMUNE SYSTEM A CHANCE TO DEVELOP THOSE RESPONSES. SO THE ELISA IS OFTEN BUT NOT ALWAYS PREDICTIVE. IF IT BINDS THE BASE, IT'S ABILITY TO NEUTRALIZE DOES CORRELATE WITH DISABILITY TO PROTECT. BUT IF IT'S SOUTH AMERICAN ELSE, WE DON'T KNOW. SO WE'VE DONE IN VIVO STUDIES OF 40S SO FAR, 17 OUT OF THE 40 NEUTRALIZE AND PROTECT, THEIR ABILITY TO PROTECT CORRELATES IS THE ABILITY TO NEUTRALIZE OR 23 OF THE 40 THEY DON'T NEUTRALIZE AND THEY DON'T PROTECT, THEY'RE JUST NO GOOD. BUT THERE'S THREE OUT OF THE 40, THE NEEDLE IN THE HAY STACK DON'T NEUTRALIRES AND DO PROTECT. AND THOSE ARE MUSEIN GLYCAN CAP-ONE THAT WE DON'T KNOW WHERE IT BINDS, IT'S A QUANTINARY THING WE HAVE TO FIGURE OUT SO THOSE ARE THE BEST IN THEIR CLASSES AND WE HAVE TO THINK OF WHY THEY PROTECT AND IF WE ONLY LOOK AT NEUTRALIZATION WE WOULD HAVE LOST THOSE AND WE WOULD NOT HAVE BEEN ABLE TO MAKE A COMPREHENSIVE COCKTAIL. >> NANCY LET ME FOLLOW UP ON THOSE QUESTIONS. I THINK THE QUESTION WAS WHY DID YOUR PASSIVE TRANSFER EXPERIMENT NOT WORK? >> SO THERE ARE A MILLION REASONS NEAR NEGATIVE. >> YES SO WE WOULD LIKE TO-- >> YOU WOULD LIKE ALL MILLION OF THEM RIGHT NOW? [LAUGHTER] SO, YOU KNOW THE WAY IT'S DELIVERED THE ANTIBODY COMPETITION, ANY NUMBER OF THINGS, WHAT--OUR AIM WAS NOT TO ANSWER THE QUESTION GENERALLY CAN ANTIBODIES PROTECT IN PASSIVE TRANSFER? WE WERE AIMING TO ANSWER THE QUESTION: WERE OUR VACCINE PROTECTION MEDIATED BY THE ANTIBODY COMPONENT OF THAT RESPONSE? SO ANTIBODIES ALONE WHEN YOU TRANSFER LARGE AMOUNTS GENERATED BY THAT VACCINE DO NOT EXPLAIN COMPLETELY THE PROTECTION BY THAT VACCINE. WOULD THE IMPLICATION BE THAT YOUR VACCINE IS NOT INDUCING A GOOD ANTIBODY RESPOBS. >> YOU KNOW AGAIN I THINK THE INTERPRETATIONS ARE AS MANY AS THE INTERPRETATIONS OF A NEGATIVE RESULT AND WHAT YOU COULD SAY IS-- >> BUT YOU'RE SHOWING THAT IF YOU TAKE THE ANTIBODY THAT IS VACCINE INDUCED IT WOULD NOT BE PROSECTIONAL ANALYSISSED. >> SO IT'S A CLEAN NICE EXPERIMENT WITH A CLEAN RESULT. >> I HAVE A QUESTION FOR THE MODERATOR. THE LITTLE PREFAS, SO A LOT OF THESE, WELL ALL OF THE NONHUMAN PRIMATE STUDIES IN RECENT YEAR VS BEEN PUSHED BACK TOWARD PRIMARY VACCINATION AGGRESSIVE HIGH DOSE FOLLOWED BY CHALLENGE AT 28 DAYS AND THAT WAS FUELED BY TRYING TO GET AN ACCELERATED PROTECTION AND ALSO BY MONKEY PER DIEMS PROBABLY AND BL-FOUR AND GET RAPID TURN AROUND BUT THE UPSHOT IS WE'RE LOOKING AT PRIMARY RESPONSE AT WHICH TIME ANTIBODY IS NOT FINISHED WITH THE ISOTYPES WITH AN AFFINITY MATURATION AND T-CELLS ARE SILL IN CIRCULATION IF YOU LOOK AT THE SAME THING SIX MONTHS LATER, YOU MIGHT SEE SOMETHING DIFFERENT AND YOU CAN SPEAK TO SOME OF THOSE. >> I THINK YOU MAKE A VERY GOOD POINT THAT CERTAINLY ANTIBODY WOULD BE MATURING AND THAT'S PROBABLY ALREADY HAPPENED BUT THE MATURATION WOULD TAKE LONGER SO YOU WOULD HAVE BETTER ANTIBODY. SO SEE THE POINT. >> QUESTION BACK THERE. KRISTI KRAMER FROM NIAID, AND I WONDERED ABOUT THE OPTIMIZATION OF THE NONHUMAN PRIMAATE MODEL IN THE TESTING OF ANTIBODIES AND I WONDER IF ANYONE HAS GIVEN CONSIDERATION TOO OR WORTH CONSIDERING MAKING THOSE ANTIBODIES WITH THE CORRELATE, THE ANALOGOUS NONHUMAN PRIMATE FC AS THE TEST AGENT TO BEST PARALLEL WHAT MIGHT BE HAPPENING IN THE HUMAN WITH THAT PARTICULAR SPECIFICITY. >> I DIDN'T ANSWER THAT. I BET YOU JOHN DYER CAN ANSWER THAT. >> I CAN ANSWER. >> WELL MAYBE YOU CAN ANSWER FOR HIV, BASICALLY IT'S RIDICULOUSLY COMP LITICATED TO GET THE RIGHT MONKEY SV BECAUSE THOSE ARE CONTEMPLATE INDED ALL THOSE PLACES, THESE ARE IMFATICALLY NONTRIVIAL EFFORTS TO MAKE THE MONKEY ANTIBODY AND THE MONKEY ISOTYPE. >> SO IF YOU RECESSIZE AN ANTIBODY, THE CLEARANCE WILL BE NOT AS FAST AS IF YOU PUT A HUMAN ANTIBODY INTO A RECESS MONK SCHEVICE VERSA SO YOU MIGHT INCREASE THE HALF LIFE BY MAKING IT A RECESS AND MAYBE ALSO THE FC FOR INTERACTION WITH RECESS SPECIFIC EFFECTOR MOLECULES? >> OKAY SO I'M GOING TO ASK A QUESTION ABOUT--MAYBE IT'S A PLEA. >> NELSON MICHAEL FROM THE WALTER ARMIES UNIVERSITY OF RESEARCH, RARE, MY QUESTION IS RELATED TO THE PLANNED NONNEUTRALLIZING EFFECTOR ASIGNIFIES THAT INVOLVE ASSAYS OR SOMETHING THAT STAND MENTIONED REEVEBLY DURING HIS PRESENTATION AND OUR GROUP DID THAT STUDY AND WE WERE INVOLVED IN THE CONTINUING DECONVOLUTION OF THAT STUDY, IT'S INCREASINGLY CLEAR THAT ADCC ISN'T THE NONNEUTRALLIZING ANTIBODY, IT'S PROBABLY THE PHAGOCYTOSIS ASSAYS, THE ALAN WAS AT THE CABD MEETING IN SEATTLE WITH ME JUST LAST WEEK. AND WHAT WE LEARN FRIDAY MA MEETING IS THAT THE BODY OF INFORMATION THAT--THE SUMMATION OF EIGHT DIFFERENT NEUTRALIZING ANTIBODY EFFECTOR FUNCTIONS AND YOU ANALYZE THEM IN A COMPUTATIONAL WAY ARE GIVING US A LANDSCAPE AND IMMUNE WAY OF LOOKING AT THOSE VACCINES THAT WORK THOSE THAT DON'T WORK AND I THINK THAT FOR EBOLA I'M INTENSELY INTERESTED IN WHETHER OR NOT HAVE YOU THAT IT NUMBER OF EFFECTOR FUNCTIONS YOU COULD PUT INTO SUCH A NUMBER OF COMPUTATIONAL APPROACH AND NORTH, SOUTH, NODS AND FROM ERICA AND FROM NANCY BUT I JUST THINK THAT AS I LISTEN TO THE TALK ABOUT PATHOGENESIS, TRUST ME I'M NOT AN EBOLA WARRIOR, I'M LEARNING A LOT ABOUT IT BUT IT WOULD BE SOMETHING TO FOCUS ON. >> WE'VE ALREADY FOCUSED ON THE SAME BOX OF ANTIBODIES AND ARE WAITING FOR THE RESULTS. >> GREAT. >> [INDISCERNIBLE] FROM IBT. I HAD THE COMMENT ABOUT WHAT WAS SAID BEFORE ABOUT DOING SOME KIND OF SUBTRACTION EALIZAS AND HOPING THAT THAT CAN ACTUALLY DEFINE THE QUALITY OF THE TYPE OF ANTIBODY RESPONSE THAT YOU GET IN THE VACCINES AND WHAT I'M SAYING IS PROBABLY OBVIOUS TO A LOT OF PEOPLE LIKE ERICA, BUT IT'S NOT NECESSARILY TO A LOT OF NEW COMERS TO THE FIELD, AND IT'S NOTES THAT SIMPLE, IF YOU START SUBTRACTING, YOU TAKE OUT THE MUSIN LIKE DOMAIN AND YOU LOOK AT THE DELTA MUSEUM SIN, THE TOTAL ANTIBODY RESPONSE IS NO LESS. SOMETIMES IT'S EVEN A BIT HIGHER. HAVE YOU ALREADY CAUGHT OFF A DOMAIN AND THE REASON NOVEMBER-YOU CAN GO FURTHER, CAN YOU CUT OFF THE GLYCAN CAP AND THE ASPECT BODY RESPONSE AND IT WILL STILL BE QUITE HIGH. IT DOESN'T REALLY JUST ADD UP A LINEAR FASHION AND THE REASON IS THAT, YOU KNOW AS ALAN SAID, THIS GLYCOPROTEIN IS DECEPTIVE AND A LOST THESE EPITOPES ARE VERY IMPORTANT ARE SOMEWHAT HIDDEN IN THE WHOLE STRUCTURE, YOU GET RID OF THE MUSEIN LIKE DOMAIN AND YOU LOSE EPITOPES AND YOU EXPOSE EPITOPES AND YOU LOSE THE GLYCAN CAP, YOU EXPOSE NEW EPITOPES AND I THINK IF YOU WANT TO REALLY QUALITATIVE ANALYZE THE VACCINE RESPONSE, YOU NEED TO COLLECT A GOOD NUMBER OF--VALIDATED ANTIBODIES EITHER BY NEUTRALIZING OR BY PROTECTION IN VIVO, AND THEN LOOK AT THE COMPETITION. AND USE THE FULL LENGTH TKPWHRAOEUBG O ROUGH ATOM TEEN BECAUSE THAT'S WHAT THE VACCINE AND THE ANTIBODIES ARE GOING TO SEE AND THE PERSON IS INTPEBTED AND THEN LOOK AT THE COMPETITIONS AND SEE, HOW THIS DIFFERENT EPITOPES ARE REPRESENTED IN A VACCINE RESPONSE. >> SO [INDISCERNIBLE] IS RIGHT SO WHEN YOU DO THE CYTOMETRY, THE ANTIBODIES WERE NOT EFFECTS BUT YOU COULD ENHANCE THEIR APPARENT AFFINITY SO YOUR ABILITY TO DETECT THINGS IN A SIMPLE ELISA IS INFLUENCED ABOUT THE THINGS THAT ARE NOT [INDISCERNIBLE] IT'S MORE COMPLICATED. >> MARK FINEBERG FROM MERCK, I HAVE A QUESTION MAYBE START WITH DR. AHMAD AND OTHER PANELS WANT TO COMMENT ON, MORE PEOPLE IN THE ROOM AND CERTAINLY OUTSIDE OF THE ROOM SPEND TIME DEVELOPING AN HIV VACCINE THAT MIGHT NOT PREVENT INFECTION BUT WOULD MODULATE DISEASE, BY INDUCTION OF CELL MEDIATED IMMUNE RESPONSES AND HOPEFULLY LOWER THE ABILITY TO TRANSMIT INFECTION TO SOMEONE ELSE AND CLEARLY THAT ISN'T BEEN SL TO DATE AS YOU ALL KNOW. BUT IN THIS CASE, YOU WONDER WITH A VIRUS LIKE E BOLA WHICH IS FILLED WITH IMMUNE EVASION STRATEGIES THAT ARE JUST MIND BOGGLING, THE DIFFERENCE BETWEEN THE HOST VIRUS INTERACTION BETWEEN SOMEONE WHO WAS NOT VAC SAEUTED AND HAD NO SORT OF EFFECTIVE IMMUNE RESPONSE PRIOR TO EXPOSURE TO THE PATHOGEN MIGHT LEAD THEM TO A VERY DIFFERENT INFECTN OUTCOME FROM SOMEONE WHO WAS VACINATED AND HAD THE ABILITY OF SOME FUNCTIONAL IMMUNE RESPONSES EITHER YOU KNOW T-CELL OR B-CELL. BUT WHAT HASN'T BEEN TALKED ABOUT YET IS WHETHER THERE'S A POSSIBILITY IN THIS INSTANCE WHERE YOU KNOW VACCINES EVEN IF THEY DIDN'T PREVENT INFECTION MIGHT MODULATE DEC AND INFECTIVITY AND I WONDER HOW YOU GIVEN ALL THE THOUGHT YOU PUT INTO, JUST HOW VIRUS CANS INDUCE INFESCKIVE, HOW YOU MIGHT THINK ABOUT THE POSSIBILITIES. >> I THINK YOU PRESENT AN INTERESTING POINT AND I OPEN IT FOR DISCUSSION, SPECIALLY FROM THE EBOLA EXPERTS. I THINK THE QUESTION MARK IS ASKING IS WHETHER IF YOU DON'T PREVENT INFECTION, I GUESS IT CAN GO BOTH WAYS, YOU MIGHT ACTUALLY GET--IF YOU GET ACUTE INFECTION SIX AND MORTALITY, THAT'S ACTUALLY A REASONABLY GOOD VACCINE IN THIS INSTANCE, BECAUSE YOU ARE THE VIRUS IS CLEAR, SO EVEN A VACCINE THAT WAS GIVEN, NOT PROTECTING INFECTION, BUT WAS RESULTING IN MUCH FASTER CLEARANCE OF INFECTION WOULD BE REASONABLY EFFECTIVE ACSEEN AND THAT'S THE WAY WE SHOULD DISCUSSION THAT ISSUE BUT YOU'RE ALSO IMPLYING NEGATIVE ASPECTS COMING OUT OF IT. COMPREHEND. THAT IS SOME ENHANCEMENT ISSUES OR SOMETHING? YEAH THAT'S--RIGHT. >> [INDISCERNIBLE]. >> RIGHT, THAT'S WHAT I THOUGHT. SO MAYBE WE SHOULD OPEN IT TO THE PANEL FOR COMMENTS ON YOU KNOW VACCINE THAT DOESN'T PREVENT INFECTION THAT ACTUALLY WILL RESULT IN SURVIVAL OF INDIVIDUAL AND WHAT THE VALUE OF THAT WOULD BE. >> UNLESS WE PROTECT THROUGH A RESPONSE LIKE A T-CELL PROTEIN AND NONENVELOPE PROTEINS, NONE OF THOSE ARE PROTECTIVE AGAINST DISEASE AND MONKEYS, THEY MAY BE PARTIALLY PROTECTIVE WHERE THE GLYCOPROTEIN HAS BEEN NECESSARY AND SUFFICIENT FOR REALLY SOLID IMMUNITY AND TO FOLLOW ON, THE ANTIGEN FOR EBOLA AND MARBURG MAY BE A MORE DIFFICULT TARGET BUT THE DISEASE IS EASIER THAN HIV BECAUSE ALL WE HAVE TO DO IS PRESENT SERIES DISEASE FROM ACUTE INFECTION, WE'RE NOT DEALING WITH INTEGRATION AND THE LIKE. >> SO THE CURRENT MODEL IS NOT THE BEST FOR ANSWERING THAT QUESTION BECAUSE IT'S--IT'S TYPICALLY PRETTY CLEAN. IF THEY GET INFECTED THEY DIE AND IT'S VERY RARE THAT YOU HAVE AN ANIMAL THAT GETS INFECTED AND DIES. SO TO ANSWER THAT QUESTION, WE WOULD NEED A CHALLENGE MODEL FROM A LOWER DOSE. >> MICHAEL FROM THE IRB DISCUSSION, THERE'S BEEN RICH DISCUSSION ON POST EXPOSURE VACCINES SO WE MIGHT WANT TO CAPTURE THIS FROM THE W. H. O. AND THE DISCUSSIONS, THE CONCERNS ARE THEORETICAL, BUT THE CONCERNS HAVE TO DO WITH A PART OF IMMUNITY AND DOES THE VACCINE CREATE TOLERANCE AND INDUCTION OF MORE OFFICIAL CELLULAR MEDIATED AND IT WOULD BE HAVE GOOD TO HAVE THIS GROUP CONVENE WITH THE IRB DISCUSSIONS SO YOU KNOW WHAT YOU CAN AND CANNOT CONDUCT AS O OPPOSE THIS, IS NOTHING TO DO WITH THE PREEXPOSURE VACCINES BUT IT'S AN IMPORTANT POINT. >> TO ADD WE DO SEE SOME IN THE INNATE MONK THAT'S GET SICK AND DO CURVIE. THE VIRAL LOAD AND LOWER AND IF YOU RELATE THAT VIRAL LOAD IS IMPORTANT FOR THE TRANSMISSION OF THE DISEASE, THEN THAT WILL BE SOMETHING VERY POSITIVE FOR A VACCINE TO PROVIDE. >> OKAY, THAT'S GOOD WE'RE PEATY CLOSE TO TIME. LET'S TAKE THE LA TWO QUESTIONS, ONE AT THE BACK AND THEN AT FRONT. >> I'M MARK WITH THE CDC, AS AN IMMUNOLOGY, SOMETHING STRUCK PLEA IN WHAT DR. WONG SAID IN THE CD-EIGHT DEPLETED ANIMAL FIST YOU RECEIVE VSV, THEY RESEARCH FINE A ESSENTIALLY SURVIVED AND WE SORT OF MENTION THAT THE CD-EIGHT DEPLETED MACAQUES THOSE ARE CLEAR MARKERS OF SURVIVAL WITH THE ADENO VIRUS VACCINE NONREPLICATING CURIOUS TO KNOW THE PANELS THOUGHTS AS WE GO FORWARD IN LOOKING AT SACK SEENS AND CORRELATES DOES THAT FUNDAMENTALLY REFLECT A DIFFERENCE IN MECHANISM BETWEEN THE VSV AND MAYBE WHAT IT WOULD STIMULATE FOR THE CORRELATE AND THE ADFOCUSED ON VIRUS AND I PROMISE WHETHER IT WAS MVA BOOST OR REPLICATED BST, BUT IT SEEMED A STRIKING DIFFERENCE THAT THE CD-EIGHT DEPLETED SURVIVED AND CDEIGHT DEPLETED WITH ADENO VIRUS DID NOT. >> YEAH, SO, IT GETS BACK TO ONE OF THE EARLY COMMENTS THAT WAS MADE BY SEVERAL PEOPLE INCLUDING MYSELF THAT THE MECHANISM OF PROTECTION BY THE DIFFERENT VACCINES MAY DIFFER. THE WAY THOSE CD-EIGHT DEPLETIONS WERE DONE ALSO DIFFERS SO WE DEPLETED CDEIGHTS AFTER VACCINATION AND JUST PRIOR TO CHALLENGE AND WE MEASURED CDEIGHT LEVELS IN THE SPLEEN AND THE LIVER AND ALL OF THE PERIPHERAL ORGANS TO INSURE WE HAD COMPLETE DEPLETION, THE VSV STUDY DEPLETED CDEIGHT T-CELLS DURING VACCINATION. AND THE RISK THERE IS THAT YOU HAVE A FEW CDEIGHT- T-CELLS REMAINING AND I DON'T KNOW IF THEY LOOKED IN PERIPHERAL ORGANS? SO IT COULD BE A DIFFERENT MECHANISM OF THE VACCINE OR MAYBE SOME CD-EIGHTS REMAINING. >> THE RECIPROCAL RISK IS IF YOU DEPLETE RIGHT BEFORE CHALLENGE YOU HAVE TO WONDER WHAT'S THE APPROPRIATE CONTROL FOR SOMETHING FOR ANTIBODY IS KILLING CELLS AND CLOGGING UP THE IMMUNE SYSTEM. AND THOSE ANIMALS MAY BE MORE SENSITIVE THAN THEY OTHERWISE WOULD BE. SO IT WAS THE TWO STUDIES ARE NOT DIRECTLY COMPARABLE IN OPEN QUESTION YET, I THINK. >> ONE COMMENT I HAVE IS I CAN'T QUITE REMEMBER WHICH ANTICD-EIGHT ANTIBODY, IT WAS, I READ THE TWO PAPERS AND BELIEVE THEY WERE CURRENT ANTICDEIGHT ANTIBODIES AND SOMETIMES IT'S--OUR CDEIGHT DEPLETION MIGHT ALSO GET DEPLETION OF UNINTENDED DEPLETION OF THE OTHER CELLS SO THEY SOMETHING LIKE SAY NK CELLS WHICH MIGHT IMPACT ADCC, SO THAT WOULD BE SOMETHING. THAT WOULD ALSO BE A FACTOR. >> GARY IN YOUR EXPERIMENTS WHAT WERE THE DISCIPLINARY MERBETWEEN THE VACCINATION AND THECHALLENGE? NUZZ BAH DEPLETED DURING IMRUINIZATION RIGHT? AND HOW MANY CHALLENGE AND WEEKS LATER? >> [INDISCERNIBLE] >> SO SOME OF THE CD-EIGHTS WOULD COME BACK IF DEPLETION WAS EFFECTED? >> SORRY. SO THE DEPLETION WASN'T--OUR EXPERIMENT BUT THE DATA CHALLENGE FOUR WEEKS LATER. >> [INDISCERNIBLE]--WE HEAR ABOUT THE DIFFERENCES IN THE EXPRESSION OF GP IN OUR NATURAL INFECTION HOWEVER ALL OF OUR VACCINES AS FAR AS I KNOW, THEY ARE BASED IN THE EXPRESSION OF WHOLE GP. HOW DO YOU--HOW DOES THE TABLE THINK THAT COULD EFFECT CORRELATES OF PROTICKETTIVE IPT GREATER IMMUNITY BETWEEN THE VIRUS OF NATURAL INFECTION AND VACCINE? >> I THINK YOU'RE ASKING ABOUT THE FACT THAT SGP, WHICH IS OUT OF FRAME WITH GP FOR PART OF ITS REGION IS NOT IN THE VACCINE INTENTIONALLY, SO THERE IS AN INTENTIONAL DESIGNED DIFFERENCE BASICALLY WE TARGETED VACCINES TO HIT GP BUT NOT THE PART OF SGP THAT'S UNIQUE TO SGP. IS THAT WHAT YOU WERE GOING WITH THE QUESTION? >> WITH WE ARE TRYING TO LOOK FOR CORRELATES, I MEAN WHEN WE TRY TO FIND OUT WHAT ARE THE CORRELATES OF PROTECTION OF IMMUNITY, OBVIOUSLY THEY ARE TRYING TO BE--OR COULD BEING DIFFERENCES BETWEEN NATURAL INFECTIONS AND THE CORRELATES PROVIDED BY A VACCINE? >> OH, ABSOLUTELY. >> JUST A QUICK ANSWER. >> [INDISCERNIBLE] FROM THE VSV VACCINE EBOLA WAS SUSPECTED BECAUSE OF THE [INDISCERNIBLE] IS IT ANYTHING ABOUT THE INTERTHAT WILL AMILLIO ICNUCLEUS LESION BECAUSE WE KNOW THAT THALAMUS VERSES [INDISCERNIBLE] DELAYED IN HUMAN SO MAYBE [INDISCERNIBLE] FROM THE METHYLATION? >> UNFORTUNATELY I DON'T HAVE ANYMORE INFORMATION ON THAT. I JUST KNOW WHAT'S IN THE NEWS, FOR MORE INFORMATION YOU WOULD HAVE TO ASK MY SUPERVISOR DR. GARY HOBBINGER. >> THANK YOU SO MUCH. >> [LAUGHTER] >> [ APPLAUSE ] >> ON THAT NOTE, LET'S THANK ALL THE SPEAKERS AND THE AUDIENCE, JUST WANT TO MAKE A PLUG FOR, AS YOU MAY KNOW, THE FDA DEPENDS UPON INPUT FROM THE PUBLIC INTO OUR DECISION-MAKING PROCESS, THROUGH WHAT WE CALL ADVISORY COMMITTEES, AND I'VE BEEN ASKED TO ADVERTISE THAT. IF YOU'RE INTERESTED IN SERVING ON THESE COMMITTEES. THEY HAVE A TENURE OF THREE YEARS? WHAT'S THE TENURE, DO YOU KNOW? BUT I THINK IT'S A THREE-YEAR TENURE BUT IF YOU'RE INTERESTED IN MAYBE HAVING YOUR EXPERIENCE AND PROFESSIONAL ABILITIES USED TO ADVISE THE FDA ON THE PRODUCTS THAT WE APPROVE AT THE CENTER FOR BIOLOGICS, OUTSIDE WHERE THE AGENDAS ARE, ON THE INFORMATION DESK IN THE LOBBY YOU'LL FIND THESE PAMPHLETS ON THE DIFFERENT COMMITTEES THE FDA USES TO GARNER PUBLIC INFORMATION AND PUBLIC INPUT INTO OUR -- AND ADVISE ABOUT PRODUCTS BEFORE LICENSURE. THANK YOU. THIS AFTERNOON WE'RE GOING TO BE TALKING ABOUT A PIVOTAL AREA, WHICH IS TO DISCUSS THE ASSAYS THAT ARE BEING USED TO CURRENTLY HAVE SOME THOUGHT ABOUT WHAT SHOULD BE OUR FUTURE. AND SO IN THAT VEIN, I'D LIKE TO CALL UP CAROL SABOURIN FROM BATELLE, WHO WILL TELL US A LITTLE BIT ABOUT WHAT'S INVOLVED WITH SOME OF THE ASSAYS THAT SHE'S WORKING WITH. BEFORE I DO THAT I'D LIKE TO INTRODUCE ALSO DR. SINA BAVARI, ONE OF MY OLD COLLEAGUES FROM USAMRIID WHO WILL RUN THE PANEL DISCUSSION THAT WE HOPE TO START AT 2:25. >> THANK YOU. I'D LIKE TO THANK THE ORGANIZERS FOR INVITING ME TO SPEAK AND ACKNOWLEDGE THAT THE VAST MAJORITY OF THIS WORK WAS CONDUCTED UNDER CONTRACT WITH THE MEDICAL COUNTERMEASURES SYSTEM JOINT VACCINE ACQUISITION PROGRAM IN ADDITION TO STUDIES H NIAID, DMID. TODAY I'M GOING TO TALK BASICALLY ABOUT THE HUMORAL IMMUNE RESPONSE, CELLULAR IMMUNE RESPONSE AND BRIEFLY THE CORRELATES OF CORRECTION. A CASE EXAMPLE WE DID FOR THE ANTHRAX VACCINES. WE ALL KNOW THE ASSAYS THAT ARE ASSOCIATED WITH BOTH THE CELLULAR RESPONSE, WE HEARD ABOUT THOSE THIS MORNING. WITH WITH REGARD TO ANTI-GP ELISA THERE'S WAYS OF GETTING REPORTABLE DATA, NOW MANY OF US ARE USING ELISA. WE HAVE TO MOVE TO GP, IgG LEVELS IN MICROGRAMS PER ML, THAT'S WHERE WE ALL WANT TO BE SO THAT WE CAN DO A COMPARISON BETWEEN VACCINES. WE USE REFERENCE STANDARDS, QQs AND NEGATIVE CONTROL. MY COLLEAGUE JAY HOOPER WILL TALK NEXT. WITH REGARD TO THE CELLULAR IMMUNE RESPONSE, INTRACELLULAR CYTOKINE STAINING WHICH NANCY SULLIVAN ARTICULATED THIS MORNING, THE ELISPOT, BUT ALSO LUNAX LOOKING AT KEY CYTOKINE. WE DEVELOPED ASSAYS IN OUR LABORATORIES WITH REGARD TO ANTI-GP ELISA WE TRANSFORMED SOP TO THE LABORATORIES LISTED ON THE LEFT SIDE. SOME OF THOSE HAVE ONLY RECEIVED SOP FROM THE FORUM. WITH REGARD TO THE INTRACELLULAR CYTOKINE STAINING, THAT'S IN THE DEVELOPMENT STAGES, WE HAVE TRANSFERRED PEPTIDES TO USAMRIID AND RARE, THOSE PEPTIDES WERE DESIGNED BY THE SCIENTISTS AT USAMRIID, THEY WILL BE USE ON NIAID SPONSORED STUDIES AT BATELLE. FREE AGENTS, IT'S IMPORTANT WE STANDARDIZE OUR REAGENTS. IT'S BEST IF WE'RE ALL USING THE SAME. LET'S TALK ABOUT HOW WE CAN GO ABOUT DOING THAT. THE CHALLENGE AGENTS, AS WE KNOW, THESE ARE THE CHALLENGE AGENTS THAT WILL BE USED. RECOMBINANT GPs FROM THE VECTORS THAT JOHN DESIGNED, AND CONSENSUS SEQUENCE, AND NONCONSENSUS, DESIGNED BY USAMRIID. IF YOU'RE GOING TO LOOK AT DIFFERENT RECOMBINANT GPs YOU THIS SLIDE ILLUSTRATE CHANGES MADE, THERE'S 11 AMINO ACIDS THAT ARE MISMATCHES, HIGH HOMOLOGY BETWEEN THE TWO, 17 AMINO ACID MISMATCHES, AND THEN MYANGA AND GUINEA. MANY VACCINES WITH BASED ON THAT, AND KIKWIK BECAUSE IT'S THE CHALLENGE STRAIN. THE RECOMBINANT GP MANUFACTURED BY ABL UNDER CONTRACT WITH BATELLE, THIS IS THE COATING ANTIGEN THAT'S BEEN USED. THERE'S A LARGE LOT OF THIS MATERIAL. IT'S BEEN DISTRIBUTED TO A NUMBER OF DIFFERENT LABORATORIES. THE PURITY IS ILLUSTRATED THERE. THIS IS BOTH REDUCED AND PURITY. THERE'S A REPORT AND CERTIFICATE OF TESTING THAT ACCOMPANIES EACH OF THE LOTS OF RECOMBINANT GP THAT WERE MADE. THESE ARE DISTRIBUTED REAGENTS. WE AT BATELLE HAVE BEEN LOOKING AT ACCELERATED LONG TERM USE WITH REGARD TO FREEZE THAWS, AND THIS HAS BEEN DONE OVER FIVE FREEZE THAWS. YOU CAN SEE THE PERCENT DIFFERENCE FROM THE INITIAL FREEZE THAW, THERE'S A GOOD INDICATION THAT IT'S STABLE TO FREEZE THAWS AT LEAST FOR FIVE AND WE'RE DOING LONG-TERM STABILITY TESTING, 12-MONTH TIME POINT IN JANUARY OF 2015. AND THAT DATA BELONGS TO JVAP. THIS IS THE PLATE LAYOUT THAT WAS DEVELOPED WITH 10 SAMPLES, REFERENCE STANDARD GOING ACROSS IN A DILUTION, A QC HIGH AND LOW AND NEGATIVE CONTROLS. EACH I JUST BRIEFLY LAID OUT THE PROCEDURE STEPS ON THE LEFT-HAND SIDE AND SHOWED A REFERENCE STANDARD CURVE. I'M GOING TO PRESENT SOME OF THE QUALIFICATION DATA IN THE COMING SLIDES. WE HAVE STANDARDIZED THIS PLATE LAYOUT AND MANY LABORATORIES IMPLEMENTED THAT. WITH REGARD TO CALIBRATION CURVE PERFORMANCE, IN THE INITIAL STAGES OF THIS ASSAY, THIS IS SOME OF THE EARLY QUALIFICATION DATA THAT WE DID. WE FOUND THAT, WELL, LET ME FIRST STATE THE REFERENCE CURVE WAS PREPARED FROM A POOL OF VACCINATED ANIMALS. AND WE JUST GAVE IT A NAME, BMI ZAIRE 001. THERE'S TWO FOLDS. THIS PRESENTS AN 11 POINT REFERENCE STANDARD CURVE. CURRENTLY, THIS REFERENCE STANDARD IS ASSIGNED THOUSAND ELISA UNITS PER MILL. WE NEED TO GET TO THIS AND GP MICROGRAMS PER ML. THE QUALIFICATION DATA THIS IS STATISTICAL ANALYSIS OF THE DILUTIONAL LINEARITY. THIS IS CONSIDERED EXCELLENT FOR ELISAs. WE DONE THIS FOR EACH OF THE ELISA AND THERE ARE QUALIFICATION REPORTS, ONE HAS BEEN COMPLETED, TWO IN PROGRESS. THIS IS THE ZAIRE NHP ANTI-GP ELISA QUALIFICATION. WE'LL FOLLOW A SIMILAR PATTERN FOR THE HUMAN ELISA. THE COATED TEST PLATE FACILITY IS UP TO 7 DAYS, WE USE 5 DAYS, HOWEVER THE PLATES CANNOT BE FROZEN. SERUM STABILITY IS INDICATED IN THE NEXT ROW AND THEN THE LOD AND LLOQ IS 3.7 LISA UNITS PER ML. IT FOLLOWS A SIMILAR PATTERN, I PREVIOUSLY SHOWED DILUTIONAL. WE ARE IN VARIOUS STAGES OF QUALIFYING ADDITIONAL LOTS, THE QC-LOW, BUT VERY IMPORTANTLY TO ASSIGN A CONCENTRATION IN MICROGRAMS PER ML, THAT'S NO TRIVIAL UNDERTAKING. WE'LL NEED TO DO A PROTEIN A COLUMN AND COLUMN IN WHICH RECOMBINANT GP, OVER A GP COLUMN TO PULL OUT ANTIBODIES FOR THE IgG. THIS IS WHERE WE'RE AT FOR THE HUMAN ZAIRE ANTI-GP ELISA, THERE'S A PARALLEL EFFORT AT USAMRIID, AND THEY ARE ASSAYING SOME OF HUMAN SAMPLES, FROM ONE OF THE CLINICAL TRIALS. INITIALLY WE WERE PROVIDED TWO HUMAN SERUM SAMPLES FROM A VACCINATED SUBJECT. ONE AT DAY 14, ONE AT DAY 41, CREATED A REFERENCE STANDARD FROM ONE OF THESE, THE PLATE COATING WILL BE SIMILAR TO THE NONHUMAN PRIMATE ASSAY, .5 MICROGRAMS PER ML OF RECOMBINANT GP UNDERGOING STABILITY TESTING. WE'VE CONFIRMED HUMAN CONGUVANT AND THE OD VALUES, BUT THE NEXT STEP FOR OUR LABORATORY IS THE QUALIFICATIONS, THAT WILL BEGIN SHORTLY. THIS IS SOME OF THE INITIAL DATA FOR THE HUMAN QCs, OUR EVALUATION OF THE QC HIGH AT STARTING DILUTION OF 1-50, CC LOW, ONE TO FOUR IN NEGATIVE CONTROL SERUMS, ADDED TO PLATE AT STARTING DILUTION OF 1 TO 50. THE AVERAGE IS QUITE GOOD WITH THE STANDARD DEVIATION AND PERCENT CV AND WE'RE HAPPY WITH THE ASSAY PERFORM AT USAMRIID AT THIS POINT. TECHNOLOGY TRANSFER OF THE ASSAY, SOMETHING THAT WILL BE IMPORTANT FOR THE EBOLA SCIENTIFIC COMMUNITY. THERE IS A SET OF SOPs, ONE MORE NONHUMAN PRIMATES, ONE FOR HUMANS. THERE ARE SOPs. THERE WILL BE REAGENTS. WE'RE DEVELOPING AN ELISA PANEL, TEN SAMPLES, THE LABORATORIES THAT RECEIVE THESE WILL BE BLINDED, THEY WILL GET SERUM VOLUMES IN APPROXIMATELY 200 MICRO LITERS AND ARE CURRENTLY BEING CHARACTERIZED TO ACCEPTANCE CRITERIA AND DATA CAN FLOW BACK TO THE CENTRAL LABORATORY AND THE LABORATORIES CAN BE CONSIDERED PROFICIENT. WITH REGARD TO THE INTRACELLULAR CYTOKINE STAINING, SOPs FOR PREPARATION OF THE PBMCs, WE USE CPT TUBES FOR THIS, AND SOP FOR RUNNING THE ASSAY. WE HAVE CURRENTLY IMPLEMENTED WHERE WE'RE USING TWO INTERFERON GAMMA CLONES, TWO IL-2 CLONES, A SINGLE TNF ALPHA CLONE FOR THE NONHUMAN PRIMATE SAMPLES. IN ORDER TO DETERMINE WHAT WE CONSIDER A TRUE POSITIVE, WE WILL CALCULATE THE DIFFERENCE BETWEEN IN THE CYTOKINE RESPONSE, DETERMINE THE 95% CONFIDENCE INTERVAL, CALCULATING THE MEAN AND STANDARD DEVIATIONS, FOR EXAMPLE OF ALL THE ANIMALS ON DAY ZERO AND THEN POSITIVE RESPONSE WILL BE CONSIDERED THAT ABOVE THE 95% CONFIDENCE INTERVAL. CURRENTLY WE'RE LOOKING AT SINGLE CYTOKINES BECAUSE MOST SAMPLES HAVE FAIRLY LOW LEVELS, AND IN SOME CASES NOT DETECTABLE LEVELS, INCREASED FOR EACH OF THE CYTOKINES BUT EVENTUALLY WILL GET TO THE POINT WHERE WE'RE LOOKING AT TWO CYTOKIS, THREE CYTOKINES AS NANCY DETAILED IN HER TALK THIS MORNING. WE USE THE INTEGRATED MEAN FLUORESCENCE INTENSITY AS THE REPORTABLE VALUE FOR THIS ASSAY. WHERE DO WE DOUGH? CORRELATES OF PROTECTION, MANY WERE PART OF THE THIS WORK, A HUGE BODY OF LITERATURE AND NUMBER OF ANIMALS AND CLINICAL TRIALS FROM ANTHRAX VACCINE PROGRAM RESEARCH HEADED BY THE CDC BUT MANY STUDIES DONE BY NIAID-DMID. THIS IS A SLIDE THAT DR. CONRAD QUINN AND JARROD SCHIFFER LOANED TO ME, PRESENTED IN 2010. BUT IN THIS CASE WE'RE LOOKING AT NHP SURVIVORS AND THEIR ANTI-PA, THE PA LEVELS AT THE TIME OF CHALLENGE. AND ALSO THE NONSURVIVORS HERE. WE THEN CAN PREDICT, GET A PREDICTED SURVIVAL REGRESSION CURVE FROM THIS DATA, THE LARGE BODY OF DATA. YOU SUPERIMPOSE THE CLINICAL TRIAL THAT WAS CONDUCTED AND THE ANTI-PA IgG LEVELS FROM THOSE INDIVIDUALS AT -- THIS IS THEIR LAST LEVEL, AND NEXT YOU CAN BEGIN TO PREDICT USING A PROBABILITY MODEL THAT AT THE LAST ANTI-PA IgG, PREDICTED SURVIVAL OF THE FOUR IM DOSES AT 42 MONTHS WAS 86.8%. LOOKS SIMPLE. MY STATISTICIANS REMIND ME IT'S NOT QUITE THIS SIMPLE. YOU WILL SEE A NUMBER OF PAPERS. SO THE VACCINE EFFICACY IS REALLY THE PROBABILITY OF SURVIVAL IN VACCINATED INDIVIDUALS ADJUSTED FOR PROBABILITY OF SURVIVAL IN UNVACCINATED INDIVIDUALS. AND AS THEY REMIND ME, A CORRELATE IS NOT ESTABLISHED FROM A SINGLE STUDY. WE WERE LOOKING AT THE ANTI-PA IgG LEVELS, A SIMILAR ANALYSIS DONE FOR TNN, INDEED WITH ANTHRAX, THE ELISA AND TNA LEVELS CORRELATE VERY WELL. IT DID INCLUDE PASSIVE TRANSFER WORK IN THE RABBIT AND IN THIS CASE A SMALL ANIMAL MODEL. SHOWING THE RELATIONSHIP BETWEEN THE CORRELATE AND SURVIVAL WAS GENERALLY INDEPENDENT OF VACCINE DELUSION AND DOSE STRENGTHED THE CASE FOR USING ELISA AND TNA DATA FOR A CORRELATE. AND IN STATISTICAL METHODS SUCH AS BOOTSTRAPPING ARE NEEDED TO ESTABLISH CONFIDENCE INTERVALS. THE FILOVIRUS ARE MOVING IT'S IMPORTANT TO HAVE A REAGENT REPOSITORY WITH QUALIFIED REAGENTS, USING SIMILAR SOPs AND FORMS, THESE ARE BE PROVIDED. YOU NEED TO HAVE A TRAINING PACKAGE FOR YOUR TECHNICAL STAFF WITH PROFICIENCY TESTING. WE WILL PROVIDE A TECH TRANSFER PACKAGE WITH A PROFICIENCY PANEL AND THIS IS ALSO PART OF THE FANG ASSAY WORKING GROUP. WE'VE ESTABLISHED A SAMPLE TRACKING SYSTEM, THERE WILL BE A BIOASSAY DATABASE. WITH RECORD TO CLINICAL TRIAL ANALYSES YOU NEED A PROCEDURE MANUAL AND PERHAPS TRAINING AT SE SITES, PERFORM THE ANALYSIS TLP, ACCORDING TO A STUDY PROTOCOL. YOU NEED QUALIFIED, ALBEIT THEY HAVE TO BE VALIDATED. A DATABASE AND CERTAINLY SOME TYPE OF DATA TRANSFER AGREEMENT WITH THE DATA MANAGEMENT ORGANIZAION CALLED FOR. I'D LIKE TO ACKNOWLEDGE THE VAST NUMBER OF PEOPLE WHO CONTRIBUTED TO THIS WORK, DR. TOM RUDGE IS HERE, AND OTHERS FOR THEIR GUIDANCE IN WORKING THROUGH THIS. JOHN DYE FROM USAMRIID, AND DR. LUCY WARD, KIM TAYLOR, LARRY WOLFRAM AND ED NUZUM. THANK YOU AND I WOULD BE HAPPY TO ANSWER QUESTIONS. >> THANK YOU FOR THAT. THIS IS HEROIC WORK, I HAVE TO TELL YOU, TO STANDARDIZE THESE ASSAYS. UNFORTUNATELY, WE'RE ABOUT TWO MINUTES LATE ON OUR TIME BUT I HOPE THE AUDIENCE WILL HAVE QUESTIONS TO ASK CAROL THEY PANEL CLOSER TO 2:30 TIME FRAME. IF I COULD ASK JAY HOOPER TO UP, A COLLEAGUE FROM USAMRIID, HE'S GOING TO TALK ABOUT THE NEUTRALIZATION ASSAYS DEVELOPED IN THE VACCINE PRODUCTS. >> THANK YOU FOR INVITING ME. I JUST WANT TO SAY THAT I'M NOT AN EBOLA EXPERT, AND I'M NOT AN ASSAY GUY, THOUGH BEAR WITH ME HERE. BUT I AM -- >> MAYBE SOMETHING WITH SAY -- [LOW AUDIO] >> I'M A BIG FAN OF NEUTRALIZED NANOBODIES, AND ONE OF THE PEOPLE LIKE YOU WHO FOUND THE NEED TO HAVE A MORE HIGH THROUGHPUT COLD SIDE NEUTRALIZATION ASSAY. WE'VE BEEN WORKING ON ONE FOR HUNTA VIRUS, ONE APPEARS TO WORK FOR FILOVIRUS. LIKE SEVERAL PEOPLE HAVE INFORMED US TODAY THAT BASIC IN VITRO NEUTRALIZATION ASSAY ONLY IS REALLY A FEW OF THE STEPS INVOLVED IN THE PROCESS. THEY ARE BASICALLY TARGETING THE GP ASSOCIATED EVENT SUCH AS ATTACHMENT, INTERNALIZATION, PROTEASE CLEAVAGE, FUSION, AND IN SOME ASSAYS THEY CAN ALSO DETECT, REGRESS AND SPREAD, BUT THEY DO NOT DETECT OTHER NEUTRALIZING FUNCTIONS OR ANTIBODY FUNCTIONS THAT ALAN AND OTHERS TALKED ABOUT TODAY. THOSE INCLUDE ADCC, AND SG BINDING. LOOKING THROUGH LITERATURE THERE'S FIVE TYPES OF EBOLA VIRUS NEUTRALIZATION ASSAYS. FIVE CATEGORIES. THE FIRST ONE IS THE CLASSIC PRNT THAT'S BEEN FORMED FOR MANY YEARS, IT INVOLVES AUTHENTIC VIRUS, EVERYBODY UNDERSTANDS WHAT A CLASSIC PRNT IS. NOW, BECAUSE EBOLA CAN BE ENGINEERED, WE CAN DO REVERSE GENETICS, A REPORTER WAS RECOMBINANT EBOLA, ANOTHER FIELD OF VIRUSES MADE THAT INCLUDE REPORTERS SUCH AS GREEN FLUORESCENT PROTEIN. ALTHOUGH THIS IS STILL A BSL 4 ASSAY, IT DOES HAVE ADVANTAGES ASSOCIATED WITH A REPORTER. THROUGHPUT IS HIGHER, IT TO GO TO 96 WELL PLATES, AND YOU CAN FIX THE PLATES, BRING THEM OUT AND DO THE IMAGING OUTSIDE OF BSL 4. THE NEXT TWO TIMES -- TYPES OF ASSAY DON'T INVOLVE EBOLA. THEY INVOLVE THE VIRUS SECONDER, ONE OF THEM INVOLVES ONE OF THE VACCINES WE'VE HEARD A LOT ABOUT TODAY, VSV EXPRESSING EBOLA GLYCOPROTEIN. YOU CAN DO A NEUTRALIZATION TEST WHERE YOU STAIN WITH CRYSTAL VIOLET AND LOOK FOR HOLES IN THE MODEL, THOSE ARE THE PLAQUES, LIKE A CLASSIC PLAQUE ASSAY, YOU ENGINEER IN A REPORTER AND NOW YOU HAVE THE ADVANTAGES OF HAVING A REPORTER IN YOUR VIRUS, AND YOUR BSL 2. THIS FIFTH TYPE OF ASSAYS ARE PSEUDOTYPE, THEY DO NOT HAVE AN EBOLA GLYCOPROTEIN ENGINEERED INTO THE VIRUS. RATHER, IT HAS TO BE SUPPLIED IN I'VE SHOWED IMAGES OF PLASMIDS HERE. THERE'S BASICALLY TWO TYPES OF PSEUDOVIRIONS, RETROVIRAL AND VSD, AND REPORTERS CAN DIFFER, YOU COULD HAVE DIFFERENT REPORTERS, I'LL TALK ABOUT ADVANTAGES AND DISADVANTAGES OF THESE ASSAYS. A S S A Y S IN THE NEXT SLIDES. THE BIG DIFFERENCE BETWEEN THE ASSAYS ARE SOME ARE BSL 4 AND SOME OF THE ARE BSL 2. THE CLASSIC IS HERE. THE OTHER ASSAYS ARE BSL 2, THAT'S THE GOOD NEWS SOME OF THEM BECAUSE THEY ARE NOVEL VIRUSES, VSV WITH A NEW SURFACE GLYCOPROTEIN, THEY ARE REGULATED. THEY ARE INFECTIOUS AND CAN SPREAD. PSEUDOVIRIONS CANNOT SPREAD. OTHER DIFFERENCE IN THE ASSAYS IS THE TIME. THE ASSAY TAKES THE LONGEST IS YOUR CLASSIC PRNT, 9 TO 12 DAYS. WHEN YOU PUT A REPORTER IN YOU CAN SPEED IT UP, YOU DON'T HAVE TO WAIT FOR A FULL PLAQUE TO FORM. SIMILARLY WITH THE VSV, THEY ARE FASTER AND THE EBOLA GFP VSV VIRUS, THAT ASSAY CHAMPIONED BY GERARDO KAPLAN IS VERY FAST. THAT'S LESS THAN TWO DAYS YOU CAN HAVE RESULTS. ANOTHER COLUMN OVER HERE IS BASICALLY ISOLATING THE VIRUS, ENGINEERING THE VIRUS, SO BASICALLY HOW FAST CAN YOU GO FROM A NEW OUTBREAK TO HAVING A VIRUS THAT YOU CAN USE IN AN ASSAY, THE PSEUDOVIRIONS CAN GO FAST BECAUSE YOU'RE SYNTHESIZING A SINGLE PLASMID AFTER YOU KNOW THE SEQUENCE OF THE GLYCOPROTEINS. JUST AGAIN SOME NOTABLE PLUSES AND MINUSES, THE CLASSIC PRNT AND OTHER VIRUSES INVOLVE AUTHENTIC VIRUS, A BIG PLUS, BUT THE MINUS IS THOSE ARE BSL 4, YOUR THE OTHER ASSAYS ARE BSL 2, A NICE PLUS. AND WHEN THEY HAVE REPORTERS, THEY CAN BE HIGHER THROUGHPUT IN . RETROVIRAL PSEUDOVIRIONS, THERE ARE COMMERCIAL COMPANIES THAT ARE PERFORMING WORK SUCH AS IN HIV THAT USE THESE, THAT'S A BIG PLUS. THE LUCIFERASE VSV PSEUDOVIRION SYSTEM HAS AN ADVANTAGE, YOU CAN MAKE NEW VIRUSES VERY FAST. HOWEVER, THE STABILITY AND PRODUCTION OF THOSE TIMES OF PSEUDOVIRIONS IS A DRAWBACK RELATIVE TO THE OTHER LIVE VIRUSES. NOW I WANT TO FOCUS ON ONE OF THESE ASSAYS, AND THIS IS THE VSV DELTA 2 PSEUDOVIRION SYSTEM, WITH LUCIFERASE AS THE REPORTER. YOU HAVE A PLASMA THAT ENCLOSE THE GLYCOPINS, TRANSFECT THAT INTO 293 CELLS, THEN AT THE INDICATED TIME COME IN WITH THE VSV, THAT DOES NOT HAVE THE GENES FOR GLYCOPROTEIN, SO IT CAN ONLY BASICALLY PRODUCE PROGENY VIRUS IF A PLASMID PRIDED THE GLYCOPROTEINS. YOU CAN PURIFY THESE, QUANTIFY THEM, IMMUNOFLUORESCENCE, HOW MANY PARTICLES ARE CAPABLE OF ENTERING A CELL. THEY LOOK LIKE VSV. TO DO THE NEUTRALIZATION ASSAY, IT'S OPERATE EASY -- PRETTY EASY TO DO. ON 96 WELL PLATES WE RUN SERIAL DILUTION IN TRIPLICATE AND COME IN WITH LUCIFERASE AGENT AND READ THAT ON A LUMENOMETER. HERE IS REPRESENTATIVE DATA. I WANT TO SHOW A MONO CLONE, KZ 52 AND HOW WE INTERPOLATE THE TITERS. WE'RE ABLE TO INTERPOLATE THE TITHERS, AND IF YOU CAN GET YOUR IC 50s OR 80s IF YOU KNOW THE CONCENTRATION OF ANTIBODIES. THESE WERE NONHUMAN PRIMATE IgGs, SOME OF THE ANTIBODIES THAT WENT INTO THOSE PASSIVE TRANSFER STUDIES, THE FIRST STUDIES THAT SHOWED THAT ANTIBODY CAN PROTECT A NONHUMAN PRIMATE, AND AGAIN THESE ARE THE TRIPLICATES OF EACH OF THESE DIFFERENT SAMPLES, AND WE ININTERPOLATE THE TITER AND CALCULATE THE GEOMETRIC MEAN. LET'S REALLY SEE IF THIS GIVES US INFORMATION THAT'S USEFUL, WE COLLABORATED WITH LUCY WARD AT NIAID. AND WE WERE COMPLETELY BLINDED TO ALL THESE SAMPLES. WE BASICALLY HAD NONHUMAN PRIMATE I.D. NUMBERS, AND WENT AHEAD AND RAN THOSE AGAINST EBOLA ZAIRE 76. ONCE WE PROVIDED TITHERS TO LUCY SHE UNBLINDED US AS FAR AS THE GROUPING. YOU CAN SEE GROUPS OF TWO ANIMALS AND PROVIDED SURVIVAL DATA WHICH IS SHOWN HERE WITH A POISON SYMBOL. WE ALSO HAVE PSEUDOVIRION 80s AND 50s, YOU CAN SEE HOW THE ANIMALS TRACK TOGETHER IN GROUP, N OF 2, THAT'S IMPRESSIVE. THE OTHER THING YOU START TO SEE IS THE LOW OR NO NEUTRALIZED ANTIBODY RESULTED IN DEATH. SHE THEN PROVIDED A SECOND GROUP OF 16 ANIMALS WHO DID THE SAME THING, AGAIN SHE UNBLINDED US TO GROUP. WE COMBINED THEM, SHE GAVE US THE SURVIVAL DATA WHICH IS SHOWN, SO AGAIN YOU CAN SEE THAT THE ANIMALS WITH THE LOWER TITERS APPEARCCUMB. WE TOOK ALL THAT INFORMATION FROM THOSE 32 ANIMALS AND WE JUST SORTED THEM FROM LOWEST TO HIGHEST TITER, AND THESE RED DOTS ARE THE NONSURVIVORS, AND BLACK ARE THE SURVIVORS. OKAY. SO THIS IS JUST THE TITERS, YOU CAN SEE I THINK WE'RE SEEING A RELATIONSHIP BETWEEN THE NEUTRALIZED ANTIBODY TITERS AND SURVIVAL. AND I'M OUT OF TIME, BUT THIS SLIDE IS JUST TO SHOW WE DID NOT ONLY ONE THESE AGAINST EBOLA ZAIRE 76, WE ALSO RAN THEM AGAINST SUDAN, M-ANGOLA AND M-MUSOKE. YOU CAN SEE WHICH WITH DUAL, MULTI-AGENTS, CONTROLS. AND LAST LID THIS IS JUST SHOWING THAT WITHIN THE ASSAY WE CAN EVEN DETECT VERY SMALL SLIGHT DIFFERENCES BETWEEN ZAIRE 76 AND ZAIRE 95. THERE IS A SIGNIFICANT DIFFERENCE BETWEEN THESE, SO IT HAS SOME FINE RESOLUTION IT CAN PROVIDE. TO SUMMARIZE, THE BSL 2 ASSAYS DO NOT INVOLVE AUTHENTIC VIRUS, DEFINITELY HAVE SIGNIFICANT ADVANTAGES, SAFETY, COST, THROUGHPUT, WE STILL DON'T KNOW THE PRECISE RELATIONSHIP BETWEEN THE BSL 4 USING AUTHENTIC VIRUS AND BSL 2 NEUTRALIZATION ASSAYS. WE ALSO DON'T KNOW THE RELATIONSHIP BETWEEN THESE TITERS AND PROTECTION, ALTHOUGH FROM THOSE TWO STUDIES IT DOES LOOK LIKE THERE IS SOME RELATIONSHIP. I AGREE WITH OTHER PEOPLE WHO SET THE NEUTRALIZING ANTIBODY LEVELS DEPENDS ON HOW THEY ARE MEASURED, ALSO DEPENDS ON WHAT THE VACCINE IS FOR THIS SENTENCE TO REALLY MEAN ANYTHING. AND JUST TO ACKNOWLEDGE THE PEOPLE THAT HAVE DOING ALL THE PSEUDOVIRION WORK RIGHT NOW. LUCY WARD SUPPLIED THOSE NONHUMAN PRIMATE SAMPLES. THOSE WERE KEY. WE GOT THE ORIGINAL CORE LUCIFERASE, PSEUDOVIRION, FROM BOB DOMES AT PENN, AND I'LL END IT THERE. >> THANKS, JAY. WE'RE GOING TO BRING YOU BACK ON THE PANEL AND HAVE MORE DISCUSSION ABOUT NEUTRALIZING ASSAYS THEN. I'D LIKE TO DO A DIFFERENT THING NOW. IN THE NEXT PART OF THIS SESSION WE'RE GOING TO GET THE MANUFACTURER PERSPECTIVE, AND WHAT I'D LIKE TO DO IS HAVE THE MANUFACTURERS COME UP AND REPRESENT US, A PANEL, I'M TALKING ABOUT MIKE FEINBERG FROM MERCK, JAY RAMSAY FROM NEWLINK, WAYNE HOGREFE FROM FOCUS, OZZY BERGER FROM GLAXOSMITHKLINE, AND KIRSTEN LUHN FROM J & J. >> WE'RE GOING TO HAVE OZZY BERGER FROM GLAXOSMITHKLINE GO FIRST. HE HAS SLIDES. I UNDERSTAND THE OTHERS WILL TALK FROM THEIR SEATS. IS THAT OKAY WITH YOU GUYS? GO AHEAD. >> THANK YOU. I'M HONORED TO BE HERE TODAY AND SPEAK ON BEHALF OF GSK AND WORK FROM INDIVIDUALS WITHIN THE ROOM. JUST AS PHIL ASKED ME TO PUT TOGETHER A MANUFACTURERS PERSPECTIVE AROUND CLINICAL ASSAYS, AND SO WE JUST WANTED TO SORT OF PUT A FRAMEWORK AROUND WHAT'S HAPPENING AND SO GIVEN THE EXTREME STUDY CONDITIONS IN WEST AFRICA AS WELL AS THE TIME LINES THAT WE'RE FACING, OUR FOCUS WAS TO KEEP THE CLINICAL PROTOCOLS AS SIMPLE AS POSSIBLE, AND THEN THIS MEANS INTRODUCING LESS ASSAYS, BUT TO MAKE THE ASSAYS THAT WE'RE GOING TO USE AS ROBUST AS POSSIBLE. THERE IS AN OPPORTUNITY TO DO ADDITIONAL TESTING, BUT THIS WOULD BE AFTER PRIMARY RESULTS ARE AVAILABLE. SO GSK DOES PLAN TO CONDUCT TWO PHASE 2 TRIALS IN WEST AFRICA, ONE IN ADULTS, ONE IN PEDIATRIC POPULATION. THIS WILL BE IN COUNTRIES OUTSIDE THE OUTBREAK AREA. PRIMARY ENDPOINT WILL BE SAFETY, SECOND AND TERTIARY ENDPOINTS WILL BE IMMUNO. AS THE SECONDARY ENDPOINT WHICH WE'RE LOOKING AT HERE FOR THE CORRELATIVE -- SORRY, WE'LL BE LOOKING AT THE ZAIRE GP ELISA, AND THIS WILL BE STUDIED IN ABOUT 1500 SUBJECTS FROM THE ADULT STUDY AS WELL AS ALL THE PEDIATRIC. IT WILL BE QUALIFIED, AND WE'LL BE PERFORMING COMPLEMENTARY EVALUATION DURING THE PHASE 2 TRIALS WITH THOSE SAMPLES. FOR THE TERTIARY ENDPOINTS WE'RE LOOKING AT ICS AND THREE CYTOKINES LISTED HERE, A SUBSET FROM BOTH POPULATIONS, ADULT AND PEDIATRIC LOOKING AT BBMCs. WE'RE LOOKING AT THE VECTORS FROM PEDIATRIC AND ADULTS, PRE AND POST VACCINATION, FOR CROSS-REACTIVITY WE'LL LOOK AT THE SUDAN IgG ELISA, THIS IS ONLY IN THE ADULTS, THIS IS MAINLY DUE TO THE LIMITATION ALSO OF BLOOD SAMPLING FROM THE PEDIATRIC POPULATION. AND THEN EXPLORER TO ASSAYS ARE POSSIBLE, THIS WOULD BE SAMPLES TO CHARACTERIZE THE IMMUNE RESPONSE, PART OF THIS BEING INCLUDED IN THE INFORMED CONSENT BASED ON PRIMARY RESULTS AND KNOWLEDGE. >> THANK YOU, OZZY, FOR INTRODUCING THAT AND YOUR PLANS AT GSK. I THINK ALSO YOU CAN TAKE MY CHAIR, OZZY, BUT I THINK WAYNE HOGREFE HAS SOME SLIDES. [LOW AUDIO] OKAY. MAYBE I COULD GET SOME COMMENTS FROM JAY RAMSAY ON PLANS FROM NEWLINK GENETICS THEN. >> SO FROM THE PERSPECTIVE OF NEWLINK, OUR BIGGEST CONCERNS ARE ATTEMPTING TO STANDARDIZE LAB ASSAYS ACROSS MULTIPLE SITES, WE'RE OPERATING SITES IN THE UNITED STATES, CANADA, WE'RE WORKING WITH W.H.O. SITES WHICH ARE LOCATED IN HAMBURG AND KENYA AND GABON. FROM OUR PERSPECTIVE, IT'S VERY NICE TO HAVE LABORATORIES INVOLVED THAT ARE ABLE TO ANALYZE THE SAMPLES BUT OUR BIGGEST CONCERN IS BEING ABLE TO TRANSFER THAT INFORMATION WITH CENTRAL LOCATION. THE ISSUE FOR US IS AT THIS POINT IN TIME WE HAVEN'T FULLY ESTABLISHED THE QUALIFICATON STATE OF EVERY ASSAY, WE HAVEN'T BEEN ABLE TO FULLY ESTABLISH THE QUALIFICATION STATE OF EVERY REAGENT. SO AS WE LOOK FORWARD TO PROGRESSING IN THE CLINICAL DEVELOPMENT OF THE VACCINE, ONE OF THE THINGS WE'RE FOCUSING ON IS BRINGING IN SOME ADDITIONAL RESOURCES TO MAKE CERTAIN THAT WE'RE ABLE TO GET ADEQUATE QUALITY STANDARDS IN PLACE. SO THAT BASICALLY INVOLVES IDENTIFYING REAGENTS FULLY QUALIFIED ON STABILITY, AND CHARACTERIZED, AND SEEING THAT THEY ARE DISTRIBUTED TO ALL SITES PERFORMING THE ASSAYS. IN THE INTERIM, WE'RE ATTEMPTING TO WORK BY DOING EXCHANGE OF REAGENTS, ACROSS SITES, AND EXCHANGE OF SERUM SAMPLES. IN THE FUTURE WE'LL NEED TO GO TO COMMERCIAL VENDORS WHO CAN SUPPLY THESE SERVICES FOR US AND WE'LL HEAR FROM THEM TODAY. BUT THAT'S OUR SINGLE BIGGEST CONCERN. OBVIOUSLY ON TOP OF THAT WE WOULD LIKE TO SEE THAT ALL THE LABORATORIES THAT ARE DOING THE WORK HAVE FULLY ESTABLISHED QUALITY SYSTEMS AND CHANGE CONTROL AND THE LIKE. THE ASSAYS WE'RE MOST INTERESTED IN OF COURSE SORT OF RELATED TO THE VACCINE WE'RE USING, WE FIND OURSELVES SORT OF FOCUSING ON ANTIBODY-BASED ASSAYS, ELISAS, WE'RE LOOKING AT THE PSEUDOVIRION NEUTRALIZATION JUST DISCUSSED, WE'RE ALSO LOOKING FOR THE DEVELOPMENT OF QPCR TO KEEP TRACK OF VACCINE DISTRIBUTION. >> MARK FEINBERG FROM MERCK, MAYBE YOU COULD COMMENT ALSO. >> SURE. WELL, FOLLOWING A DISCUSSION I HAD WITH PHIL KRAUSE, I THOUGHT IT WOULD BE BETTER NOT TO FOCUS ON THE SPECIFIC ASSAYS THEMSELVES BUT REALLY THE SORT OF CHARACTERISTICS OF THE CIRCUMSTANCES IN THE CONTEXT IN WHICH WE HAVE TO THINK ABOUT THIS, AND, YOU KNOW, IN THE COURSE OF TODAY'S DISCUSSION WE HEARD ALL KINDS OF INTERESTING THINGS ABOUT THE PUBLIC HEALTH IMPLICATIONS AND INTERESTING SCIENCE BUT PUTTING ON A MANUFACTURER'S HAT THE QUESTION IS WHAT INFORMATION IS IT GOING TO BE NECESSARY TO GET LICENSURE OF AN INVESTIGATIONAL EBOLA VACCINE, AND SUBSIDIARY QUESTION FOR THIS PANEL WHAT ROLE MIGHT IMMUNE RESPONSE ASSAYS PLACE IN THAT PROCESS, THOSE ARE QUESTIONS THAT PHIL TALKED ABOUT IN HIS OPENING COMMENTS, AND WE DON'T REALLY KNOW, AND HOWEVER COMPLICATED THAT IS THE CONTEXT ISSUE OF THIS BEING SUCH A DYNAMIC SITUATION IS APPARENT TO ALL OF US. IF YOU TAKE THE TRADITIONAL QUESTION AND MODIFY IT, IT'S LIKE WHAT WILL WE KNOW AND WHEN WILL WE KNOW IT, BECAUSE IT'S GOING TO HEAVILY IMPACT WHAT ROLE IMMUNE RESPONSE ASSAYS CAN PLAY IN REGULATORY DECISIONS, AND WE HAVE IN A WAY THIS PECULIAR WINDOW OF OPPORTUNITY BEFORE US WHERE THERE ARE THESE PLANNED EFFICACY TRIALS THAT WILL BE HOPEFULLY INITIATED SOON, AND THAT IS A REAL OPPORTUNITY TO UNDERSTAND THE VACCINES ARE EFFICACIOUS TO POTENTIALLY IDENTIFY CORRELATIVE PROTECTION AND HAVE A DISCUSSION ABOUT WHAT DIFFERENT IMMUNE RESPONSE ASSAYS MEAN. IF WE'RE ABLE TO HAVE THOSE STUDIES GO FORWARD, THEY PROVE TO BE POSSIBLE AND THE INFECTION PERSISTS AT A HIGH LEVEL THAT ALREADY LOGISTICALLY POSSIBLE TO CONDUCT WE MAY GET AN ANSWER TO THOSE QUESTIONS BUT IF WE'RE NOT ABLE TO GET THAT INFORMATION IN THE COMING MONTHS, THEN WE'LL BE BACK TO A DIFFERENT PLACE THAN WE ARE NOW, BUT A DIFFERENT ONE THAT WE'LL HAVE TO THINK ABOUT WHERE WE GO FROM THERE, AND THAT IS WHAT ARE WE GO GO TO DO WHEN WE HAVE ALL THIS INFORMATION BUT DON'T HAVE A CORRELATIVE PROTECTION AND DON'T NECESSARILY KNOW A WHOLE LOT MORE ABOUT THE RELEVANCE OF IMMUNE ASSAYS. I WANT TO TALK ABOUT PARAMETERS. ONE IS THE ATTRIBUTES. WHAT DO WE WANT TO LOOK FOR IN THE ASSAYS? A LOT OF THESE ISSUES HAVE BEEN TALKED ABOUT. WE WANT VALIDATED QUALIFIED ASSAYS, WE'D LIKE TO KNOW COMPARE BUILT OF THE DIFFERENT ASSAYS, YOU KNOW, TO JAY'S POINT, TO APPLY THE SAME AND BEST ASSAYS TO DIFFERENT VACCINES SO WE CAN UNDERSTAND ARE THEY BEHAVING SIMILARLY OR DIFFERENTLY, DO THEY HAVE DIFFERENT MECHANISMS OF PROTECTION POTENTIALLY ALL IMPORTANT QUESTIONS, CLEARLY THE BIOLOGICAL RELEVANCE OF WHAT'S BEING MEASURED MATTERS IN AVOIDING POTENTIAL CONFOUNDERS MATTERS. THE SECOND CATEGORY IS APPLICATIONS, AND THIS IS REALLY TO MY MIND VERY IMPORTANT. YOU USE IT TO DOSE SELECT, BRIDGE TO POPULATION AND AGES AND DEVELOP NEW FORMULATION, FOR CONSISTENCY STUDIES, MANUFACTURING CHANGES, AND IN THIS CASE WE'RE GOING TO BE IN A SOMEWHAT UNUSUAL SITUATION BECAUSE EVERYONE HAS A DESIRE OF A MULTI-VALENT VACCINE BUT WE'LL ONLY GET A MONO-VALENT. CLINICAL TRIALS WILL BE INFORMATIVE IF SUCCESSFUL BUT IF NOT, BASED ON EFFICA, WE'LL HAVE TO TRY TO UNDERSTAND THAT, OR NOT BASED ON LOGISTICS OR EPIDEMIOLOGY THAT'S DIFFERENT. ONE THING THAT NEEDS TO BE CONSIDERED IS ARE WE COLLECTING THE APPROPRIATE SAMPLES SO WE WOULD BE ABLE TO IDENTIFY CORRELATE. IF WE DO THE STUDIES WE HAVE EFFICACY DATA, IT'S POSITIVE BUT WE STILL DON'T HAVE A QUARREL. THAT'S NOT - HAVE A CORRELATE, THAT'S NOT A GOOD SITUATION. THE TIME LINE IS IMPORTANT BECAUSE WE DON'T KNOW WHERE THIS IS GOING TO LAND SIX OR EIGHT MONTHS FROM NOW. WILL WE GET PROVISIONAL APPROVAL? BASED ON ANTIBODY ASSAY, CLEARLY THOSE ARE THE ONLY ONES BEING CLOSE TO BEING READY FOR PRIME TIME IN THE CURRENT CONTEXT. THE CMI AND OTHER ASSAYS ARE IMPORTANT, WE'LL LEARN ABOUT THAT IN THE COURSE, I DON'T THINK THEY ARE GOING TO BE RELEVANT FOR REGULATORY CONTEXT AND WE'LL NEED TO UNDERSTAND HOW TO GET TO THE OPTIMAL VACCINE. THERE ARE A LOT OF INTERESTING BIOLOGICAL QUESTIONS THAT COULD BE ANSWERED BUT THOSE WILL BE FOR ANOTHER DAY AND WE REALLY NEED TO ADDRESS THE QUESTION THAT IT STARTED WITH, WHAT IS THE PATH TO LICENSURE AND ROLE THE IMMUNOLOGIC ASSAYS WILL PLAY IN THAT. >> THANKS, MARK. NOW, MAYBE IF I COULD GET SOME COMMENTS FROM KIRSTEN LUHN FROM J & J. >> I WOULD LIKE TO FOCUS ON THE FEASIBILITY OF T-CELL STUDIES. WE HEARD TODAY THAT LOOKING AT T-CELL RESPONSES IS REALLY IMPORTANT IN VACCINE DEVELOPMENT, SO IN OUR PHASE 1 AND 2 CLINICAL TRIALS WE WILL LOOK AT RESPONSES AND ALSO WE'LL PERFORM ICS, LOOKING AT INTERIM GAMMA ISL 2 OF ALPHA. I WOULD LIKE TO BRING UP AN ADDITIONAL THING, DUE TO EXPEDITED TIME TIME LINES WE HAVE TO THINK ABOUT CORRELATING T-CELL RESPONSES TO OUTCOME OF DISEASE OR INFECTION AND A LOT OF QUESTIONS ARE COMING UP THERE THAT WE NEED ANSWERS FOR. SO ONE QUESTION IS WILL WE BE ABLE TO GET THE RIGHT SAMPLES FROM SUBJECTS TAKING PART IN OUR PHASE 3 TRIALS, SO I THINK WE HAVE TO START TO SPEAK TO PEOPLE IN THE FIELDS TO GET A BETTER GRIP ON WHAT'S GOING ON THERE, AND WHAT IS FEASIBLE. SO WHICH RESOURCES AND INFRASTRUCTURE WILL BE NECESSARY AND HAS TO BE PROVIDED TO BE ABLE TO OBTAIN SAMPLES FROM PHASE 3 SUBJECTS. I GUESS IT MIGHT BE IMPOSSIBLE OR NOT FEASIBLE TO COLLECT PBMCs OF PHASE 3 SUBJECTS AT A QUALITY THAT WE NEED OR THAT WE WOULD LIKE TO HAVE. SO WE HAVE TO START THINKING ABOUT WHAT IS FEASIBLE AND HOW WOULD WE LIKE TO DRAW ANY CORRELATIONS, SO ONE IDEA WOULD BE COULD WE LOOK IN SERUM AND TO LOOK INDIRECTLY AT T-CELL RESPONSES, FINDING CYTOKINE EXPRESSION PROFILES IN SERUM, OR COULD WE DO DNA PROFILING OR GENE-EXPRESSION PROFILING, AND GET AN IDEA ON T-CELL RESPONSES, THAT WE HAVE TO FIND ANSWERS, AND WE HAVE TO DO THAT PRETTY SOON BECAUSE THE TRIALS ARE STOPPING SOON AND WE HAVE TO DESIGN OUR PHASE 2 TRIALS ACCORDINGLY. >> I UNDERSTAND THAT, WAYNE, YOU HAVE SOME SLIDES. YOU'RE ONLY GOING TO HAVE THREE MINUTES. >> THAT'S ALL I NEED. I'LL BE VERY BRIEF SINCE I'M THE ONLY LABORATORY PERSON HERE, MY PERSPECTIVE IS A LITTLE DIFFERENT BECAUSE WE'RE LOOKING AFTER ALL THE WORK YOU'VE STARTED, WE GET INVOLVED. AND JUST A COUPLE BULLET POINTS, WHEN WE'RE LOOKING AT THIS, IT'S REALLY HOW DO WE HANDLE THROUGHPUT, THE LAST BULLET POINTS. THROUGHPUT, QUALIFICATION AND VALIDATION. IT LOOKS LIKE ELISA WILL BE A TOOL USING FOR NOW, NEUTRALIZATION TOOLS, MAYBE PSEUDOVIRION, ON THE ISSUE OF CMI BEING A CENTRAL LABORATORY IT COMES DOWN TO LOGISTICS AND STANDARDIZATION. IF WE'RE COLLECTING FROM MULTIPLE SITES THE ISSUES AND VARIABILITIES INVOLVED, WE DO NOT GET INVOLVED BECAUSE WE DON'T FEEL THE LOGISTICS CAN ALLOW THE CONSISTENCY FROM GETTING FROM SAMPLE TO TESTING FACILITY. WHAT'S UNIQUE IS RIGHT NOW THIS IS -- WE DO A LOT OF VACCINE TRIAL WORK AT FOCUS, THIS IS THE FIRST TIME AND THE ONLY TIME ABOUT STANDARDIZING AN ASSAY ACROSS ALL VACCINES. TOTALLY UNIQUE. SO IT'S A GOOD OPPORTUNITY TO START, MAYBE IT'S NOT THE TOOL HAVE AN OPPORTUNITY TO TAKE, AS CAROL TALKED ABOUT, TAKE IT FROM NHP TO HUMANS, AND STANDARDIZING ACROSS MULTIPLE SITES. THE LAST WORD IF WE'RE LOOKING AT TAKING THESE ASSAYS, FORGET THE DEVELOPMENTS, PRE-WORK THAT'S DONE, IF YOU'RE JUST LOOKING AT THE THREE PHASES, OR TWO OF GETTING IT READY FOR TRIALS, QUALIFYING IT AND VALIDATING IT, JUST TO GIVE YOU AN IDEA, YOU MIGHT ONLY USE 400 DATA POINTS FOR A QUALIFICATION. YOU DO FOUR OR FIVE X NUMBER OF SAMPLES TO GET THERE BUT YOU'RE LOOKING AT YOUR MINIMAL OF INTERASSAY PRECISION. TO GET VALIDATED YOU'LL DOUBLE DATA POINTS BUT TRIPLE THE NUMBER OF LAB ACTIVITY TO GET THERE, YOU HAVE TO DEVELOP ACCEPTANCE CRITERIA AND MAKE THAT AVAILABLE TO THE REGULATORY BODIES. AND JUST TO PUT THAT IN PERSPECTIVE LOOKING AT IV DIAGNOSTIC, FDA CLEARED, YOU'RE LOOKING AT 1500 TO 2000 DATA POINTS. NONE OF THIS ACTIVITY WOULD BE POSSIBLE RIGHT NOW BECAUSE THIS IS -- THE MATERIAL ISN'T AVAILABLE EXCEPT TO COLLABORATIONS WITH USAMRIID AND FOLKS AT BATELLE TO DO THE QUALIFICATIONS AND VALIDATIONS IN THE NEXT FIVE OR SIX WEEKS WHICH ISN'T VERY LONG. WE ALL HAVE A CHALLENGE, THIS INCLUDES TESTING LABORATORIES AS WELL. >> THANK YOU, WAYNE. ACTUALLY, I'D LIKE TO TAKE MAYBE A MINUTE. DOES SOMEONE HAVE FUNDAMENTAL QUESTIONS FOR THE MANUFACTURERS THAT THEY WOULD LIKE TO ASK AT THIS TIME? THIS MIGHT BE THE LAST TIME WE GET THEM ALL TOGETHER HERE AT THIS SESSION. ANYBODY HAVE A FUNDAMENTAL QUESTION? >> THANKS, ALAN. >> I THINK THIS IS FUNDAMENTAL, IT'S APPROPRIATE THAT THE SPONSOR DO THE IMMUNOGENICITY STUDIES ON THE SAMPLES, BUT I'M WONDERING WHETHER YOU'RE SUFFICIENTLY PLANNING FOR SUCCESS OR PARTIAL SUCCESS BANKING ENOUGH SERUMS SO THAT THE MODEL OF WHAT'S BEEN DOING WITH HIV, AGAIN, WHERE YOU HAVE SOME SUCCESS AND THEN A LOT OF -- THE PRIMARY ASSAYS DON'T TELL YOU MUCH BUT YOU KNOW SOMETHING WORD AND YOU NEED TO DISTRIBUTE, COLLABORATE WITH THE WORLD TO MINE WHAT YOU KNOW AND ARE YOU PLANNING FOR THAT KIND OF STAGE 2 EVENT? YOU SAID IT'S TOO HARD TO CRYOPRESERVE T-CELLS BUT YOU CAN AT LEAST DO THAT WITH ANTIBODIES. >> YEAH, WE'LL DEFINITELY DO IT IN PHASE 1 AND PHASE 2, TIME POINTS MOST IMPORTANT IMMUNOLOGY-WISE WE'RE PLANNING TO TAKE LARGER SAMPLE AMOUNTS AND WE WILL PROVIDE POSITIVE SAMPLE MATERIAL. >> YEAH, YOU'RE SORT OF GETTING AT ONE OF THE POINTS I WAS TRYING TO MAKE AS WE THINK ABOUT THE TRIAL DESIGNS, WHICH ARE ACTUALLY BEING THOUGHT ABOUT BY A NUMBER OF DIFFERENT PUBLIC SECTOR PARTNERS, SO IT'S A VERY OPEN AND EVOLVING DIALOGUE BUT ONE OF THE KEY THINGS THAT DOES NEED TO BE CONSIDERED IN THAT DIALOGUE, HOW DO YOU PROVIDE THE IMMUNOLOGIC SUPPORT TO ACTUALLY GET THE MOST INFORMATION OUT OF THE STUDY, BUT YOU'RE TALKING ABOUT DOING THAT IN VERY DIFFICULT CIRCUMSTANCES AND I THINK TRYING TO FIND THE RIGHT BALANCE BETWEEN WHAT'S FEASIBLE AND WHAT WOULD ACTUALLY POSITION YOU TO GET THE GREATEST SCIENTIFIC AND PRACTICAL INSIGHTS IS REALLY THE CHALLENGE THAT WE ALL FACE, AND THAT NEEDS TO GET SORTED OUT VERY SOON. YOU KNOW, I THINK THE R.V.-144 EXAMPLE IS A GOOD ONE, BECAUSE THE IN DEPTH ANALYSIS OF DATA TRANSFORMED A NUMBER OF SKEPTICS, MYSELF INCLUDED, TO THINK THERE IS SOMETHING THERE THAT WE'VE LEARNED FROM THIS, AND WE CAN'T DO THIS UPCOMING STUDIES AND BE AT A POINT AT THE END WHERE WE REALLY DON'T KNOW WHAT HAPPENED. >> IF THERE ARE NOT ANY QUESTIONS, I DISMISS THE MANUFACTURER PANEL AND I APPRECIATE YOUR TIME TODAY TO TALK TO US ABOUT YOUR EFFORTS. >> EXCUSE ME. >> YEAH? >> OH, ONE MORE QUESTION. I'M SORRY, I DIDN'T SEE IT, ED. >> SO ED NEWSOME. THINKING BACK TO ANTHRAX WE HAD THE FAIRLY STRAIGHTFORWARD CORRELATE BUT ALSO A FAIRLY SMALL GOVERNMENT INDUSTRY GROUP WHERE THE GOVERNMENT CONTROLLED THE FUNDS AND ALL THE ACTIVITIES, SO WE CAN HAVE A FAIRLY SMALL WORKING GROUP THAT MEANT -- MET WEEKLY OR MONTHLY FOR SEVERAL YEARS, IT WAS A COLLABORATIVE EFFORT, CDC, FDA, BATELLE, PRODUCT MANUFACTURERS, AND THAT WORKED WELL. THE DIFFERENCE NOW OF COURSE IS THERE'S MANY PLAYERS. SO I GUESS MY QUESTION FOR THE MANUFACTURERS, ARE YOU WILLING TO COLLABORATE, DEVELOP ASSAY WORKING GROUP, MEET ROUTINEY, AND REALLY COMBINE RESOURCES TO ADDRESS ALL THESE QUESTIONS? >> I THINK ONE THING THAT'S REMARKABLE ABOUT THIS RESPONSE IS IT'S A RESPONSE, A COLLECTIVE RESPONSE OF THE SCIENTIFIC AND PUBLIC HEALTH COMMUNITY. I DON'T SEE THERE BEING A DISTINCTION BETWEEN PRIVATE AND PUBLIC SECTOR. MY SENSE IS PEOPLE WANT TO WORK TOGETHER. THE ANSWER IS DEFINITELY, QUESTION. [LOW AUDIO] >> ERIC CAN I -- BEORE YOU DISBAND THE GROUP CAN I ASK ONE QUESTION? FROM FDA. THIS IS MORE OF A COMMENT RATHER THAN A QUESTION, BUT I THINK IT'S REALLY RELEVANT. I THINK THE CONUNDRUM FOR THE PREPARING FOR THE PHASE 3 TRIAL WHERE AT THIS POINT THERE ARE VARIOUS UNCERTAINTIES ABOUT WHETHER THAT TRIAL, NUMBER ONE, IS FEASIBLE, AND NUMBER TWO WILL PROVIDE THE ANSWER TO EFFICACY, AND WE'RE ENTERTAINING THE POSSIBILITY OF BEING ABLE TO DEVELOP A COROLLARY PROTECTION FROM THESE PHASE 3 TRIALS, AND THE CONUNDRUM, AND I THINK, WITHOUT COLLECTING SAMPLES FROM ALL THE PARTICIPANTS SO THAT YOU COULD FIGURE OUT POST HOC THE CONDITIONS THAT DISTINGUISH VACCINES IN WHICH THE VACCINE WORKED WELL, VERSUS THOSE THAT DID NOT WORK, AND COMPARING THAT CONTROL GROUP, WITHOUT THOSE SPECIMENS I THINK IT'S GOING TO BE VERY DIFFICULT TO BE ABLE TO FIGURE OUT, AND YET TO COLLECT SPECIMENS FROM EVERY SINGLE PARTICIPANT IS A TREMENDOUS EFFORT, AND THERE ARE ALSO SOME I THINK DISINCENTIVES FOR DOING THAT FOR ANY PARTICULAR MANUFACTURER, BECAUSE IF WE'RE TALKING ABOUT A PHASE 3 EFFICACY TRIAL, THE ANSWER IS GOING TO BE BASED ON CLINICAL ENDPOINTS, AND SO ALL OF THAT INVESTMENT INTO COLLECTING SPECIMENSMAY NOT BE NECESSARY FOR LICENSURE FOR THAT PARTICULAR VACCINE, SO I THINK WE'RE WORKING AT THESE CONFLICTING DEMAND AND REQUIREMENTS AND I WONDER IN THE CASE OF THIS PARTICULAR DISEASE, EBOLA, WHETHER THERE SHOULDN'T -- THERE SHOULD BE A REAL COLLABORATION BETWEEN THE PUBLIC AND PRIVATE SECTORS AND HOW WE COMPARE THE VACCINES TO INVEST REALLY IN MAKING SURE THAT WE HAVE SPECIMENS THAT WE CAN'T FIGURE OUT WHAT THE COROLLARY PROTECTION IS. >> THAT'S A GOOD IDEA. I THINK WE ALL UNDERSTAND THE CHALLENGES WE FIND BOTH FOR FEASIBILITY AND LOGISTICALLY FOR COLLECTING SAMPLES, I GIVE THAT TO MANUFACTURERS AND SPONSORS IN THE FUTURE. NOW PERHAPS WE CAN DISMISS THE MANUFACTURER PANEL AND NOW I ASK FOR THE SCIENTIFIC PANEL TO JOIN US AND I'M GOING TO TURN CHAIRMANSHIP OVER TO STEVE RUBIN, CAROL SABOURIN, JAY HOOPER, MARK PAGE, MARIA BACA ESTRADA, AND MARCO CAVALERI TO COME UP, SENA WILL LEAD THE DISCUSSIONS FOR THIS. >> MIKE HAS SLIDES TO GO THROUGH. HOW MANY SLIDES DO WE HAVE? [LOW AUDIO] MIKE WILL BE PRESENTING THIS FROM HERE. OKAY. MIKE PAGE IS GOING TO BE GIVING A COUPLE SLIDES ABOUT HIS IDEAS OF HOW HE'S THINKING ABOUT GOING FORWARD WITH SOME OF THE ASSAYS. THANK YOU VERY MUCH. >> I'M FROM NIBSC, A UK INTERNATIONAL INSTITUTE, STANDARDS OF CONTROL, WE'RE A W.H.O. COLLABORATING CENTER MAKING REFERENCE MATERIALS, AND W.H.O., WE'RE WORKING WITH THEM TO PRODUCE THESE REFERENCE MATERIALS, AND WE'VE HEARD TODAY HOW THAT'S VERY IMPORTANT IN TERMS OF INTERPRETING ASSAY DATA AND THE COMPARATABILITY. WE HAVE A TWO-PRONGED ATTACK, A SLIGHTLY DIFFERENT APPROACH TO CAROL'S APPROACH BUT WE'RE MAKING AN ANTIBODY STAND TO BEGIN WITH, UTILITY ACROSS A LARGE RANGE OF ASSAYS, ELISA DIAGNOSTIC ASSAYS, IN-HOUSE KITS. WHAT WE THINK OUR IDEAL VACCINE WILL BE A POOL OF CONVALESCENT SERUM FROM HEALTH CARE WORKERS OR FROM THE FIELD, BUT AS YOU CAN SEE SAFETY CONSIDERATIONS, WE HAVE TO CONSIDER THIS BECAUSE YOU DON'T WANT TO BE PUTTING TOGETHER INTERNATIONAL REFERENCE MATERIALS THAT WE DISTRIBUTE GLOBALLY AND FIND OUT WE'VE GOT EBOLA IN IT, THAT WOULDN'T BE GOOD, I DON'T THINK. SO WE'RE LOOKING AT TREATING PATIENTS AS WELL BECAUSE THOSE TREATED WITH ZMapp MIGHT HAVE SOME -- MIGHT COMPROMISE THE ASSAYS, WE'RE LOOKING FOR SERUM FROM CLINICAL TRIALS AND FROM INFECTED OR IMMUNIZED ANIMALS, AND THIS IS A BIT OF AN INFOMERCIAL, A QUICK INFOMERCIAL FOR YOU ALL TO -- WE'RE LOOKING SOURCES OF THESE MATERIALS, WORKING WITH W.H.O. TO DERIVE CONVALESCENT SERUM AND PLASMA AND WITH VACCINE AND SERUM COMPANIES TO GET VACCINE SERA AND ASKING IF ANYONE WOULD BE PART OF OUR COLLABORATORY STUDIES. AND WE'RE ALSO MAKING PCR STANDARDS USING AGAIN INACTIVATING VIRUS WITH SAFETY IMPLICATIONS, AND ALSO WE'RE USING OTHER METHODS, MORE OF A SYNTHETIC APPROACH TO PACKAGE THE LENTIVIRUS AND FLU REPLICONS. OUR PLAN IS TO COMPILE OUR PANELS OF 10 TO 20 SAMPLES, DISTRIBUTE THEM TO COLLABORATING LABORATORIES, WHO ANALYZE THE DATA, AND WHEN IT GETS RETURNED WE COMPILE THAT AND HAVE A BIG DISCUSSION. MY REQUEST, IF ANYONE HAS SOURCES OF ANTIBODIES OR WOULD BE INTERESTED, AND ANYONE WHO WOULD WISH TO COLLABORATE IN THESE TWO IDENTIFYING, WE'RE ASKING FOR COOPERATION. THANK YOU VERY MUCH. >> THANK YOU, MIKE, FOR SHARING YOUR THOUGHTS WITH US. NICE ADVERTISEMENT. THERE ARE A FEW THINGS I WOULD LIKE TO DISCUSS. ONE OF THEM IS WE'RE ACTUALLY LOOKING AT THE RIGHT -- ARE WE LOOKING AT THE RIGHT PARAMETERS? SERUM AND T-CELLS ARE THE RIGHT PARAMETERS OR NOT? IF T-CELLS ARE THE RIGHT PARAMETERS I'D LIKE TO DISCUSS ARE WE LOOKING AT THE CORRECT CYTOKINES EVEN? JUST CAUSE IT'S TYPICAL TO DO INTERFERON GAMMA, IS THIS CORRECT? DETAIL ABOUT THE ASSAYS, VALIDATION, DO THEY HAVE TO BE VALIDATED? ARE THESE ASSAYS GOING TO BE TLP OR NOT? IF THEY ARE, THEN WHO IS GOING TO STAND UP TO ACTUALLY VALIDATE THESE ASSAYS? AND WHO IS GOING TO BE DOING THEM? AS WE'RE DOING CLINICAL STUDIES, AND CLINICAL SAMPLES THAT ARE ARRIVING, WHAT KIND OF CONDITIONS SHOULD THEY BE KEPT? I THINK THERE ARE A LOT OF ISSUES HERE. I'D LIKE TO HAVE SOME DISCUSSIONS OVER THAT AND THEN MAYBE I'LL COME UP WITH ANOTHER HUNDRED QUESTIONS AFTER THAT. MAYBE LET'S START AT THE TOP TO SEE ARE WE LOOKING AT THE RIGHT PARAMETERS? SERUM AND BLOOD ARE THE CORRECT PLACES? OBVIOUSLY THESE ARE THE ONLY PLACES WE CAN LOOK RIGHT NOW, BUT ARE WE GETTING ALL THE ANSWERS OUT OF THAT? I'LL OPEN IT UP TO THE PANEL AND THEN MAYBE START ASKING THE AUDIENCE TO START ASKING QUESTIONS FROM THE PANEL ALSO. >> ARE WE LOOKING AT THE RIGHT ASSAYS? WELL, WE'RE LOOKING AT WHAT WE HAVE. AND, NO, WE'VE BEEN ABLE TO USE A NONHUMAN PRIMATE STUDIES AND WE'RE TRANSLATING TO THE CLINIC. IMPORTANT. WE'VE SEEN THAT IN OTHER VACCINES. BESIEGE IT IZATION WILL BE THE WAY TO TELL THAT. THE ASSAYS ARE QUALIFIED FOR THE NONHUMAN PRIMATE, QUALIFYING THEM FOR THE HUMAN, BUT ULTIMATELY WE ALL KNOW WE'VE GOT TO VALIDATE THEM. WE DON'T DO GLP STUDIES WITHOUT VALIDATED ASSAYS UNLESS YOU WANT TO CALL IT OUT THAT THAT THEY ARE NOT VALIDATED. YOU HAVE TO HAVE A QUALITY MANAGEMENT SYSTEM, A QA, YOU CAN DECIDE THE LEVEL OF QUALIFY ASSURANCE REVIEW BUT IT'S A GLP STUDY SO YOU WANT IT WELL DOCUMENTED, YOU'RE GOING TO HAVE CONFIDENCE IN THE DATA THAT COMES FROM HAVING IT REVIEWED BY A QUALITY ASSURANCE TEAM. SO, YES, THE ANTIBODY LEVELS ARE SIMPLE. AND THEY CAN BE DONE QUITE EASILY. BUT IT'S NOT BEYOND THE CAPACITY OF THIS GROUP TO DO CELL MEDIATED IMMUNITY ASSAYS. YOU CAN COLLECT PBMCs, SHIP OVERNIGHT AND THEY CAN BE ISOLATED. WE ALL KNOW THEY CAN BE FROZEN. IT MAY NOT BE OPTIMAL BUT AS LONG AS YOU DO STANDARDIZATION, YOU CAN GET THE RESULTS THAT YOU WANT. >> ONE THING I THINK WOULD BE CRITICAL IS TO RECOGNIZE WE OBVIOUSLY DON'T HAVE A LOT OF PROTECTION IN HUMANS AND MIGHT NOT. SOME TRIALS TO BE CONDUCTED, THERE'S INSTANCES IN 7 CASES PER THOUSAND, SO EVEN A VERY LARGE TRIAL, YOU WOULD NEED 2, 3, 4000 PAIRED SERA IF YOU WENT TO LOOK AT ANTIBODY WITH THE HOPE OF IDENTIFYING MAYBE 10 OR 15 CASES OF EBOLA TO BE ABLE TO LOOK AT EFFICACY. I GUESS ONE OF THE QUESTIONS I HAVE WOULD BE COULD WE NONETHELESS USE THESE ASSAYS AND DATA WE'VE GLEANED IN ABSENCE OF A CORRELATE OF PROTECTION. IF THERE WERE ONE, IT'S LIKELY TO VARY BY PLATFORM AS HAS BEEN MENTIONED, ANTIBODIES SEEM TO BE NECESSARY BUT NOT SUFFICIENT FOR THE ADENOPRODUCT. ANTIBODIES ARE NECESSARY AND SUFFICIENT BY THEMSELVES CLEARLY FOR THE VSV, T-CELLS ARE IMPORTANT FOR ONE, MAYBE NOT SO MUCH IMPORTANT FOR THE OTHER. SO I THINK THESE ARE CONSIDERATIONS WE NEED TO DEAL WITH. >> MARCO CAVALERI WOULD EUROPEAN MEDICINE AGENCY. WE HAVE TO START LOOKING FROM THE DATA WE COLLECTED IN MONKEYS AND THAT SHOWED QUITE RELEVANT CORRELATION WITH RESPECT TO PROTECTION, THAT'S THE STARTING POINT. OF COURSE THERE ARE STILL A LOT OF UNKNOWNS, SO I THINK IT'S IMPORTANT AND ON ONE SIDE THAT OUR GOOD EFFORTS LOOKING TO PRIMARY IMMUNOGENICITY ENDPOINT MOVING TO HAVING QUALIFICATION OF THESE ASSAYS AND QUITE IMPORTANTLY TO TRY TO AVOID THE TOO MANY LABS ARE RUNNING THE TESTS WITH DIFFERENT FORMATS, WE NEED TO BE ABLE TO COMPARE THE RESULTS COMING UP AND TRY TO BRING THEM BACK TO WHAT IS SEEN IN MONKEYS AS MUCH AS POSSIBLE. INCLUDE COMPARABILITY EXERCISE IF NEW ASSAYS ARE BROUGHT FORWARD WITH WHAT'S GENERATED SO FAR. THIS IS PARTICULARLY RELEVANT OF COURSE FOR THE ELISA IgG, WHICH IS PRETTY MUCH ESTABLISHED AS IMPORTANT AS TO CARRY FORWARD. ICS IS ALSO QUITE IMPORTANT, AND WE DO RECOGNIZE THE VALUE OF CMI, PARTICULAR FOR ADENOVIRAL VACCINES. WE MAY HAVE CONCERN WITH RESPECT TO THE SENSITIVITY OF SUCH ASSAY WHICH MAY LIMIT SOME HOW ITS VALUED BUT STILL BASED ON WHAT WE'VE SEEN IN MONKEYS WITH THIS VACCINE IT COULD BE EXTREMELY VALUABLE TTRY TO MEASURE THIS THROUGHOUT THE HUMAN STUDIES. I THINK IT'S QUITE IMPORTANT BEHIND THESE KEY IMMUNOGENICITY ASSAYS TO LOOK INTO OTHER EXPLORATORY ASSAYS, CONTRIBUTING IN EVERYBODY WILL WHAT ARE THE KEY PARAMETERS FOR IMMUNOGENICITY. WE TALK ABOUT NEUTRALIZATION ASSAY, EFFORTS HAVE TO BE PUT INTO UNDERSTANDING QUALITY OF ANTIBODIES, LOOKING WITH DIFFERENT KIND OF TESTS BUT THAT SHOULD BE PART OF WHAT HAS TO BE DONE BECAUSE WE NEED TO KNOW WHAT MIGHT CORRELATE WITH PROTECTION. IT WOULD BE GREAT TO HAVE A LARGE SET OF SAMPLES COLLECTED BUT WE HAVE TO BE REALISTI%WE KNOW WHAT CA N BE ACHIEVABLE HERE MIGHT BE QUITE LIMITED AND WE HAVE TO LIVE WITH THE FACT IT MIGHT BE BE DIFFICULT TO COLLECT A LARGE AMOUNT OF SAMPLES FROM THE STUDY. >> MARIA BACA ESTRADA FROM HEALTH CANADA. I WOULD LIKE TO ADD SOMETHING IN TERMS OF HOW TO MOVE FORWARD. AND I THINK WE COULD LOOK BACK AT WHAT HAS WORKED BEFORE, AND I THINK THE CONJUGATE VALUE VACCINE AND CORRELATES OF PROTECTION THERE'S A LOT OF LESSONS TO BE LEARNED, AND I THINK THE INTERNATIONAL COMMUNITY CAME STRONGLY WHEN CORRELATES OF PROTECTION THRESHOLD ARE ESTABLISHED, THE INTERNATIONAL COMMUNITY STARTED WORKING HARD AT ESTABLISHING REAGENTS NEEDED, IT WAS CALIBRATED, THERE WAS AN ELISA PROTOCOL DEVELOPED, TWO LABORATORIES W.H.O. QUALIFIED RUNNING ASSAYS, SO A LOT OF THESE ISSUES THAT WE ARE DISCUSSING TODAY WERE CRITICAL IN SUPPORTING THE FUTURE AND THE OTHER VACCINES THAT WERE LICENSED. SO THERE'S REALLY A LOT OF LESSONS THAT WE CAN MAYBE REFLECT ON, ON HOW THE INTERNATIONAL COMMUNITY CAME TOGETHER. I THINK IT MAY BE WORTH REFLECTING HOW THAT WAS DONE. >> OKAY. MAYBE WE CAN SPEND A FEW MINUTES DISCUSSING THE NEUTRALIZATION AND JAY PRESENTED A DECENT UPDATE ON WHAT HE THINKS THE NEUTRALIZATION ASSAY SUPPORTS LOOK LIKE. I'D LIKE TO HEAR MORE ABOUT IS NEUTRALIZATION PLAYING A ROLE HERE, DO WE BELIEVE THIS IS SOMETHING THAT WE SHOULD BE REALLY CONSIDERING AS ONE OF THE PANELS TO LOOK AT, OR ARE WE GOING TO -- IT'S OBVIOUSLY MORE TIME CONSUMING, COMPLEX THAN JUST RUNNING A SIMPLE ELISA, ARE WE GOING TO MOVE FORWARD WITHOUT THINKING ABOUT NEUTRALIZATION? IS THIS REALLY ARM OF WE SHOULD BE LOOKING AT IN THE CONTEXT OF WHAT IMMUNOGENICITY AND PROTECTION? I'D LIKE JAY TO START A COUPLE SENTENCES AND HE'S ONE OF THE ADVOCATES OBVIOUSLY FOR THIS, BUT THERE ARE OTHER PEOPLE HERE IN THE AUDIENCE, MAYBE KAPLAN, AND MAYBE ALAN MAY SAY A FEW THINGS ALSO, AND THEN WE'LL OPEN IT UP TO OTHER PEOPLE TO DISCUSS IT. I'M REALLY CONCERNED ABOUT CAN WE ACTUALLY VALIDATE THESE TYPE OF ASSAYS OR NOT. STANDARDIZATION IS ONE THING BUT CAN WE VALIDATE THEM, AND IF THEY ARE VALIDATED CAN THEY BE EASILY TRANSFERRED TO OTHER LABS AND ARE THEY SCALABLE? JAY, YOU CAN START SAYING SOME THINGS ABOUT IT. I'M PRETTY SURE CAROL AND OTHER PEOPLE WHO MIGHT BE THE RECIPIENT OF THESE WOULD LIKE TO KNOW AT LEAST A FEW THINGS BEFORE WE ALL CAN CONSIDER THAT ARE THESE ARE THE TYPE OF ASSAYS WE SHOULD CONSIDER IN THE PORTFOLIO. THANK YOU. >> RIGHT NOW THE WAY I SEE THIS ASSAY, IT'S ALMOST LIKE AN ELISA THAT IS SELECTING FOR ANTIBODIES THAT ARE BINDING TO THE KEY REGIONS OF THE PROTEIN AS OPPOSED TO ANY REGIONS, AND SO FOR A VACCINE THAT IS PROTEIN BASED, THE PURIFIED PROTEIN, I CAN IMAGINE A LOT OF ANTIBODIES, TWO EPITOPES THAT ARE IMPORTANT, AND THIS TYPE OF NEUTRALIZATION ASSAY WILL HELP SORT THAT OUT. IT WOULD BE NICE TO HAVE OTHER, YOU KNOW, ASSAYS TO MEASURE ADCC AND THAT KIND OF THING BUT IT'S EVEN HARDER TO IMAGINE GETTING THOSE HIGH THROUGHPUT, SO I DON'T KNOW, WE HAVE A LOT OF MONKEY DATA RIGHT NOW. ALTHOUGH SAMPLES WE RAN, 32 ANIMALS THAT LUCY WARD HAS OR WILL PROVIDE, AND WE KNOW THE SURVIVAL DATA, AND THERE WAS A RANGE, AND THOSE WERE DIFFERENT VACCINES. THAT'S A PRETTY GOOD 32 ANIMALS THAT COULD BE LOOKED AT MORE DEEPLY. >> CAROL, DO YOU WANT TO COMMENT ON THAT A LITTLE BIT? I'M GERARDO KAPLAN. YES, THE ASSAYS IS HIGH, THERE ARE MAJOR DIFFERENCES. THE ONE JAY JUST DESCRIBED IS BASED ON THE LUCY PHRASE AND SINGLE REPLICATIONS PLATFORM SO THEY CAN NOT COME OUT FROM THERE, YOU'RE LIMITING TO A SPECIFIC SCENARIO, THE ONE THAT WE HAVE DEVELOPED IS A REPORTER HAS GSP, MULTIPLE ROUNDS OF REPLICATION. SO I THINK IT'S A BIT DIFFERENT. PROBABLY IT'S A LITTLE BIT FASTER, AND AS WELL THE TRANSFERABILITY OF THESE ASSAYS, WE HAVE STRETCHED IT, HOW THIS CAN BE DONE, SO WE DON'T NEED BASICALLY EXTENSIVE -- IT CAN BE DONE FROM A FROZEN CELL, DIRECTLY FROM A TUBE. >> AT THE END DO THEY GIVE YOU THE SAME ANSWER OR NOT? >> YEAH, I DON'T KNOW. THAT'S A GOOD POINT. WE'RE HAVEN'T COMPARED IT. BUT THEY MAY LOOK INTO DIFFERENT THINGS. BUT LET ME GO A LITTLE MORE OF WHAT -- >> HOLD ON. HAVE YOU LOOKED AT THE 32 SAMPLES THAT JAY HAS, FOR EXAMPLE? >> WE HAVE TESTED THOSE, WE DON'T KNOW THE OUTCOME YET. THE ASSAY HAS NOT BEEN -- THE TRACK HAS NOT BEEN BLINDED FOR US YET. HOWEVER, WE HAVE NOT COMPARED THE SAMPLES, SO WE'RE GOING TO DO -- WE'RE GOING TO DO THAT. BUT THE OTHER POINT I WANT TO -- >> HAVE YOU ONE MINUTE. >> OKAY. TRANSFERABILITY OF THESE ASSAYS, I THINK THAT IT'S VERY IMPORTANT TO LOOK AT TRANSFER TO AFRICA AT THIS POINT, NOT ONLY TO OTHER LABS IN THE U.S., BECAUSE IT'S DIFFICULT TO BRING SAMPLES HERE. IF THIS ASSAY CAN BE TRANSFERRED TO AFRICA, IT WILL BE VERY IMPORTANT TO JUST DEVELOP THE ONES THAT ARE TRANSFERABLE, AND SO THERE'S A TECHNOLOGY GAP HERE, I THINK ONCE WE DEVELOP IT, THERE'S HIGH POTENTIAL. >> WE'LL MOVE TO ALAN. YOU GOT ONE MINUTE ALSO. >> HUH. SO, JAY -- >> QUIT INTERRUPTING ME, SINA. >> TO THE QUESTION OF NEUTRALIZATION MEASURES, SOME ASSAYS ARE ENTRY ONLY, SOME MIGHT BE SPREAD AND MIGHT BE MEASURING SOMEBODY ELSE AS WE'VE SEEN WITH SOME EBOLA MONO CLONES WHERE THEY DON'T REDUCE PLAQUE NUMBER OR REDUCE PLAQUE SIZE BUT NOT PLAQUE NUMBER AND DOES IT INHIBIT SPREAD, YES, IT DOES, THOSE ARE DIFFERENT NEUTRALIZATION. IN TERMS OF ADCC, IT MAY BE DIFFICULT AND INAPPROPRIATE TO RUN AS A PRIMARY ENDPOINT, BUT HIGH THROUGHPUT CAN BE DONE, WE DON'T KNOW WHAT KIND OF ADCC ASSAY WILL CORRELATE. >> DEFINITELY. I'M THINKING ABOUT POINT MUTATION FOR KZ52, IS THAT VIRUS STILL VIABLE? IN OTHER WORDS, IF THAT GLYCOPROTEIN WAS PUT ON A PSEUDOVIRION AND HAD THAT MUTATION AND WE RAN A POLYCLONAL SERA AND IT NEUTRALIZED WOULD IT BE HITTING OTHER EPITOPES THAN THE BASE? >> I THINK THAT ANTIBODY WAS FOUND BY GARY'S LAB IN AN ESCAPE STUDY SO IF IT ESCAPED IT MUST BE VIABLE. >> THAT MEANS IT COULD GET IN, GET A PSEUDOVIRION IN, AND SO IF ANTIBODIES ARE KNOWN TO BIND, THAT'S THE SAME EPITOPE FOUND BY ALMOST EVERY POTENT NEUTRALIZED ANTIBODY IDENTIFIED, IF WE EVALUATE MONKEY SERA HAVE A VACCINEE AND IT HAS THE NEUTRALIZING ACTIVITY THAT DOESN'T CHANGE, WE'RE PSEUDOTYPE BE WITH THAT MUTANT THERE WOULD BE OTHER NEUTRALIZED ANTIBODY, AND IF THEY BIND TO AN AREA THAT YOU GET ADCC YOU COULD DO THE SAME THING AND SO THE PSEUDOVIRION TYPE OF APPROACH YOU COULD MODIFY THE ASSAY TO START LOOKING AT DISSECTING THE NEUTRALIZING ACTIVITY. >> OKAY. PHIL HAS SOMETHING ELSE. >> YEAH, I GUESS WE'VE HEARD A NUMBER OF VERY GOOD RECOMMENDATIONS IN THE AREA OF ASSAYS HERE, ESPECIALLY RELATED TO STANDARDIZATION OF ANTIGENS AND ANTIBODIES, AND WE ALSO HEARD FROM ED, I THINK THE IDEA WHICH I THINK THOSE ON THE PANEL ENDORSE AS WELL, THE MANUFACTURERS PANEL, CRYING TO CREATE A CLINICAL ASSAYS WORKING GROUP. WHAT I'D LIKE TO HEAR FROM THIS PANEL, WHERE DO YOU SEE THE OTHER GAPS? WHAT ELSE NEEDS TO BE DONE TO MAKE SURE WE ARE WHERE WE NEED TO BE WITH ASSAYS? FOR INSTANCE, IF THE STANDARDIZATION EFFORTS GO FORWARD WOULD THEY BE ABLE TO PRODUCE ENOUGH MATERIAL FOR PHASE 3 STUDIES OR ARE THERE OTHER THINGS YOU SEE SOMEBODY SHOULD START WORKING ON RIGHT NOW? >> OUR PLAN IS TO GENERATE 400 FOR THE REFERENCE FOR THIS CURRENT OUTBREAK, WE COULD IDEALLY -- IDEALLY YOU WANT TO MAKE SEVERAL THOUSAND VIALS FOR THE REFERENCE MATERIAL, BUT THAT'S PART OF MY QUESTION, HOW MUCH IS THIS VIRUS GOING TO CHANGE? IF WE MAKE A LARGE REFERENCE PANEL, A LARGE NUMBER OF VIALS FOR REFERENCE STANDARD NOW, IN THE NEXT OUTBREAK WILL THAT BE RELEVANT? >> I GUESS I WOULD COMMENT IT ALL STARTS WITH HAVING A CONTROLLED ASSAY, WITH A REFERENCE STANDARD, QCs AND NEGATIVE CONTROL AND CONTINUING TO QUALIFY NEW REAGENTS IN. CONCERTED EFFORT, THAT'S GOING TO BE, YOU KNOW, INVOLVING A LARGE NUMBER OF PEOPLE, BUT YOU HAVE TO START SOMEWHERE. WE'RE READY. WE'VE ALREADY STARTED. SO YOU CONTINUE TO QUALIFY IN, IT'S BEEN DONE FOR OTHER VACCINES, IT CAN BE DONE FOR THESE VACCINES TOO. >> MARIA? >> I'D LIKE TO ADD TO THE QUESTION OF CONSENSUS ON WHAT REAGENTS AND THE SOURCE OF THE REAGENT, IS IT GOING TO BE IMMUNIZED INDIVIDUALS, THERE'S A LOT OF IMPORTANT ASPECTS FROM THE ASSAYS, ESPECIALLY IN THE LIGHT OF IF THAT IS GOING TO GO FORWARD THAT BEFORE SOMEBODY RUNS AHEAD MAYBE THERE'S A NEED FOR A CONSENSUS, WHAT IS IT WE NEED, WHAT KIND OF CODING ANTIBODIES, WHAT IS RELEVANT, THINGS AT THE END WILL IMPACT TREMENDOUSLY THE -- >> SO MY THOUGHTS ARE THAT THE CONVALESCENT SERUM PLASMA, WHAT YOU GET FROM THE CONVALESCENT T-CELLS, WOULD BE PROBABLY DIFFERENT THAN WHAT YOU WANT TO BE VACCINATING SO YOU'RE LOOKING AT THE CORRELATES OF PROTECTION OF VACCINE. MY THOUGHTS ARE THAT EACH OWN CORRELATES OF PROTECTION ALSO. >> WE SHOULD NOT GET CONFUSED BETWEEN WHAT A CORRELATE IS FOR A PARTICULAR VACCINE AND REAGENT UNIQUE TO VALID AND STANDARDIZE AN ASSAY WHICH MAY IN THE CASE I BROUGHT UP, THE ISSUE OF PNEUMOCOCCAL CONJUGATE, WE HAVE LESSONS THERE, THE SERA USED TO QUANTIFY THE IMMUNE RESPONSE WAS FROM ADULTS THAT WERE IMMUNIZED WITH A COMPLETELY DIFFERENT VACCINE, BECAUSE THE IDEA OF THAT SERUM IS TO QUANTIFY THE IMMUNOGLOBULIN IN THE SAMPLE, NOT TO BE A CORRELATE OF PROTECTION, IT'S NOT CORRELATED. >> YEAH, YOU'RE REALLY LOOKING FOR A GOLD STANDARD IN THIS CASE THAT EVERYBODY CAN USE? >> I THINK YOU NEED TO HAVE CONSENSUS, WHAT ARE THESE ELEMENTS GOING TO BE, BECAUSE THE ASSAY IS GOING TO -- IF YOU CHANGE THE CODING ANTIBODY --œ >> HOLD ON. I'D LIKE TO GO TO THE AUDIENCE AND WE'LL COME BACK. >> WHEN THE INTERNATIONAL CONSORTIUM WAS FORMED BETWEEN 140 LABORATORIES, DIRECTED BY THE SEATTLE STATISTICS GROUP, THE FIRST THING THEY DID TO ELIMINATE ASSAYS AND ELIMINATE REDUNDANCY BECAUSE THEY HAVE TO GET IT DOWN TO FOUR OR FIVE OR THERE WOULD BE TOO MUCH CORRECTION, THEY ELIMINATED THOSE THAT MEASURED THE SAME THING. THAT'S THE FIRST KEY TO FINDING A CORRELATE. SO IF ALL THE NEUTRALIZATION ASSAYS ARE MEASURING THE SAME THING, YOU ONLY NEED ONE. THE FIRST THING I RECOMMEND IS YOU SEE WHICH NEUTRALIZATION ASSAYS MEASURE SOMETHING DIFFERENT AND INCLUDE ELISA IN THAT. IF THEY DON'T MEASURE SOMETHING DIFFERENT FROM ELISA, YOU DON'T NEED ANY OF THEM. I DON'T KNOW THE ANSWER BUT I'VE HEARD REPEATEDLY WHEN ASKED HOW DOES THIS COMPARE TO THIS, THE ANSWER IS I DON'T KNOW. WELL, THAT'S THE ONLY WAY WE -- WHY BOTHER VALIDATING ASSAYS THAT ARE MEASURING THE SAME THING? IT'S A LOT OF WORK TO DO THAT. AND I AGREE WITH WHAT YOU SAID. MAYBE YOU'RE JUST -- THE ELISA MAY NOT BE DIFFERENT FROM NEUTRALIZATION OR THAT MAY MEASURE SOMETHING DIFFERENT. ELISA DID NOT CORRELATE AT ALL, FOR PEOPLE'S INFORMATION. >> ONE OF THE PRACTICAL QUESTIONS THAT I THINK THE PEOPLE WHO ARE DESIGNING THE VACCINE TRIALS NEED TO -- NEED SOME HELP ON, I'M SPEAKING NOW SPECIFICALLY FOR THE PHASE 3 TRIALS, WHERE SAMPLES WILL BE TAKEN FROM PEOPLE WHO ARE POTENTIALLY INFECTED, THERE'S NO VALIDATED DECONTAMINATION PROCESS THAT THE CDC CAN SAY ABSOLUTELY RENDERS THE SERUM SAMPLE SAFE AND GIVEN THE HIGH THROUGHPUT NATURE, THESE WILL END UP IN COMMERCIAL LABORATORIES PRIMARILY FOR HIGH THROUGHPUT SCREENING, SOME GUIDANCE ON HOW TO HANDLE AND RENDER THESE SAMPLES AS SAFE AS POSSIBLE IS ABSOLUTELY NEEDED, IT'S NOT AVAILABLE TODAY. >> THAT'S REALLY A CDC AREA THEY NEED TO COME UP WITH SOME SORT OF HELP THERE FDA. >> I WANT TO COME BACK. >> YEAH, I'M CONCERNED ABOUT THE PROTEINS USED IN THE LABS. MAYBE CAROL CAN FURTHER ELABORATE BUT WHAT I KNOW IS WHEN YOU PUT A TRIMERIC PROTEIN INTO PLASTIC, THEY DEFORM. SO WE -- YOU KNOW, HE THINK THAT'S ANOTHER CONCERN WE NEED TO GET TO. WHAT WE'RE MEASURING WITH ANTIBODIES, IF WE'RE USING MONOMERIC, YOU'RE NOT MEASURING SOMETHING SEEN IN THE NATURE. >> COMING BACK IN HERE -- GO AHEAD PLEASE. >> BUT GERARDO, I THINK WHAT THE DATA FROM THE MONKEY STUDIES SHOW, ACROSS THE BOARD, MAYBE GENERALIZATION, THE ELISA DATA DOES PROVIDE YOU WITH SOMETHING MEANINGFUL. IT SEEMS CONSISTENTLY TO PREDICT SOMETHING ABOUT PROTECTION, WHEREAS SOME OF THE OTHER ASSAYS IT'S MORIVEY. MONOCLONAL ANTIBODIES ARE NOT NEUTRALIZING YET PROTECTIVE AND VICE VERSA, WHATEVER IS HAPPENING IN THE ELISA PLATE YOU'RE PROBABLY CORRECT BUT IT IS MEASURING SOMETHING MEANINGFUL. MAYBE IF WE COULD LEAVE HERE WITH THE CONSENSUS AS TO WHAT TYPE OF ASSAY WE NEED TO GO FORWARD WITH PHASE 3, SOMETHING PRACTICAL, I LIKE THE IDEA OF ALL THE OTHER ASSAYS FOR TERTIARY INVESTIGATION. WE SHOULD LOOK AT EVERYTHING. WE DON'T KNOW WHAT WILL BE A CORRELATE IF WE HAVE THAT OPPORTUNITY. AT SOME POINT WE NEED TO MOVE FORWARD, THAT'S SOMETHING WE CAN AGREE ON, THAT WILL PROVIDE US WITH SOMETHING WE THINK IS MEANINGFUL. >> THE DATA WITH ASSAYS ARE COMPLETELY DIFFERENT. ONE IS MEASURING ORANGES AND APPLES, SO YOU CANNOT DO A COHERENT INTERPRETATION. MY POINT IS THAT REALLY WE ARE LOOKING FOR A CORRELATE OF IMMUNITY, IF YOU'RE USING THE FLAT PROTEIN, IT'S NOT RELEVANT IN NATURE, WE WOULD NEVER GET THAT CORRELATE.>> SO WE NEED TO -- OKAY, O NE LAST 30-SECOND QUESTION. >> IT'S A GOOD CRITIQUE, AND DOESN'T THE PSEUDOVIRUS ASSAY ANSWER THAT? SO YOU HAVE THE PRIMARY GP IN ITS NATIVE STATE ON THE SURFACE OF THE PSEUDOVIRION. >> MAYBE. THAT PROBABLY WOULD BE THE ANSWER, YOU KNOW, BUT I'M NOT SURE JAY CAN ANSWER THAT. I HASN'T DONE CRYSTALLOGRAPHY. >> VIRIONS AND ELISA ANTIGEN, ARE BASICALLY VLPs. >> YOU ASKED ABOUT REAGENTS. >> LET ME GO BACK TO NEUTRALIZATION AND WE'LL STOP. EACH ONE OF THE NEUTRALIZATION ASSAYS ARE MEASURING DIFFERENT THINGS, AND THAT NEEDS TO BE DISSECTED CAREFULLY BECAUSE ONE OF THOSE ITEMS MIGHT BE ACTUALLY DIRECTLY CORRELATING TO THE -- AS TO CORRELATIVE IMMUNITY. OBVIOUSLY ELISA IS CRITICAL, IT'S BEEN SHOWN OVER AND OVER, OVERABUNDANCE OF ANTIBODY IN THE CORRECT FORMAT, EVERYTHING ELSE GIVEN, IT DOES PROTECT FOR THE HIGH END AND WE KNOW THE LOW END ALSO. THE MIDDLE IS A PROBLEM. WE HAVE SOME GRAY AREA. I DON'T THINK ANYBODY WILL STAND UP IN HERE AND SAY I KNOW THIS ANIMAL WILL SURVIVE FOR SURE, I'VE DONE IT AND I'VE FAILED AT IT. AND I'M PRETTY SURE OTHER PEOPLE HAVE DONE IT AND IT MAY NOT STAND HERE AND TELL YOU THAT BUT IT'S VERY, VERY DIFFICULT IN THE MIDDLE, WHEN YOU HAVE TEN TO THE THIRD, TEN TO THE FOURTH ANTIBODY TITER BASICALLY, IT'S DIFFICULT TO SAY IF THE ANIMAL WILL MAKE THE. TEN TO THE FOURTH, THEY ARE PROBABLY GOING TO MAKE IT BUT IN THE MIDDLE IS A PROBLEM. AND I'D LIKE TO STOP AT THIS AND AT THIS POINT THANK THE PANEL FOR ATTENDING HERE AND SPENDING THEIR TIME IN HERE. AND THANK YOU ALL FOR ASKING INSIGHTFUL QUESTIONS. [APPLAUSE] >> THANKS TO THE AUDIENCE AND THE PANEL MEMBERS. WE'RE GOING TO FORM BACK HERE AT 3:30. 3:30 FOR THE FINAL LOOK FORWARD. >> WE'RE GOING TO TALK ABOUT IMMUNOGENICITY STUDIES FROM PHASE 1 TRIALS, THE CONTEXT FOR THE PANEL IS TO LISTEN TO THE IMMUNODATA AND THINK ABOUT HOW IT'S GOING TO INFORM DOSE SELECTION, HOW IT'S GOING TO HELP TO GUIDE THE DESIGN OF CLINICAL ENDPOINT TRIALS THAT WILL BE DONE AND STIMULATE DISCUSSION ABOUT IMMUNOLOGIC PROFILING OF NATURAL INFECTIONS AS WELL AS VACCINE IMMUNOGENICITY. OUR FIRST SPEAKER TODAY IS GOING TO BE DR. GRAHAM TO TALK ABOUT CHIMP AD 3 VECTORED VACCINE. >> I'M NOT JULIE. THIS IS JULIE. THIS IS LAUREN, THE STUDY COORDINATOR, WHO HELPED. WE'LL DISCUSS OUR FIRST VOLUNTEER AND YOU MET NANCY EARLIER. YOU ALSO HEARD EARLIER THAT THE CHAMP AD 3 IS A RARE ADENOVECTOR SIMILAR TO AD 5, I'M GOING TO BRIEFLY TELL YOU HOW WE SELECTED VECTOR AND INSERTS OVER THE LAST 10 YEARS TO GET TO THIS INITIAL TRIAL. THE AD VECTOR WAS DEVELOPED BY OKIORS, CONSTRUCTION SHOWN HERE, FULL LENGTH WILD-TYPE GLYCOPROTEIN. IN THE E 1 REGION, REPLACES THE E 1 GENE, THE ADENOVECTOR. IT HAS THE DELETION IN THE SUDAN, NOT ZAIRE. THIS IS FROM THE EBOLA OUTBREAK IN 1976. IN THE CHALLENGE VIRUS THAT HAS BEEN USED, AND THESE ARE THE ISLETS FROM GUINEA, HIGHLY RELATED VIRUSES, AND WAS SAID EARLIER BY ERICA, ALMOST ALL THE MUTATIONS SHOWN HERE IN RED LINES IN THE PROTEIN STRUCTURE FOR THE GP ARE IN THIS MUCIN DOMAIN, A COUPLE IN GLYCANE CAP, NONE ARE IN THIS SITE AREA THAT'S IN THE MIDDLE OF THIS CHALICE, AND SO WE THINK THAT THE ANTIGEN IN THE VACCINE NOW IS A GOOD REPRESON FOR THE GP THAT'S IN THE OUTBREAK STRAIN. AS WAS NOTED EARLIER BY NANCY, THIS HAS BEEN A SERIES OF STUDIES TO GET HERE, STARTING WITH DIFFERENT GENE-BASED DELIVERY APPROACHES, DNA, AND THEN AD 5 AND DNA, AND DIFFERENT ANTIGEN CONSTRUCTS, FIRST DELTA TM, POINT MUTATION, THAT REDUCED PATHOGENICITY, AND NOW FULL LENGTH GP TESTED IN THE DNA A FEW YEARS AGO. THIS STUDY VRC 207 STUDY EVALUATED CHIMP AD 3, FULL LENGTH EBOLA ZAIRE AND SUDAN. TWO TIMES 10 DO THE 11th IS A PHASE 1 STUDY, ESCALATION WITH 10 SUBJECTS IN EACH GROUP. THOSE ARE OBJECTIVES. THERE WAS NO SERIOUS ADVERSE EVENTS TO REPORT, TWO SUBJECTS IN THE HIGH DOSE GROUP HAD FEVER, FEVER FROM AD VECTOR INDUCED FEVER ALWAYS HAPPENS IN 8-12 HOURS POST-INJECTION, RESOLVED IN 24 HOURS, ANYTIME A VECTOR IS INDUCING FEVER IN SETTING OF EBOLA OUTBREAK IT'S GOING TO BE COMPLICATED. AND THEN THERE'S ACTIVATED PTT ASSAY, WE CAN TALK ABOUT THAT LATER, AN ARTIFACT OF INFUSING ANTI-PHOSPHYLIPIDS, IT'S NOT A COAGULATION PROBLEM. ANTIBODY RESPONSES HAVE BEEN PUBLISHED NOW SO MANY OF YOU HAVE SEEN THOSE, AND BASICALLY THE RESULT WAS USING THE GP ELISA DR. SULLIVAN MENTIONED EARLIER THAT'S USED IN THE NONHUMAN PRIMATE STUDIES, AGAINST ZAIRE, SUDAN OR GUINEA STRAINS, YOU CAN SHOW THIS IS THE LOWER DOSE GROUP, THIS IS HIGHER DOSE GROUP. THERE'S A DOSE EFFECT, PEAK RESPONSE NOT TWO WEEKS, MAYBE AT FOUR WEEKS TO SIX WEEKS, AND SO BASICALLY WHAT YOU SEE IS A DOSE EFFECT AND NOW YOU'RE INDUCING RESPONSES IN THE 2000 OR SO RANGE MEDIAN, AT THE HIGH DOSE GROUP AT WEEK FOUR, WHICH IS VERY COMPARABLE TO WHAT YOU SEE IN THE NONHUMAN PRIMATES, IMMUNIZED WITH 10 TO THE 10th. AND SO THERE IS ABOUT A LOG DIFFERENCE IN POTENCY IN A HUMAN COMPARED TO A NONHUMAN PRIMATE SO KEEP THAT IN MIND. THESE ARE THE T-CELL RESPONSES, MEASURED BY ICS, AND THE N VITAL FACILITY, TEASE ARE CD4 RESPONSES ON TOP, THE FIRST SET ARE THE LOW DOSE, SECOND SET ARE THE HIGH DOSE. ZAIRE ON THE LEFT, SUDAN ON THE RIGHT. THESE ARE THE MAGNITUDE OF CD4 RESPONSE AND CD8 RESPONSES, CELLS MAKING CYTOKINES EITHER IL 2, TNF OR INTERFERON GAMMA. BECAUSE THIS IS DONE BY MULTI-PARAMETER FLOW YOU CAN LOOK AT THE SAME KINDS OF CYTOKINE EXPRESSION COMBINATIONS THAT DR. SULLIVAN MENTIONEDDER. AT THE LOW DOSE AND HIGHER DOSE YOU INDUCED CD8 T-CELL RESPONSE WITH VERY MUCH THE SAME PROFILE AS YOU SEE IN THE NONHUMAN PRIMATES, THIS IS CONSISTENT WITH BOTH THE MAGNITUDE OF RESPONSE HERE AND THE QUALITY OF RESPONSE DR. SULLIVAN IS DESCRIBING, ESPECIALLY IN TERMS OF THIS. THESE ARE STUDIES IN BETHESDA, EMORY, AND FOUR OTHER COUNTRIES, ALTHOUGH UGANDA HAS NOT YET STARTED THE STUDIES, IN THE U.K. THAT YOU'LL HEAR MORE ABOUT, AND LUZAN, 120 PEOPLE IN QUICK O RDER, AND MALI ENROLLED 81 PEOPLE. AFTER THE PHASE 1 STUDIES, WE'LL HAVE THE SAFETY AND IMMUNOGENICITY PROFILES IN MONO THERE'S VALUENT ZAIRE AND THE BIVALENT ZAIRE, AT THESE DOSE LEVELS, FREQUENCY OF ANTIBODY RESPONSE WHICH WILL HELP MAKE A DOSE SELECTION FOR THE ADVANCE STUDIES, YOU'LL KNOW THE DIFFERENCE IN MAGNITUDE OF RESPONSE AND FREQUENCY OF RESPONSE IN WESTERN COHORT AND AN AFRICAN COHORT, EVEN THE WEST AFRICAN COHORT IN MALI, AND THEN WE'LL ALSO KNOW IMMUNOGENICITY OF BOOSTING DNA PRIMED SUBJECTS IN BETHESDA OR UGANDA WHERE STUDIES WERE DONE WITH THE SAME INSERTS. MVA DOES BOOST, AS YOU SAW DID DR. SULLIVAN, THE RESPONSE TO CHIMP AD 3 PRIMING, THEY WILL BE MONOVALENT OR TRIVALENT BOOSTS THAT WILL BE AVAILABLE, YOU'LL SEE SOME DATA MAYBE EVEN FROM ADRIAN TODAY, SO THAT'S A SECONDARY SET OF DATA THAT WILL BE COMING OUT OVER THE NEXT SEVERAL MONTHS. THEN YOU'VE HEARD THERE'S GOING TO BE PHASE 2 TESTING IN NIGERIA, CAMEROON, GABON AND MALI, PEDIATRIC HOPEFULLY IN A MONTH. WE'LL STOP THERE. >> WE'LL SAVE QUESTIONS FOR THE END. SO DR. HILL. >> THANK YOU VERY MUCH FOR THE INVITATION. IT'S GOOD TO BE AT THIS EXCELLENT MEETING. THIS FOLLOWS FROM WHAT BARNEY NG YOU ABOUT. THIS IS THE STUDY WE'VE BEEN DOING AT OXFORD OVER THE LAST FEW MONTHS WITH THE SAME CHIMP ADENOVECTOR, BUT AS A MONO VALENT FORMULATION WITH THE ZAIRE INSERT BOOSING WITH MVA. YOU'VE HEARD ABOUT THE OVERALL PROGRAM, WE'RE USING MONO VALENT ZAIRE STRAIN, VECTOR PREVIOUSLY USED FOR HEPATITIS C, IT'S IN A PHASE 2B EFFICACY TRIAL HERE IN THE UNITED STATES FOLLOWING PHASE 1 TRIALS IN THE U.K. AND THE PROGRAM THAT WAS PUT TOGETHER BACK IN SEPTEMBER HAS BEEN LARGELY DESCRIBED TO YOU, WE WERE TO VACCINATE ABOUT 60 PEOPLE IN OXFORD, I BELIEVE MIKE LEVINE VACCINATED 91 IN MALI, 100 IN LAUSANNE, AND 20 NOT FAR FROM HERE TO GENERATE SAFETY DATA IN OVER 250 PEOPLE WITH MONOVALUENT FORMULATION WE HOPE TO USE NEXT MONTH AND GET IMMUNOGENICITY COMPARABLE TO PROTECTED MACAQUES, NANCY SULLIVAN DESCRIBED THIS MORNING, COULD WE ACHIEVE IN HUMANS WHICH WOULD INCREASE CONFIDENCE THE VACCINE WOULD WORK IN THE PHASE 3 3 TRIAL. WE STARTED IN SEPTEMBER. WE HAD THREE DOSE GROUPS. THIS WAS NOT REALLY A SAFETY DOSE ESCALATION. WE HAD A GOOD IDEA WHAT A SENSIBLE DOSE WAS AND FIVE TIMES 10 TO THE 10 HAS ALWAYS BEEN SAFE. WE WERE ACTUALLY DOSE DEESCALATING, AND IMPORTANTLY WE HAD TO SHOW SAFETY DATA AS QUICKLY AS POSSIBLE SO THAT THE TEAM IN MALI COULD GET GOING IMMUNIZING THERE. WE SENT A GRANT APPLICATION 14 AUGUST, WE HAD REGULATORY APPROVAL FOUR DAYS AFTER WE SUBMITTED TO THE MHRA IN LONDON. THE BRC RAPIDLY FILLED THE MONOVALENT FORMULATION AROUND WE STARTED IN SEPTEMBER, IN THE LAST COUPLE WEEKS WE STARTED BOOSTING WITH MDA, THE PLAN TO BOOST HALF, 30 OF EACH, AND NOT BOOST HALF. THESE ARE OUR DATA WITH A DIFFERENT ASSAY. THIS IS A SIMPLE COMMERCIAL KIT FROM ALPHA DIAGNOSTICS INTERNATIONAL THAT WE BUY, RUN THIS ELISA IN HOUSE, AND WE'VE BEEN ABLE TO VALIDATE IT TO SOME EXTENT OR CORRELATE IT WITH THE ASSAY THAT NANCY SULLIVAN'S LAB DOES AT NIH AND THE R VALUE WAS VERY GOOD AND VERY REASSURING, WE'LL BE DOING MORE SAMPLES, BUT THAT ALLOWS US TO TAKE THE OD VALUE IN THE ADI ASSAY AND ESTIMATE WHAT THAT WOULD BE ON THE ASSAY DONE HERE AT THE VRC IN THE U.S. AND YOU CAN SEE THAT AT THE DOSE LEVELS WE USE, GROUP 1, 2 AND 3, MOST PEOPLE RESPOND, 93% RESPONSE RATE, HIGHER AT DAY 28 THAN DAY 24, NOT A SIGNIFICANT DIFFERENCE IN GEOMETRIC MEAN TITERS BETWEEN THE THREE GROUPS BUT BETWEEN HIGH 200s, 360 FOR THE HIGH DOSE GROUP. THAT'S FAIRLY SIMILAR TO WHAT BARNEY'S SHOWN YOU FOR HIS TWO TIMES 10 TO THE 10 GROUP. WE DIDN'T HAVE A 1 TIMES 10 TO THE 11, THAT'S BEING LOOKED AT IN TWO OTHER TRIALS. THE POINT IS THIS IS ABOUT A LOG BELOW THE 3500 OR 3700 THAT CORRELATES WITH HIGH LEVEL EFFICACY IN MACAQUE MONKEYS SO WE FEEL WE'RE A LOG DOWN ON WE WOULD LIKE TO BE. T CRIMINAL IMMUNOGENICITY WAS DONE ON FRESH CELLS BY FLOW CYTOMETRY, THE LE SPOTS, THE GROUP 3 HIGH DOSE GROUP GAVE A PEAK RESPONSE AT 14 DAYS, AS OTHER GROUPS DID. THAT DROPPED LOWER AT 28 DAYS. IN THE TOP DOSE GROUP ESSENTIALLY EVERYBODY RESPONDED WITH FAIRLY GOOD RESPONSES AS YOU CAN SEE HERE, 600 AND SOMETHING ON AVERAGE. VERY SIMILAR PROFILES BY FLOW CYTOMETRY ON THE POLY FUNCTIONALITY, NICE PERCENTAGE, WHICH NANCY MENTIONED MIGHT BE A CORRELATE OF PROTECTION AND I SHARE HER VIEWS THE T-CELLS ARE PRETTY IMPORTANT WITH THIS VACCINE. WHAT WAS DISPOINTING WHEN THE CD8 MEASURED BY FLOW CYTOMETRY THE RESPONSE RATE WAS 60%, AND THE MEAN WAS 0.07% OF CD8, WHEREAS IN MACAQUES THAT ARE PROTECTED IT'S .4, SO MAYBE WE'RE FIVE FOLD DOWN ON WHERE WE WOULD LIKE TO BE AT LEAST AT DAY 28. WHAT CAN WE DO IF WE'RE 10 FOLD DOWN ON THE T-CELLS? WE'VE BEEN WORKING ON THIS, BEING USED SAFELY IN OVER 100 CLINICAL TRIALS FOR A WHOLE VARIETY OF DISEASES, SAFELY. SO WE WERE FAIRLY CONFIDENT THAT GIVEN THE BOOSTING RECORD OF THIS VECTOR WE MIGHT BE ABLE TO INCREASE THE T-CELLS AND ANTIBODIES IN HUMANS, WE'VE DONE A LOT OF WORK WITH OKAIROS, SINCE 2003, 2004 AND WORKED ON THIS REGIME WITH THEM. THIS IS THE 30th CLINICAL TRIAL OF CHAD-MVA PRIME BOOST, SEVEN IN AFRICA IN OVER 600 PEOPLE, ADULTS, CHILDREN AND INFANTS, AND THE SAFETY PROFILE IS VERY REASSURING AND VERY IMPORTANT IF YOU'RE GOING TO TAKE RELATIVELY NEW VECTORS INTO A PHASE 3 TRIAL IN TERMS OF THOUSANDS OF PEOPLE NEXT MONTH. THIS IS A TYPICAL PROFILE IN HEPATITIS 3 WITH A CHAD3 VECTOR SHOWING CHAD-MVA IS MORE IMMUNOGENIC, YOU GET A HIGHER PLATEAU SHOWN WITH COMPARISON, SOMETHING WE'VE SEEN IN MALARIA A LOT COMPARING DIFFERENT VECTORS, CHAD WAS IMMUNOGENIC, CHAD MVA GAVE A FOUR-FOLD INCREASE ACROSS A RANGE OF TRIALS IN T-CELL RESPONSE. MVA BOOSTS ANTIBODIES QUITE WELL. IN NANCY'S WORK THE MVA BOOSTED OF THE ANTIBODY LEVELS IN MACAQUES ABOUT 30 FOLD. OUR LARGEST DATA SET IN HUMANS IS WITH OUR TRAPILARRY ANTIGEN, 14 FOLD BOOST AFTER MVA COMPARED TO WITHOUT MVA, AND THE NICEST DATA COME FROM SIMON WITH T WELL KNOWN ANTIGENS, RISE AFTER THE MVA BOOST THERE COMPARED TO BEFORE, THE BLUE IS ADENOALONE, 35-FOLD OR 30-FOLD. I WANT TO POINT OUT DAY 56 IS STANDARD BOOSTING DAY, THE ANTIBODIES GO UP IN THE NEXT WEEK BY AROUND ABOUT 5-FOLD HERE, AND A FURTHER 5-FOLD IN THE NEXT FEW WEEKS WITH AMA1 AND MSP1. I CAN SHOW YOU DATA AFTER A WEEK IN THE FIRST 14 VOLUNTEERS, WE BOOSTED EVERYONE WE'RE GOING TO BOOST, 30 INDIVIDUALS, AT 3 TO 10 WEEKS AFTER THE CHAMP ADENOPRIME, TYPICAL INTERVAL IS 8 WEEKS, WE WOULD LIKE TO DO A SHORTER INTERVAL AT PHASE 3, TEN SUBJECTS FROM THE PRIMING DOSE LEVELS SO FAR AROUND IMMUNOGENICITY IS COMING UP BUT JUST IN PASSING THE MVA AS MVA ALWAYS IS WAS PRETTY WELL TOLERATED. THESE ARE ANTIBODY RESPONSES AFTER THE CHAD PRIME AT DAY 28. 359 WAS THE GEOMETRIC MEAN, AND THEY HAVE GONE UP 4-FOLD IN 7 DAYS. WE GOT THERE A COUPLE DAYS AGO, THESE ARE YESTERDAY'S ASSAYS, WE WOULD ANTICIPATE IN ANOTHER FEW WEEKS THEY WOULD GO UP ANOTHER 4-FOLD THAT WOULD TAKE US BEYOND THE 1450 WE'RE AT AT THE MOMENT TO, WELL, AROUND ABOUT 5000 BUT WE'LL HAVE THAT RESULT BY THE END OF THE YEAR. WE ARE SEEING A SUBSTANTIAL BOOST IN ANTIBODIES, AND T-CELLS AS ALWAYS THE CHAMP ADENOPRIME, PEAK IS 14 DAYS, AND THERE'S THE BOOST WITH HIGHER DOSE AND LOWER DOSE, SPRIT IN FULL AND HALF MVA AND YOU'RE GETTING A SUBSTANTIAL BOOST INTO THE 2000s ABOUT 4 OR 5-FOLD. THE BREADTH INCREASED, WE'RE SEEING MORE CD8 THAN CD4 WHICH WAS NOT THE CASE AFTER THE PRIME. FINISHING UP, WE THINK THATVA SHOULD BE LOOKED AT AS AN OPTION WHERE USABLE IN A PHASE 3 TRIAL TO MAXIMIZE IMMUNOGENICITY. THERE ARE TWO OPTIONS IN WEST AFRICA OUT OF THE PRODUCT WE USED PROVIDED BY BAVARIAN NORDIC WITH NIH FUNDING THAT WE USED IN OXFORD. HAVING THE FOUR IN THERE WE DON'T SEE AS A PROBLEM BECAUSE IT WILL STILL BOOST THE ZAIRE STRAIN ANTIBODIES IF YOU HAVE PRIMED WITH JUST ZAIRE, AND VERY LARGE SCALE MANUFACTURING OF THAT IS ONGOING AT BAVARIAN NORDIC, ALTERNATIVE ALREADY MANUFACTURED BY NIH IS THE MONOVALUENT STRAIN, SOME DOSES ARE AVAILABLE. LARGE SCALE MANUFACTURE IN A FEW WEEKS. ANTIBODIES AND T-CELLS ARE LOWER THAN ASSOCIATED WITH ROBUST PROTECTION IN MACAQUES. IF YOU BOOST FROM 3 WEEKS TO 10 WEEKS WITH MVA, 30 INDIVIDUALS, FIRST DATA INDICATES THAT'S WELL TOLERATED AND WE CAN BOOST T-CELLS-FOLD, ANTIBODIES QUITE A LOT MORE. THESE DATA SUPPORT EVALUATION NOT JUST OF CHAD3 ALONE IN LIBERIA BUT HOPEFULLY PRIME BOOST GROUP AS WELL TO TRY NOT JUST TO INCREASE THE DURABILITY OF EFFICACY OF CHAD3 SHOWN IN MACAQUES, WE NEED A BOOST TO GET THE MAXIMAL EFFICACY IN MY VIEW AND I HOPE WE CAN EVALUATE THAT. AS WELL. IN CONCLUSION THIS HAS BEEN THE WORK OF A TEAM OF TEAMS, WE THANK NIH FOR PROVIDING THE CHAD3 VACCINE PARTICULARLY BARNEY GRAHAM AND HIS GROUP FOR COLLABORATION, MIKE LEVINE'S GROUP, BAVARIAN NORDIC FOR MVA BOOSTER, GSK, WHO, AND PEOPLE IN OXFORD DOING THE CLINICAL TRIAL AND LAST BUT NOT LEAST OUR U.S. FUNDERS PROVIDING THE VACCINE, NIH, A CONSORTIUM OF UK FUNDERS AND NATIONAL INSTITUTE OF HEALTH RESEARCH IN THE U.K. FOR FUNDING THE TRIAL. THANK YOU VERY MUCH. >> OUR NEXT SPEAKER IS DR. RIPLEY BALLOU FROM GSK. >> I'M GOING TO GIVE TWO BRIEF SLIDES, ONE OF THE QUESTIONS WE GET IS HOW ARE WE GOING TO USE THESE DATA TO SELECT A DOSE FOR THE PHASE 3 AND IT'S IMPORTANT TO RECOGNIZE THAT WE HAVE BEEN PREPARING TO BE ABLE TO GO WITH ANY OF THESE DOSES IN PHASE 3, AND THE DOSE SELECTION PROCESS IS REALLY BEING DRIVEN BY THE PHASE 1 PROGRAM. YOU SAW A LIST OF A TOTAL OF 6 DIFFERENT CLINICAL TRIALS WHICH ARE UNDERWAY IN THIS EXPANDED PHASE 1 PROGRAM. THERE ARE FIVE OF THESE THAT ARE LIKELY TO HAVE DATA THAT CAN HELP US GENERATE THE DOSE SELECTION PROCESS FOR THE PHASE 1 AND THESE ARE THE STUDIES YOU'VE ALREADY HEARD ABOUT. THE FRAMEWORK FOR THE DOSE SELECTION IS GOING TO BE BASED ON SAFETY AND TOLERABILITY, WE BELIEVE THE SELECTED DOSE SHOULD NOT BE ASSOCIATED WITH RELATED SAEs, UNEXPECTED ADVERSE EVENTS SUGGESTING IMMUNOPATHOLOGY OR SEVERE LOCAL OR SYSTEMIC SYMPTOMS. AND IN ORDER TO EVALUATE THIS, WE HAVE PUT IN PLACE A COMMON PROCESS TO COLLECT SAFETY DATA FROM ALL OF THE TRIALS IN REALTIME, AND THESE ARE BEING EVALUATED BY AN INTERNAL SAFETY REVIEW TIME TABULATING AND BEING ABLE TO GIVE US REALTIME DATA ON THE SAFETY PROFILE OF THE VARIOUS DOSES. WE DO SEE AND WILL REPORT EXPECTED ADVERSE EVENTS, TYPICAL OF CHAD WHICH ARE LOCAL PAIN, WARMTH, THE FEVER, MYALGIA, HEADACHE, THE TIMING IS IMPORTANT, IT'S QUITE PREDICTABLE THERE'S FEVER IN THE FIRST 24 HOURS OR SO, AFTER A CHAD VACCINATION AND IT DOES APPEAR TO BE DOSE DEPENDENT. FEVER GOES ON BEYOND THAT OF COURSE IS GOING TO BE MORE PROBLEMATIC IN THE CONTEXT OF A PHASE 3 TRIAL WITH ENDPOINTS THAT COULD BE INTERPRETED AS OTHER INFECTIOUS DISEASES INCLUDING EBOLA. IMMUNOGENTY, IT'S IMPORTANT TO COMPARE APPLES AND APPLES. ALL THE INVESTIGATORS AGREED TO SUBMIT SERA AND CELLS TO THE VRC LABORATORY WHERE ALL OF THEM WILL BE RUN USING THE SAME METHODOLOGY IN A FORM AD THAT ALLOWS US TO COMPARE ACROSS THESE DOSE RANGES AND WE DO THINK THAT WITH ALL OF THE WARTS AND BLEMISHES, ANY INDIVIDUAL ASSAY AT LEAST THE VRC HAS BEEN CLINKED TO NONHUMAN PRIMATE PROTECTION AND WE THINK THAT'S AN IMPORTANT BENCHMARK, OUR DATA IS DATA FROM 200 SUBJECTS, MALI REPRESENTATIVES CLOSEST TO A REAL LIFE EXPOSURE IN TERMS OF HLA BACKGROUND, CONCOMITANT OTHER DISEASES IN THE POPULATION, SO THIS WILL BE AN IMPORTANT BENCHMARK FOR US TO USE IN THE DOSE SELECTION PROCESS. WE EXPECT TO HAVE DATA, TO MAKE A FIRM DOSE DECISION BY MID-JANUARY AND FROM EVERYTHING I'M HEARING FROM THE GROUPS PREPARING THE PHASE 3 TRIALS THAT THIS WILL BE PERFECTLY ALIGNED WITH THE ABILITY TO PROVIDE VACCINE IN A SMOOTH FASHION FOR THOSE TRIALS. THANK YOU. [APPLAUSE] >> OKAY. NOW FOR OUR LAST SPEAKER FROM NEWLINK GENETICS, DR. JAY RAMSAY. >> THANK YOU, EVERYONE. I APPRECIATE THE INVITATION. I WOULD LIKE TO GIVE A SUMMARY OF OUR DEVELOPMENT OF THE VSV VACCINE NOW BEING IN COLLABORATION, PARTNERSHIP WITH MERCK. BRIEFLY TO DESCRIBE THE VECTOR, IT'S A REPLICATION COMPETENT MONOVALUENT SINGLE DOSE VACCINE, PROTECTS IN NONHUMAN PRIMATE MODELS, AGAINST INTRAMUSCULAR AND AEROSOL CHALLENGED. THE PRODUCT IS ACTUALLY BEING DEVELOPED FOR TWO INDICATIONS, ONE IS POST EXPOSURE PROPHYLAXIS WHERE WE USE A HIGHER DOSE, 1 TIMES 10 TO THE 8th AND GENERAL USE PROPHYLAXIS, WE'RE LOOKING AT 3 TIMES 10 TO THE 6th, BUT EXPLORING LOWER DOSES AS WE GO FORWARD. AND THE EVALUATION OF THE PRODUCT TAKES INTO ACCOUNT THAT THE PRODUCT WILL EVENTUALLY BE AVAILABLE PERHAPS NOT ONLY AS JUST PARENTERAL BUT ALSO MUCOSAL. THE VACCINE IS STRAIGHT FORWARD. G PROTEIN WAS REMOVED FROM WILD-TYPE VSV, INDIANA STRAIN, A , REPLACED WITH THE ZEBOV GLYCOPROTEIN, TO REMOVE SIDE EFFECTS ASSOCIATE THE WITH THE VSV SURFACE GLYCOPROTEIN, WHAT WE FOUND IS THAT THERE'S A SLIGHT CHANGE IN HOST RANGE BUT NOTHING PARTICULARLY NOVEL ABOUT THAT. IT'S A VERY HIGHLY CHARACTERIZED PRODUCT IN TERMS OF NONHUMAN PRIMATES, A LARGE BODY OF PUBLICATION SUPPORTING ITS DEVELOPMENT AS A VACCINE. OUR IMMEDIATE CLINICAL OBJECTIVES SLIGHTLY DIFFERENT THAN LONG-TERM IS DEVELOPMENT OF THE EBOLA ZAIRE VACCINE AS A SINGLE AGENT AS OPPOSED TO TRIVALENT COMPOSITION WORKING ON THE GENERAL USE PROPHYLAXIS, SAFE CLINICAL DOSES USED IN AFRICA AND POTENTIALLY THE REST OF THE WORLD DEPENDING ON POTENTIAL CIRCUMSTANCES. POST EXPOSURE PROPHYLAXIS USED INTERMITTENTLY ON EMERGENCY IND BASIS FOR INDIVIDUALS THAT MIGHT HAVE HAD EXPOSURE PROVIDING CLINICAL CARE. WE'RE LOOKING AT ESSENTIALLY THE SAFETY AND EFFICACY OF THESE PRODUCTS, WE'RE ALSO TRYING TO MOVE FORWARD INTO SPECIAL POPULATIONS IF THERE'S GOING DISTRIBUTION OF THE VACCINE IN WIDE AREAS, WE ALSO NEED TO START ADDRESSING PEDIATRIC, PREGNANT AND/OR IMMUNOCOMPROMISED SUBJECTS. WE'RE HOPING TO GATHER INFORMATION FROM OUR CLINICAL STUDIES ON CORRELATES AND SURROGATES BUT WE HAVE NO PARTICULAR EXPECTATION THAT THE CURRENT SITUATION WILL PROVIDE THAT. WE'RE JUST MOVING FORWARD IN THE HOPE THAT WE CAN GATHER ENOUGH TO BEGIN DOWN THAT PATHWAY. OUR CURRENT PHASE 1 STUDIES ARE FOCUSED ON SAFETY AND IMMUNOGENICITY. THE ONES BEING PERFORMED IN NORTH AMERICA ARE AT WALTER REED. PHASE 1 RANDOMIZED STUDY, 39 SUBJECTS, THEY ARE GETTING DOSE RANGING FROM 3 TIMES 10 TO THEth, 10 TO THE 8th PFU, SINGLE DOSE, NIAID IS CONDUCTING STUDY AT NIH WHERE WE'RE DOING ESSENTIALLY A PRIME AND RECHALLENGE WITH THE VACCINE AT A 28-DAY INTERVAL, THEY HAVE ENROLLED 39 OF 39 SUBJECTS, THEY HAVE STARTED O THE SECOND DOSE OF THE LOWEST DOSE COHORT, WE EXPECT TO HAVE SOME MORE INFORMATION FROM THEM GOING FORWARD, THIS STUDY WILL TAKE A LITTLE LONGER THAN THE ONE AT RARE BECAUSE WE HAVE A SECOND DOSE TO PROVIDE. CONDUCTED IN HALIFAX, CANADA, IS NOW PROCEEDING IN IT'S LAST ENROLLMENT 36 OF 40, THEY HAVE DROPPED, GOING DOWN TO 10 TO THE 5th PFU. THE SITES THAT ARE CURRENTLY ENROLLING PATIENTS, OR IMMEDIATELY PREPARED TO. WALTER REED, NIH, HALIFAX, THE STUDIES AT HAMBURG, GENE EVA, GABON AND KENYA SHOULD BE STARTING SOON. 120 HAVE BEEN VACCINATED SO FAR. ON THE SAFETY DATA I'M GOING TO FOCUS ON WHAT'S BEEN SEEN AT WALTER REED. IT'S NOT THAT WE HAVEN'T GATHERED DATA FROM OTHER SITES BUT THERE'S NOT A WHOLE LOT OF DIFFERENCE BETWEEN DOSES AND/OR SITES. SO AS WAS MENTIONED EARLIER, ACTUALLY FOR THE GSK VACCINE, WE HAVE A FAIRLY TYPICAL CONSTELLATION OF SYMPTOMS WHICH FOLLOW VACCINATION, A FAIR NUMBER OF PATIENTS EXPERIENCED FATIGUE OR MYALGIA, HEADACHE, SUBJECTIVE FEVER, FEVER, CHILLS, MILD ARTHRRALGIA, OFTEN RESOLVING BY THE NEXT MORNING OR NEXT DAY, SOME PERSIST FOR TWO TO THREE DAYS AFTER VACCINATION. WE HAVE A COUPLE LABORATORY ABNORMALITIES, LYMPHOPENIA RESOLVES QUICKLY AND CAN BE FOLLOWED IN SOME PATIENTS BY TRANSIENT NUTRIPENIA WHICH RESOLVES. POTENTIAL FOR SHEDDING, BASICALLY I'LL TALK ABOUT THE WALTER REED EXPERIENCE, THERE WERE 13 PATIENTS, 10 RECEIVED VACCINE, 3 PLACEBOS, BLINDED SO WE CAN'T TELL FOR CERTAIN BUT 10 OF 13 HAD A POSITIVE CPR SIGNAL ON DAY 3, THE URINE, ONE OF 13 PATIENTS HAD A POSITIVE PCR SIGNAL IN THE URINE PELLET, WHICH WE COULDN'T TELL, WE HAVE NOT BEEN ABLE TO DETERMINE WHETHER THAT WAS JUST GENOMES OR WHETHER THAT WAS VIABLE VIRUS. BY DAY 7 THE SERUM SIGNAL DISAPPEARING IS GONE BY DAY 14, WE HAD ONE PATIENT ON DAY 14 WHO HAD A SIGNAL IN THE SALIVA. IF YOU LOOK AT THE NEXT DOSE COHORT WHICH WAS DONE AT WALTER REED WHICH GOES UP FACTOR OF 5-FOLD, 10 TO THE 7th PSU, WHAT WE FOUND WAS ESSENTIALLY THE SAME DISTRIBUTION, PERHAPS WITH A SLIGHTLY LONGER PERSISTENCE IN SERUM. WE'RE STILL WAITING TO FINISH THE PCR ANALYSIS SO FOR DAY 14 THERE'S SAMPLES THAT HAVEN'T BEEN ANALYZED YET. SO 120 PATIENTS HAVE BEEN TREATED WITH ANYWHERE FROM 10 TO THE 5th TO 10 TO 8th PFU, NO SERIOUS EVENTS. THIS READS LIKE ANY OTHER LIVE ATTENUATED VACCINE. FATIGUE, MYALGIA, HEADACHE. OBJECTIVE FEVERS, LOW GRADE, TRANSIENT LYMPHOPENIA, MOST RESOLVED OVERNIGHT, RESOLUTION OF THE VAST MAJORITY BY DAY 4. I WANT TO MENTION WHAT WE'VE SEEN IS THE VACCINEMIA, IT MAY BE POSSIBLE TO GO TO A LOWER DOSE WE THINK THAT REPLICATION OF THE VECTOR WILL ALLOW SUBSTANTIALLY LOWER DOSES TO PROVIDE THE SAME IMMUNE BOOST. ONE THING CAME UP EARLIER TODAY THAT WE DIDN'T DWELL ON, I WON'T DWELL ON IT HERE BECAUSE I DON'T HAVE ENOUGH INFORMATION TO SATISFY PEOPLE, WE RECENTLY WERE NOTIFIED THAT POSSIBLE REACTIVE ARTHRITIS WAS BEING SEEN AT 4 OF 59 SITES, MOSTLY GRADE 1, GRADE 2, AT GENEVA. WE DON'T HAVE ALL THE DETAILS YET. WE MAY BE ABLE TO OBTAIN SOME LATER. BUT OTHERWISE THESE ARE NOT KNOWN TO BE PARTICULARLY SERIOUS. WE'RE INVESTIGATING IT, AND ARE INCORPORATING THAT INTO OUR TRIAL DESIGN AND INFORMED CONSENT FORMS. AS FAR AS THE PCR, MINIMAL EVIDENCE OF SHEDDING, LOW POTENTIAL FOR MOVEMENT OF THE VACCINE OUTSIDE OF THE STUDY SUBJECTS. SO THIS IS JUST A BRIEF THROWBACK TO WHAT WE SAW OR WHAT I MENTIONED ABOUT THE ARTHRALGIA. IF YOU LOOK AT THE UNITED STATES, AT THE STUDIES DONE, THIS IS WHAT WE SEE. OURS ARE SHOWING UP IN THE FIRST DAY OR SO, AND ARE RESOLVING OVER THE FIRST WEEK. THE ARTHRITY IN GENEVA 9-13 POST VACCINATION, REACTIVE ARTHRITY. THE REASON I'M HERE IS TO TALK ABOUT THE PROTECTION AFFORDED BY THE VACCINE. IN NONHUMAN PRIMATES THE PROTECTION IS AFFORDED BY ANTIBODIES. THE BEST CORRELATION WITH SURVIVAL COMES FROM THE PRESENCE OF THE ANTI-GP ANTIBODIES. NEUTRALIZING ANTIBODIES AND T-CELL INPUT WERE MINIMAL IN DETERMINING SURVIVAL. AND THE ROLE OF ANTIBODIES WERE DEMONSTRATED BY PASSIVE IMMUNIZATION STUDIES AND T-CELL DEPLETION IN RODENTS AND NONHUMAN PRIMATES. SO IN THESE MODELS, ONE SEES ADENOVIRAL VECTORS ARE LESS DEPENDENTENT ON HUMORAL ACTIVITY, IT'S A GOOD INDICATOR OF LIKELIHOOD OF SURVIVAL BUT PASSIVE TRANSFER IS NOT SUFFICIENT AND NEUTRALIZING ANTIBODIES HAVE NO CORRELATION WITH SURVIVAL. WHEN WE LOOK AT SERAL CONVERSION OF PATIENTS AT WALTER REED THIS IS A STATISTICIAN-ORIENTED SLIDE BUT WE DIDN'T HAVE TIME TO DO BETTER. BASICALLY WHAT HAPPENS IS S PRECIOUS ALSO ON DAY 7 BUT BY DAY 14 THERE'S A PRETTY ROBUST RESPONSE IN TERMS OF SEROCONVERSION. THIS IS THE IgG ANTIBODY ELISA DATA. WHAT WE HAVE HERE IS I THINK SIX DOTS REPRESENTING 13 PATIENTS, THERE'S OVERLAPPING EACH OTHER, WE BELIEVE BUT WE HAVEN'T UNBLINDED OURSELVES THAT THESE REPRESENT THE NONVACCINATED PLACEBO PATIENTS. THE PLACEBO PATIENTS, AND WHAT WE LOOK AT GEOMETRIC MEAN TITERS, WHAT WE SEE IS IF WE DO A LITTLE BIT OF WIZARDRY HERE BY IDENTIFYING THE PCR POSITIVE PATIENTS AND COMPARING THAT TO THOSE HAVING POSITIVE ELISA RESPONSES WE SEE ALL THE PCR POSITIVE PATIENTS HAVE 14 IS GOOD, DAY 28 IS BETTER, WE LOOK FORWARD TO DAY 56. THESE ARE THE PCR NEGATIVES. WE WERE BLESSED UNFORTUNATELY WITH A PATIENT WHO HAD MODERATE SIGNALS FROM DAY 1 ON, AND NEVER CHANGED THROUGHOUT, UNINDUCED BUT AT LEAST IN THIS ASSAY THEY SHOW UP TO HAVE A SIGNAL. THIS IS ONE OF THE REASONS WE'RE TRYING TO ESTABLISH ASSAYS WHERE MAYBE WE CAN UNDERSTAND SOME OF THOSE PATIENTS. ONE OF THE THINGS WE ALSO LOOKED AT WERE THE PSEUDOVIRION NEUTRALIZIZATION ASSAY. WE SEE A SIGNAL. IF WE LOOK AT PCR-POSITIVE PATIENTS YOU WHAT YOU SEE IS THAT BY DAY 14, YOU ARE STARTING TO GET A NEUTE SIGNAL, COMPARED TO WHAT WE ASSUME ARE PLACEBO, YOU CAN SEE THERE'S NO RESPONSE ON THAT SIDE. WE'RE NOT ENTIRELY CLEAR WHAT THAT MEANS BUT WE ARE AT LEAST AWARE OF IT. WHAT WE WOULD SUMMARIZE OUR DATA AS, WE HAVE A GOOD VACCINE TAKE WITH A LOT OF THE SUBJECTS EXPERIENCING A VACCINEMIA, SHEDDING IS MINIMAL, IT MAY REPRESENT GENOMES. WE HAVE ENCOURAGING ANTIBODY RESPONSES WHICH ARE SEEN AT 3 TIMES 10 TO THE 6 PFU, WE MAY BE ABLE TO SEE IT AT LOWER DOSES AS WE MOVE FORWARD. WE GET INDUCTION OF ROBUST ENDPOINT TITERS, SOME NEUTRALIZING ANTIBODIES, AND I THINK EVERYONE IS PROBABLY NOTICED WE HAVE NO T-CELL DATA HERE AND PROBABLY WILL NOT FOR SOME PERIOD OF TIME DUE TO DIFFICULTY OF SETTING UP ALL OF THE ASSAYS. THAT DOES BRING ME TO WHAT OUR CLINICAL ASSAY GOALS ON. WE'RE HOPING TO GET ANTIBODIES WORK UP AGAINST THE GLYCOPROTEIN, HAVE A COMMON STANDARD REAGENT SAID AND HOPEFULLY MAKE ARRANGEMENTS TO FOR THE CONVALESCENT SERA. WE'RE NOT CERTAIN WHAT THE SIGNIFICANCE IS BUT WE'RE SEEING A SIGNAL SO WE THOUGHT WE WOULD FOLLOW IT UP. AGAIN, RT-PCR TO KEEP TRACK OF VACCUNEMIA AND POTENTIAL FOR SHEDDING. ONE OF THE THINGS I WANT TO TALK ABOUT AS WE DISCUSS MOVING INTO POTENTIALLY CRITICAL TRIALS IN WEST AFRICA, LARGE SCALE, IS THAT WE FOUND THAT THE MANUFACTURING OF THE VACCINE IS ACTUALLY A LITTLE SIMPLER THAN ORIGINALLY THOUGHT, AND THAT WE'VE REACHED A POINT WHERE WE'RE NOW SORT OF AT EXCESS OF VACCINE, HOPEFULLY WE CAN MAINTAIN THAT GOING FORWARD. ONE OF THE FACTORS OF COURSE THAT WILL COME INTO PLAY HERE IS THE FINAL DOSE SELECTION, WE HAVE ENOUGH MATERIAL ALREADY FROZEN BULK DEPENDING ON THE DOSES THAT WE FINALLY SETTLE ON THE RANGE IS 180,000 TO 180 MILLION DOSES OF VACCINE COULD BE MANUFACTURED FROM THE BULK THAT'S AVAILABLE. WE'RE HOPEFUL THAT WE WON'T NEED ALL OF IT BUT IT'S THERE IF WE DO. THIS IS A STUDY THAT WE HOPE TO INITIATE VERY SHORTLY. THIS IS AN 8-SITE DOSE RANGING STUDY BEING CONDUCTED IN THE UNITED STATES. WE'LL HAVE A TOTAL OF 4 DOSE COHORTS AND 5th COHORT OF PLACEBO, WE ANTICIPATE HAVING DATA FROM THAT BY THE END OF JANUARY AT WHICH POINT WE COULD MAKE A SPECIFIC DOSE-FINDING DECISION. I'D LIKE TO THANK THE GROUPS THAT WORKED WITH US DURING THE DEVELOPMENT OF THIS PRODUCT, AND AGAIN BECOME SORT OF A COLLABORATION OF MANY GROUPS. WE'D LIKE TO RECOGNIZE PUBLIC HEALTH AGENCY CANADA WHO D THIS PRODUCT INITIALLY. WE ARE WORKING WITH CLINICAL VACCINE DEVELOPMENT CENTER AT HALIFAX. IN THE UNITED STATES WE'VE HAD A GREAT AMOUNT OF SUPPORT FROM THE DEPARTMENT OF DEFENSE, NIAID, CDC, AND WE'RE STILL WORKING WITH BARDA IN TERMS OF OUR INTERACTIONS WITH GROUPS OVERSEAS, WELLCOME, W.H.O. CLINICAL CONSORTIUM, AND THAT DOES IT FOR ME. >> I'M GOING TO ASK THE SPEAKERS TO COME UP HERE TO THE PODIUM AND THE MICS ARE NOW OPEN FOR PEOPLE TO QUESTION THE SPEAKERS. DR. GRAHAM, DR. HILL, DR. BALLOU. >> WE'RE SEEKING QUICK QUESTIONS ONLY TO GET YOU INTO THE FINAL PANEL DISCUSSION. IF THERE'S NOBODY ASKING A QUESTION I'LL ASK YOU, IT SOUND LIKE LOOKING AT THE DATA, THAT THERE IS AT LEAST AT THIS POINT SOME UNCERTAINTY ABOUT DOSE SELECTION, AND WITH THE GOAL TO START A STUDY IN A MONTH'S TIME DO YOU ON THE PANEL THINK THAT STUDY CAN BE CONDUCTED WITH AN OPTIMALLY SELECTED DOSE? >> I THINK THE THING THAT'S GOING TO DRIVE THAT DECISION IS WHEN THOSE PHASE 3 PROTOCOLS ARE FINALIZED AND APPROVED. WE'RE STILL SOME TIME FROM THAT HAPPENING. THEY WILL BE DISCUSSED WITH THE REGULATORS AT W.H.O. NEXT WEEK, THEY WILL BE FINALIZED ONCE THAT BUT FROM GSK'S PERSPECTIVE WE HOPE TO BE ABLE TO MAKE A DECISION ON DOSE SELECTION BY MID-JANUARY, THE PRODUCTS ARE -- DO I PICK THIS BOX OR THIS BOX, THE BOXES ARE READY, AND SO IF THEY CAN THEN -- IF THE SITES ARE READY TO VACCINATE IN JANUARY WE'LL BE ABLE TO SUPPLY THEM AT LEAST FOR THE INITIAL PORTIONS OF THE STUDIES BECAUSE THEY DO STAGE IN. THEY DON'T NEED ALL THE DOSES ON DAY 1, BUT I THINK THIS REALLY IS GOING TO BE DRIVEN BY THE FOR THOSE PHASE 3 PROGRAMS. >> FROM OUR PERSPECTIVE, THE ISSUE IS NOT SO MUCH DRUG SUPPLY ANY LONGER. WE'RE GOING TO BE ABLE TO FILL AT SEVERAL CONCENTRATIONS, MOVE FORWARD AND DEPENDING ON THE DOSE-RANGING STUDY INFORMATION RECEIVED WE'LL GO FORWARD WITH A SELECTED DOSE. >> WHY DON'T WE TAKE THESE TWO QUESTIONS AND MOVE QUICKLY TO THE FINAL PANEL. >> A GENERAL QUESTION, ARE YOU ALSO MEASURING RESPONSES TO YOUR VECTOR, TO THE CHIMP AD AND VSV? >> YES, IN THE STUDIES WE'RE MEASURING ANTIBODY TO CHIMP AD 3 AND ALSO ANTIBODY TO AD 5. >> ARE YOU LOOKING AT T-CELL DISPOSAL TO CHIMP AD? >> NOT YET. WE'RE NOT PLANNING. >> IS THERE ANY CONCERN? >> WELL, I MEAN IF YOU LOOK AT CHIMP AD T-CELL RESPONSE YOU FIND PRE AND POST VACCINATION THEY WERE POSITIVE. >> HOW MUCH OF A BOOST ARE YOU GETTING? >> THERE'S DOZENS OF SHARED EPITOPES. >> THAT'S WHAT I'M GETTING AT. >> WE KNOW THAT DATA FROM AD 5 -- BOTH IN AD 5 NEGATIVE AND AD 5 POSITIVE THE PEOPLE YOU BOOST THOSE RESPONSES, ESPECIALLY CD4 RESPONSES. >> BUT ARE YOU PLANNING TO MEASURE THOSE IN THE STUDIES IN AFRICA? >> THERE WILL BE IN THE PHASE 2 PROGRAM THAT YOU HEARD DESCRIBED, OUTSIDE OF THE EBOLA ENDEMIC AREA, THERE WILL BE T-CELLS COLLECTED FOR -- PBMCs COLLECTED BUT NOT PHASE 3. >> WE'VE DONE A LOT OF MEASURING OF T-CELL RESPONSES TO CHAD 63, A LITTLE TO THE CHAD 3 BACKGROUND, YOU'RE RIGHT, YOU SEE PREEXISTING RESPONSES, BOOST THEM STRONGLY, WHAT'S INTERESTING IS THAT YOU GET A VERY STRONG CORRELATION BETWEEN THE INCREASING RESPONSE TO THE VECTOR AND THE INDUCTION OF INSERT-SPECIFIC T-CELL SO YOU CAN PREDICT ONE FROM THE OTHER VERY WELL. INDUCE TO THE INSERT CORRELATE. >> GERARDO KAPLAN OFFICE OF FOOD AND DRUG ADMINISTRATION. LOOKING AT THE DATA WAS INTERESTING. THE THING THAT JUMPS AT ME LEVELS OF ANTIBODIES HAVE LOW, EVEN UNDER THE BOOST, SO COMPARED TO THE DATA MONKEY EFFICACY WILL BE LOW OR NONE, MY QUESTION IS DO YOU PLAN TO DO FURTHER BOOSTINGS OR MAKE THE AD -- CHIMP AD WITH VSV OR GO TO PLOTTING? IF THE ANTIBODIES REMAIN AT THIS LEVEL DO YOU HAVE ANY CONTINGENCY PLANS HOW TO BOOST IMMUNITY? >> LET ME JUST CLARIFY SOMETHING FROM THE PART I GAVE AT LEAST IS THAT THE CHAMP AD 3 IMMUNOGENICITY IN HUMANS IS VERY COMPARABLE TO THE CHIMP AD 3 IMMUNOGENICITY IN THE MONKEYS. IT'S MAYBE, YOU KNOW, ONE LOG DIFFERENCE IN POTENCY BUT VERY COMPARABLE. IT'S NOT FAR OFF. SO WE WOULD EXPECT AT LEAST SHORT-TERM PROTECTION FROM CHAMP AD 3 AT DOSES USED. >> THE BOOST AFTER A WEEK YOU'RE IN THE THOUSANDS, AFTER FOUR WEEKS WE EXPECT 5000, THAT'S ABOVE 3500 WITH PROTECTION IN MACAQUES, YOU WOULD EXPECT GOOD PROTECTION WITH THAT. IF T-CELLS ARE THE PROTECTIVE MECHANISM WE'RE GETTING THE SAME AS CHAD 3 WITH MACAQUES. >> AS TO WHETHER OR NOT WE'RE LOOKING AT OTHER POSSIBLE COMBINATIONS, YES, ONE OF THE THINGS THAT CHARACTERIZES THIS RESPONSE TO THIS OUTBREAK IS THE INCREDIBLE COLLABORATION THAT'S GOING ON BETWEEN THE COMPANIES THAT ARE DEVELOPING THESE VACCINES, AND YOU SAW THAT IT'S BAVARIA NORDIC PROVIDING THE BOOST FOR THE CHAT 3, ADRIAN PRESENTED, AND WE'RE WELL ALONG IN DISCUSSIONS WITH J & J AND BAVARIA NORDIC SO WE WILL HAVE DATA ON ALL POSSIBLE COMBINATIONS OF VACCINES THAT COULD BE INTRODUCED IN THE SETTING OF THE RESPONSE. >> OKAY. I SAID TWO QUESTIONS. WE'LL TAKE THIS ONE AS LONG AS IT'S ONLY DIRECT THE AT ONE PANEL MEMBER AND CAN BE ANSWERED QUICKLY. >> I WAS WONDERING ABOUT YOUR VSV DOSE STUDY, BUT CORRELATE THAT TO NHP, AND IF SO HOW DOES YOUR DATA CORRELATE WITH NHP? >> RIGHT NOW WE HAVE A STUDY UNDERWAY, DoD IS RUNNING A STUDY FOR US THAT IS CORRELATING LOWER DOSES OF VACCINATION WITH PROTECTION, SO THE VAST MAJORITY, ACTUALLY THE ENTIRETY, OF THE NHP DATA WITH THE VACCINE WAS BASED ON A MAXIMAL ACHIEVABLE DOSE. IN ESSENCE WHAT WE'RE TRYING TO DEMONSTRATE IN THIS STUDY IS THAT SUBSTANTIALLY LOWER DOSES WE BELIEVE THAT WE CAN USE THE IgG ELISA RESPONSE AS A RELATIVE INDICATOR OF EQUIVALENCY, BIOLOGIC EFFECT OF A GIVEN DOSE. IF WE'RE SEEING THE SAME IgG TITERS FOLLOWING A VACCINATION WITH 3 TIMES 10 TO THE 4th, AS WE DO WITH 3 TIMES 10 TO THE 6th OR 8th WE SEE NO COMPELLING REASON TO PROVIDE THAT EXTRA ANTIGEN LOAD WITH ANY ATTENDANT ADVERSE EVENTS THAT MIGHT ACCOMPANY IT. WE'RE TRYING TO TAKE INTO THE ACCOUNT IT'S A BIOLOGICALLY ACTIVE SUBSTANCE, YOU USE WHAT YOU NEED AND IF IT ACHIEVES THE DESIRED GOAL IN TERMS OF THE CORRELATIVE PROTECTION WE ASSIGN TO IgG, ANTI-ZBOV IgG, THAT WILL BE OUR DETERMINANT. >> THANK YOU VERY MUCH. I'D LIKE TO INVITE BARNEY GRAHAM TO STAY AND ASK STANLEY PLOTKIN AND MIKE LEVINE TO COME UP. WE HAD DISCUSSION OF DOSE SELECTION, SO WE'LL LEAVE THAT TO THE END IF THERE'S TIME, AND AS WE GO INTO THIS PANEL THEN WE'LL ASK THE PANELISTS TO START OFF WITH THEIR THOUGHTS ABOUT WHAT WE CAN GET FROM FUTURE VACCINE STUDIES THAT WILL HELP US ANSWER THIS QUESTION OF CORRELATIVE PROTECTION AND THEN WE'LL OPEN THAT QUESTION UP TO THE AUDIENCE AS WELL. >> WELL, I'M GOING TO START THE DISCUSSION BECAUSE I HAVE TO LEAVE AT 5:00. YOU KNOW, IT'S OFTEN SAID THAT IF YOU GET A DELIVERY OF LEMONS YOU SHOULD MAKE LEMONADE. AND THE FIRST THING I WOULD LIKE TO SAY HERE IS THAT THIS MEETING HAS BEEN VERY IMPRESSIVE TO ME, NOT ONLY WITH REGARD TO THE SCIENCE, BUT WITH REGARD TO THE SOCIAL IMPLICATIONS OF WHAT IS HAPPENING. I THINK IT IS ACTUALLY SALUTARY THIS EPIDEMIC HAS REMINDED US THAT INFECTIOUS DISEASES ARE IMPORTANT AND ARE STILL AROUND, AND OF MAJOR IMPORTANCE TO THE ENTIRE WORLD. AND HERE WE SEE AN EXAMPLE OF A GLOBAL DISEASE, SINCE INDEED IT HAS ALREADY SPREAD TO SOME DEGREE FROM AFRICA. THE POSITIVE FEATURES THAT I SEE HERE ALSO ARE THAT, AND THIS IS PROBABLY GOING TO INSULT SOME PEOPLE, BUT WE'RE GOING BACK TO SOME CLASSICAL VIROLOGY. VIROLOGY IS IMPORTANT. AND ALTHOUGH THE HIV FIELD HAS ALSO HELPED TO SOME EXTENT, IT HASN'T BEEN AS VIRALLOLOGYICALLY ORIENTED AS THIS CURRENT EBOLA PROBLEM. AND LASTLY, THE MOBILIZATION OF RESOURCES, INTERNATIONAL MOBILIZATION, IS IMPRESSIVE TO FACE THIS CHALLENGE. I THINK IT'S SOMETHING THAT SHOULD BE RECOGNIZED, NOT ONLY BY US BUT BY OTHER PEOPLE AS WELL. NOW, COMING TO THE -- SOME OF THE SCIENTIFIC ISSUES, OBVIOUSLY THERE IS A CERTAIN OPPOSITION HERE BETWEEN ANTIBODY AND CELLULAR IMMUNITY. BUT I HAVEN'T HEARD ANYONE SAY THAT ANTIBODIES ARE NOT IMPORTANT. SO I THINK WE CAN INFER FROM WHAT'S BEEN SAID THAT ANY VACCINE THAT'S GOING TO WORK IS GOING TO HAVE TO INDUCE ANTIBODY RESPONSE. IT MAY WELL BE THAT THE DIFFERENCES BETWEEN A NONREPLICATING VACCINE CANDIDATE AND REPLICATING VACCINE CANDIDATE MEANS THAT THE CORRELATES OF PROTECTION WILL BE DIFFERENT, AS PERHAPS NOT AN EXACT ANALOGY BUT WE HAVE TWO VACCINES AGAINST POLIO IPV AND OPV THAT DON'T INDUCE THE SAME RESPONSE BUT THEY BOTH WORK. WITH REGARD TO THE SPECIFIC ISSUE OF ANTIBODY AND WHAT ANTIBODY IS NEEDED, CLEARLY THERE ARE SOME IMPORTANT SCIENTIFIC ISSUES, AND WE'VE HEARD PARTICULARLY FROM DR. SMALLJOHN, THE VARIETY OF FUNCTIONAL ASSAYS THAT MAY PLAY A ROLE AND SHOULD BE TESTED TO DETERMINE WHETHER THE ELISA ANTIBODY WE'RE SEEING IS REALLY FUNCTIONAL, IS IT SOMEHOW BY BINDING IMPEDING THE ENTRY OF THE VIRUS INTO CELLS LIKE MACROPHAGES, OR IS THERE SOME OTHER FUNCTIONAL ACTIVITY THAT CAN BE MEASURED? AND THE ANSWERS TO THIS WILL COME OUT OF THE STUDIES, CLINICAL STUDIES, THAT WILL BE DONE BUT I STRESS THAT IN A WAY, IT MATTERS, BUT IT DOESN'T MATTER IN THE SENSE THAT WE KNOW THAT WE NEED TO INDUCE AN ANTIBODY RESPONSE, AND THE ISSUE WILL BE THE QUALITY, AND I MUCH ADMIRE THE STRUCTURAL BIOLOGY STUDIES THAT WILL TELL US WHICH PART OF THE EBOLA GP IS THE FUNCTIONAL PART AND WHICH PART -- AGAINST WHICH WE NEED TO DEVELOP ANTIBODIES, ALTHOUGH BECAUSE ANTIBODY RESPONSES ARE POLYCLONAL AS WELL AS MONOCLONAL, A GENERAL RESPONSE COVERING MULTIPLE EPITOPES MAY BE IMPORTANT AS WAS SUGGESTED BY THE ZMapp EXPERIENCE. AND AGAIN WITH RESPECT TO CELLULAR IMMUNE RESPONSES, I THINK AS I MENTIONED EARLIER THIS MORNING THE IDEA OF A VECTOR CD8 T-CELLS THAT ABORT INFECTION, MAY NOT GIVE STERILE IMMUNITY BUT IF THOSE CELLS WHEN PRESENT AT THE TIME OF EXPOSURE CAN ABORT INFECTION, THEY MAY WELL BE A MECHANISTIC CORRELATE OF PROTECTION AND MAY EXPLAIN SOME OF THE PHENOMENA THAT HAVE BEEN OBSERVED WITH THE CHIMP ADENOVACCINE. NOW, I WOULD LIKE TO POINT OUT THAT THE INTERVAL BETWEEN IMMUNIZATIONS IS IMPORTANT. AND THAT IS TRUE BOTH FOR IMMUNIZATION WITH THE SAME MATERIAL AND CERTAINLY TRUE WITH REGARD TO PRIME BOOST. NOW, WE ALL WANT A VACCINE THAT'S GOING TO WORK QUICKLY, BUT FOR A PUBLIC HEALTH USE OF A VACCINE IT MAY TURN OUT THAT WE WILL NEED TO HAVE LONGER INTERVALS BETWEEN DOSES. BY PUBLIC HEALTH, I MEAN NOT TO RESPOND TO AN EMERGENCY BUT TO IMMUNIZE A POPULATION AHEAD OF AN OUTBREAK. NOW, THE QUESTION IS ASKED IN MATERIAL THAT YOU'VE RECEIVED WHAT CAN WE LEARN FROM FUTURE VACCINE STUDIES? WELL, YOU KNOW, SOME OF THAT IS OBVIOUS. WE'VE HEARD ABOUT DEFINING THE DOSE, AND LOOKING AT THE IMMUNE RESPONSES, BUT LET'S SAY THAT WE GET INTO A PHASE 3 TRIAL, WHAT CAN WE LEARN, HOW CAN WE DEFINE THE CORRELATIVE OF PROTECTION? WELL, AS ALREADY SUGGESTED, FAILURE IS THE BENEFICIAL FACTOR IN DEFINING THE CORRELATE OF PROTECTION AND I HAVE NO DOUBT THERE WILL BE FAILURES. THESE VACCINES WILL NOT BE 100% PROTECTIVE. IF ONLY BECAUSE THE ISSUE OF CHALLENGE DOSE IS KEY AND IN THE PRESENCE OF A LARGE CHALLENGE DOSE SOMEONE WHO IS EXPOSED TO VOMITUS WITH A HIGH TITER, I EXPECT FAILURE. WE NEED SPECIMENS FROM THE PHASE 3 STUDIES. THE QUESTION OF FEASIBILITY OF OBTAINING AT LEAST SERUM SPECIMENS FROM EACH INDIVIDUAL IN A STUDY HAS BEEN RAISED. I THINK IT'S FEASIBLE AT LEAST TO COLLECT THE SERUM. IT MAY NOT BE FEASIBLE TO TEST ALL OF THE SERA BUT WE CAN COLLECT POST VACCINATION SERA FOR SUBSEQUENT ANALYSIS. AND THEN THE OTHER POINT IS WHEN A CASE OCCURS, SERUM AND CELLS SHOULD BE TAKEN AT THAT POINT BECAUSE IF SOMEONE HAS BEEN VACCINATED AND OBTAINS A RESPONSE AND THEN THAT RESPONSE DISAPPEARS AND THE INDIVIDUAL BECOMES ILL, THAT SUGGESTS THAT THE FACTOR THAT DISAPPEARED IS A CORRELATIVE PROTECTION. ONE THAT COMES TO MIND IS PROTECTION, WHEN BLOOD WAS TAKEN AT THE TIME OF THE CASE OF LYME DISEASE, AND COMPARED TO CONTROLS THAT WERE NOT ILL, IT SEEMED 400 UNITS WERE PROTECTIVE, AT THAT POINT. AND SO THAT'S AN EXAMPLE OF THE USE OF SPECIMENS OBTAINED AT THE TIME OF DISEASE. NOT THE MECHANISTIC CORRELATIVE PROTECTION, IT'S THE ANTIBODY IN THE TICK THAT PROTECTED. I THINK WE CAN OBTAIN INFO FAMILY STUDIES. IN OTHER WORDS, IN A FAMILY WHERE MULTIPLE INDIVIDUALS ARE VACCINATED, AND ONE OF THEM BECOMES ILL AND OBTAIN SPECIMENS KNOWING THERE'S BEEN EXPOSURE, AND AND TRY TO INFER WHAT PROTECTED SOME AND NOT THE OTHER. TO STRESS THE LOSS OF AN IMMUNE INFORMATION ABOUT THE IMPORTANCE OF THAT IMMUNE MARKER, THAT IS IF VACCINE EFFICACY BEGINS TO FALL, WE CAN DETERMINE THE IMMUNE MARKERS THAT CORRELATE WITH THAT FALL. WHAT ELSE CAN I SAY THAT HASN'T BEEN SAID? PERHAPS NOTHING EXCEPT TO SAY THAT I'M NOT AT THIS STAGE PESSIMISTIC ABOUT THE DEVELOPMENT OF A VACCINE, BUT I DON'T EXPECT THAT WE WILL HAVE 100% EFFICACY. THAT BEING SAID, IT MUST BE REMEMBERED THAT THE EFFECTIVENESS OF VACCINES DEPENDS ON THE IMMUNITY OF THE POPULATION AND NOT SOLELY ON INDIVIDUAL IMMUNITY AND IF WE CAN DECREASE THE REPRODUCTIVE NUMBER OF EBOLA, TO LESS THAN ONE, ESTIMATES ARE LIKE TWO OR THREE, IF WE CAN REDUCE TO LESS THAN ONE EVEN IF WE CAN'T PROTEWITH A VACCINE WEHAVE ACHIEVED CONTROL OF THIS OUTBREAK AND ONE HOPES WITH GENERAL VACCINATION IN THE FUTURE, PERHAPS VACCINATION OF , TO SAY NOTHING OF BATS, WE CAN REVE THIS SCOURGE FROM THE POPULATION THAT IS NOW BEING AFFECTED. I'LL STOP THERE. >> THANKS. NOW THAT STANLEY HAS REALLY EXHAUSTED EVERYTHING THAT CAN BE SAID, WHO IS NEXT? >> THANK YOU. IT'S GREAT TO BE HERE. I MISSED THE MORNING SESSIONS. I WAS NOT ABLE TO LEAVE THE UNIVERSITY BECAUSE OF A CONFLICT THIS MORNING SO I ONLY HEARD THE AFTERNOON SESSIONS. AND I KNOW THERE WAS SOME GREAT TALKS. I WAS PARTICULARLY KEEN TO HEAR ERICA'S TALK ON THE SCIENCE STRUCTURE, SO I'LL MAKE COMMENTS RELATED TO THE AFTERNOON SESSION AND PERHAPS BE BROADER. A COUPLE IMPORTANT POINTS THAT STAN MADE ABOUT HOW CONSORTIUM WAS PUT TOGETHER TO TRY TO TAKE VACCINES THAT EITHER HAD NEVER BEEN IN A HUMAN BEING BEFORE BUT HAD VERY EXCITING ANIMAL PROTECTION DATA, OR HAD BEEN MINIMALLY USED IN HUMANS, AND TO TRY TO GET THEM VERY, VERY QUICKLY TO PHASE 1 TRIALS, INCLUDING IN TARGET POPULATIONS IN AFRICA. AND WHAT ONE SAW, I BELIEVE, IF IN OTHER LESSON COMES OUT OF THE EBOLA EXPERIENCE OF THE NEXT FEW ACCORDION OF TIME IT TAKES AND STEPS AND SQUEEZE THAT. WE SAW IT IS POSSIBLE. IT WON'T OR CAN'T BE DONE ROUTINELY BUT AN IRB THAT USUALLY TAKES A WEEK OR TEN DAYS TO GIVE YOU AN ANSWER CAN DO IT IN 12 OR 24 HOURS. WHEN YOU TAKE EACH OF THESE STEPS INCLUDING REGULATORY STEPS AND MAKE THEM SHORT ONE CAN REALLY MOVE THE EVALUATION PROCESS FORWARD. I WOULD AGREE VERY MUCH WITH THE IMPORTANCE TO COLLECT AS MANY SPECIMENS AS POSSIBLE. JUST BEFORE THE BREAK IN A LITTLE CLIQUE FOLKS WERE TALKING ABOUT TRYING TO GET SPECIMENS FROM EVERY SINGLE INDIVIDUAL IN THE TRIAL. THE NUMBERS ARE TENS OF THOUSANDS OR SCORES OF THOUSANDS FOR SOME TRIALS. WE'VE DUNCE THAT ONCE -- WE'VE DONE THAT ONCE IN AFRICA THAT INVOLVED OTHER 4000 INDIVIDUALS. THIS IS AN IMMUNIZATION, A RANDOM ALLOCATION OF THIRD TRIMESTER PREGNANT WOMEN TO GET INFLUENZA VACCINE OR GET A MENINGOCOCCAL VACCINE. HAVING BLOOD FROM MOTHERS AND INFANTS THAT BE POWERFUL BECAUSE WE'RE ZEROING IN ON TITER THAT ACTUALLY IS ASSOCIATED -- CORRELATED WITH PROTECTION. CAN IT BE DONE ON 20,000 OR 40,000 OR 60,000? I DON'T KNOW BUT IT'S WORTH A TRY AND AT LEAST STORE THE MATERIAL. I THINK IT IS CRITICAL TO COME UP WITH A GAME PLAN VERY FORMAL TO LINK THE HUMAN RESPONSES THAT WERE SEEN WITH THE VACCINE WITH THE NONHUMAN PRIMATE RESPONSES WITH DEFINITIVE EVIDENCE OF PROTECTION. WE'RE ALL HOPING THE FIELD TRIALS WILL TAKE OFF, THAT ANSWERS WILL BE GAINED, BUT WE DON'T KNOW EPIDEMIOLOGY OF EBOLA. WE JUST DON'T KNOW. AT THE MOMENTRE IS VERY POSITIVE FOR THE PEOPLE OF WEST AFRICA NEWS OF TRANSMISSION DIMINISHING, IS THAT BECAUSE OF INTERVENTIONS PUT IN PLAY ARE ACTUALLY RESPONSIBLE OR ARE WE SEEING THE SAME KIND OF SEASONALITY THAT WE SAW FOR EXAMPLE WITH SMALLPOX IN WEST AFRICA AND OTHER PLACES. DEPENDING UPON WHAT MONTH OF THE YEAR YOU LOOKED AT SMALLPOX, YOU GOT A VERY DIFFERENT PICTURE, BUT THE DISEASE BOUNCED BACK AGAIN WHEN THE HIGH SEASON RETURNED. THE REASON I MENTION THAT IS IF IT'S NOT POSSIBLE BECAUSE OF ENOUGH CASES TO GET ANSWERS FROM THE EFFICACY TRIALS, NOT BECAUSE THE TRIALS WEREN'T DESIGNED PROPERLY, BUT IF THERE JUST IS NOT CONTINUING TRANSMISSION THEN THE NONHUMAN PRIME PROTECTION DATA BECOME IMPORTANT AGAIN AND THERE'S GOT TO BE A REALLY GOOD LINK BETWEEN THE HUMAN IMMUNE RESPONSE AND WHAT ONE SEES IN THE NONHUMAN PRIMATES. MY PERSONAL COMMENTS ON T-CELLS, THEY ARE CLEARLY IMPORTANT. AT LEAST ONE OF THE VACCINES, BUT TRYING TO VALIDATE AND STANDARDIZE ACROSS LABORATORIES T-CELL MEASUREMENTS AND TRYING TO DO THAT WITH SPECIMENS COMING FROM AFRICA, IT'S HARD ENOUGH TO DO IN A MULTI-CENTERED TRIAL IN NORTH AMERICA OR EUROPE. I THINK THAT TRYING TO DO THAT WITH SPECIMENS COMING FROM AFRICA I THINK JUST MEANS YOU'RE SWIMMING UPSTREAM IN A FASTER CURRENT. IF YOU'RE A ABOUT SWIMMER PERHAPS IT CAN BE DONE BUT YOU'RE SWIMMING AGAINST THE CURRENT. STANLEY USED TO POINT OUT I KNOW THERE'S AN EXCEPTION OR TWO NOW, EVEN VIRAL VACCINES FOR WHICH WE KNOW CMI IS VERY IMPORTANT, THE CORRELATE OF PROTECTION IN MOST OF THOSE IS AN ANTIBODY. ANYWAY, NEUTRALIZING ANTIBODIES, I STILL DON'T UNDERSTAND WHY WE CAN'T SEE THE FUNCTIONAL ACTIVITY CORRELATE WITH PROTECTION. IT'S NICE TO HAVE THAT BUT THERE ARE OTHER VIRAL VACCINES FOR WHICH NEUTRALIZING ANTIBODY DOESN'T MAKE THE CORRELATE, ONE EXAMPLE IS ROTOVIRUS. WITH RESPECT TO THE ULTIMATE TARGET AGE GROUPS, TARGET POPULATIONS, AS WE LOOK AT THE VACCINES AND LOOK AT THE IMMUNOLOGIC MEASUREMENTS, THERE ARE I BELIEVE THREE VERY DISTINCT RISK GROUPS, POPULATION TARGETS THAT HAVE BEEN IDENTIFIED HERETOFORE WITH THE OBSERVATION OF DISEASE IN WEST AFRICA. ONE OF COURSE ARE HEALTH CARE WORKERS. THAT GROUP IS SUCH AN IMPORTANT TARGET BECAUSE IN EACH OF THE COUNTRIES, INCLUDING THE SMALL COUPLE OUTBREAKS IN MALI, WE HAVE SEEN WHAT HAPPENS AT THE HOSPITALS, AND AT THE HEALTH CENTERS, WHEN THERE IS DISEASE AND DEATH AMONGST HEALTH CARE WORKERS. PEOPLE, HEALTH CARE WORKERS, ARE NOT KEEN TO WORK IN THAT AREA. WE'VE GOT TO GIVE PROTECTION TO THAT POPULATION. THAT POPULATION IS KIND OF CAPTIVE, AND THEY NEED LONG-TERM PROTECTION. THEY NEED ENDURING PROTECTION. IT'S FOR THAT TARGET GROUP THAT I THINK THE HETEROLOGOUS BOOST REGIMENS NEED TO BE LOOKED AT VERY CAREFULLY. ANOTHER GROUP THAT WOULD SIMILARLY BENEFIT WOULD BE THE FOLKS WHO DO RITUAL BURIALS AND RITUAL FUNERAL PRACTICES. WE'VE SEEN THE IMPORTANCE OF THAT BEING DONE BY TRAINED, IF YOU WILL, CADRES AND THAT'S A POPULATION TO BE VACCINATED, AGAIN PERHAPS WITH BEST REGIMEN GIVING ENDURING PROTECTION, A HETEROLOGOUS PRIME BOOST, BUT FOR INTERRUPTING TRANSMISSION IN THE WIDER POPULATION, THE MODEL THAT I PERSONALLY SEE IS THAT A SINGLE DOSE VACCINE IS FAR MORE IMPORTANT BECAUSE IT'S SO MUCH MORE PRACTICAL, AND EVEN IF THAT VACCINE ONLY GAVE A SHORT-TERM -- RELATIVELY SHORT-TERM PROTECTION, AS LONG AS IT'S A HIGH LEVEL OF PROTECTION, THEN ONE CAN TRULY INTERFERE WITH TRANSMISSION. ONE OF THE TRIALS AT LEAST WILL BE LOOKING AT RING VACCINATION VERSUS A CONTROL APPROACH, AND GOING BACK TO THE OLD SMALLPOX DAYS, I SEE THAT FINDING CASES, HAVING THE ABILITY TO DO A RAPID DIAGNOSIS, DON'T HAVE THE CLINICAL PICTURE LIKE THE SMALLPOX, AND UNFORTUNATELY EBOLA TOO YOU GET THE POSITIVE RESULT, LOOKS LIKE FEVER, DIARRHEA, FEVER, VOMITING, GASTROENTERITIS AND A SICK PATIENT BUT DOING RING VACCINATION WITH SINGLE DOSE VACCINE I BELIEVE MY GUT FEELING IS THAT CAN REALLY MAKE AN IMPACT AND THEREFORE FOR THAT REGIMEN ONE NEEDS TO BE ABLE TO VERY CAREFULLY MONITOR THE KINETICS OF THE IMMUNE RESPONSE AFTER THE PRIMING, THE SINGLE INITIATING VACCINATION. I THINK THAT'S IT. ALTHOUGH I'LL SHARE ONE COMMENT I HEARD TODAY. THE MEETING I WAS AT THIS MORNING, BOB GALLO WAS THERE, AND HE QUOTED MAURICE HILLEMAN WHO SAID THAT THE ONLY CORRELATE OF PROTECTION IS PROTECTION. AND THAT'S VERY MAURICE HILLEMAN, BUT WHAT A GREAT OPPORTUNITY NOW TO TRY TO MAKE THIS LINK SO IMPORTANT, AN IMPORTANT QUEST, SO GREAT. THE AFTERNOON I HEARD, FANTASTIC MEETING, AND THANK YOU FOR THE PRESENTATIONS. >> SINCE YOU QUOTED MAURICE HILLEMAN, I SAID THIS TO SOMEONE ELSE TODAY, ANOTHER QUOTATION, AN EPIGRAPH, ALBERT EINSTEIN'S STATEMENT THAT EVERYTHING SHOULD BE MADE AS SIMPLE AS POSSIBLE, BUT NOT SIMPLER, THAT'S THE SITUATION WE FACE WITH CORRELATES OF PROTECTION. WE TRY TO SIMPLIFY, BUT KNOWING THAT THERE'S A COMPLEXITY BEHIND THAT, WHICH IMPACTS ON OUR ABILITY TO INTERPRET IMMUNOLOGIC PHENOMENA. >> OKAY. SO IF YOU THOUGHT EVERYTHING HAD ALREADY BEEN SAID BEFORE, STAN, NOW IT REALLY HAS ALREADY BEEN SAID. FOUR QUICK POINTS. FIRST, WHAT A PRIVILEGE IT'S BEEN TO NOT JUST BE PART OF THIS PANEL BUT PART OF THE RESPONSE TO THIS OUTBREAK AND SORT OF THIS UNPRECEDENTED ATTEMPTO USE A VACCINE IN THE MIDST OF A PUBLIC HEALTH EMERGENCY HASN'T EVER BEEN DONE BEFORE. SO ONE OF THE POINTS I WANT TO MAKE IS THAT WE'RE COMPRESSING WHAT'S USUALLY FIVE TO TEN YEARS OF WORK, OF CAREFUL DOSE FINDING AND EVERYTHING ELSE, DOWN INTO THREE MONTHS. AND MIKE MADE THAT A POINT TOO, SO IF YOU ASK IF WE'RE IDENTIFYING THE OPTIMAL DOSE, OPTIMAL WAY, IT'S NOT -- WE'RE DOING THE BEST WE CAN BUT IT'S ALL BASED ON PRETTY GOOD RATIONAL CHOICES AND DECISIONS. BUT ONE THING THAT I CAN SAY ABOUT THE COMPRESSION INTO THIS THREE-MONTH DEVELOPMENT PLAN IS THAT I DON'T THINK THERE'S BEEN ANY SHORT CUTS ON SAFETY. THERE MAY BE SOME SHORT CUTS ON PERFECTLY UNDERSTANDING DOSE AND IMMUNOGENICITY BUT I DON'T THINK THERE'S BEEN ANY SHORT CUTS ON SAFETY. THE SECOND POINT IS THAT I THINK THAT WE HAVE A GREAT OPPORTUNITY IN THE UPCOMING TRIAL TO TRULY FIGURE OUT THE CORRELATE OF PROTECTION IN HUMANS, WHICH MEANS THAT A LOT OF THE DIFFICULT DECISIONS ABOUT WHICH ASSAY TO USE REALLY ISN'T THAT, TO ME, YOU NEED TO THINK ABOUT IT BUT IT'S NOT THAT IMPORTANT YET. IT'S IMPORTANT IF WE CAN FIND AN EFFICACY RESULT IN THE HUMAN TRIAL BECAUSE IF WE CAN, WE CAN APPLY THE SAME KIND OF APPROACH THAT NELSON MICHAEL AND MERLIN ROB APPLIED IN THE R.V.-44 STUDIES, WITH A GOOD DYNAMIC RANGE THAT MEASURE DIFFERENT THINGS AND ARE DOABLE. AND YOU DO A SELECTED NUMBER OF THOSE AND YOU END UP RETROSPECTIVELY GETTING A CORRELATE OF IMMUNITY IN HUMANS WHICH ALLOWS YOU TO VALIDATE ANIMAL MODELS WHICH MAY MAKE IT EASY TO GET THROUGH THE VACCINE PROJECTS IN THE FUTURE. THE THIRD POINT, WE'RE DOING THIS TRIAL IN ZAIRE ONLY BECAUSE IT'S A MONOVALENT OUTBREAK AND EPIDEMIC AND CRISIS BUT TO PUT EBOLA OR FILOVIRUS IN THE STOCKPILE IT DOESN'T MAKE SENSE TO HAVE A MONOVALENT VACCINE, IT NEEDS TO BE FOR SUDAN AND MARBURN. IN WE FIND A RESULT IN THE EFFICACY TRIAL AND KNOWING THAT MONOVALENT HELPS BUT IS NOT THE FINAL ANSWER MAYBE THERE NEEDS A FOURTH CATEGORY OF LICENSURE IN BETWEEN ACCELERATED AND ANIMAL WHERE YOU CAN USE DATA FROM MONOVALENT TO LICENSE PRODUCT SO I'D LOVE TO HEAR SOME THOUGHTS ABOUT THE REGULATORY AUTHORITIES ON HOW TO ACHIEVE THAT BECAUSE I THINK WE DON'T REALLY WANT A MONOVALENT PRODUCT, WE WANT AT LEAST A TRIVALENT PRODUCT. THE FOURTH POINT, BECAUSE WE'VE SET A PRECEDENT OF A DEVELOPMENT PLAN IN THREE MONTHS INSTEAD OF FIVE TO TEN YEARS, TRYING TO USE BE A EXPERIMENTAL VACCINE IN A PUBLIC HEALTH CRISIS, WHY CAN'T WE USE THIS EXPERIENCE TO BROADLY THINK MORE ABOUT FUTURE PUBLIC HEALTH CHALLENGES AND PUBLIC HEALTH CRISES, AND YOU KNOW ONE OF THE REASONS WE WERE ABLE TO RESPOND IN THIS WAY IS BECAUSE THERE HAD BEEN WORK ON THESE VACCINES IN THE FUTURE, AND SO TYPICALLY VACCINES ARE A LONG-TERM DEVELOPMENT PLAN, MEASURED IN DECADES, NOT SOMETHING YOU PULL OUT OF YOUR HAT, AND SO THIS IDEA THAT YOU CAN DO THESE EMERGENCY RESPONSES WITHOUT PRIOR PREPARATION I THINK NEEDS TO BE DISCUSSED IN MORE DETAIL TO LEVERAGE WHATEVER WE CAN TO HAVE BETTER PREPARATION, BETTER SURVEILLANCE, BETTER VIRUS DISCOVERY, DISCOVERY OF HUMAN PATHOGENS AND DEVELOPMENT AND WORK ON PLATFORMS FOR ALL FAMILIES OF VIRUSES THAT COULD POTENTIALLY BE HUMAN THREATS, IT NEEDS TO BE DONE AHEAD OF TIME, NEEDS TO BE FUNDED AND IT'S NOT JUST KNOWLEDGE FOR KNOWLEDGE'S SAKE BUT LIKE THE PRESIDENT SAID THE OTHER DAY, YOU DON'T KNOW WHAT YOU NEED TO KNOW UNTIL YOU NEED TO KNOW IT AND IT'S SOMETHING THAT WE NEED TO USE THIS EPIDEMIC AS A WAY TO PUSH THROUGH TO IMPROVE FUNDING FOR THIS KIND OF WORK. I'LL STOP THERE. >> WHAT I'D LIKE TO DO IS GIVE THOSE IN THE AUDIENCE AN OPPORTUNITY TO MAKE COMMENTS RELATED TO THE CONCLUSIONS OF THE MEETING, STEPS GOING FORWARD AND RECOMMENDATIONS FOR HOW WE CAN FURTHER ADDRESS THESE ISSUES. >> I'M ANITA McELROY FROM EMORY AND CDC. I'M CURIOUS WHAT YOUR THOUGHTS ARE ON WHAT WE SHOULD BE LOOKING AT IN HUMANS NATURALLY INFECTED RATHER THAN GETTING AWAY FROM THE IDEA OF YES, THE VACCINE IS GOLD STANDARD, AND CORRELATES OF IMMUNITY, BEYOND ANTIBODIES AND T-CELLS, ANY THOUGHTS ON THINGS WE SHOULD BE LOOKING AT IN HUMANS? WE HAVE LOTS OF SAMPLES BEING COLLECTED IN WEST AFRICA AND STORED, WHAT SHOULD WE BE LOOKING AT? >> I THINK STUDYING SURVIVORS IS A GREAT THING TO DO. WE WERE ABLE TO IDENTIFY SOME KIKWIT SURVIVORS AND HAD THEM TO COME OVER AND WERE STUDIED IN DETAIL. WHAT HAPPENS IN RECOVERY DOESN'T NECESSARILY TELL YOU WHAT YOU NEED TO DO TO PREVEN, AS STANLEY POINTED OUT EARLIER, PEOPLE WITH T-CELL DEFICIENCIES DIE OF MEASLES, BUT MEASLES IS PROTECTED BY ANTIBODY RESPONSE. YOU RECOVER WITH T-CELLS WHAT YOU PROTECT WITH ANTIBODY GENERALLY SO IT DOESN'T ENTIRE INFORM WHAT YOU NEED FOR PREVENTING VACCINE BUT CERTAINLY IS A WAY OF PROVIDING REAGENTS, YOU CAN CLONE UNIQUE MONOCLONAL ANTIBODIES OUT OF SURVIVORS THAT CAN BE REAGENTS FOR FUTURE PROPHYLACTIC STUDIES OR GUIDE ANTIGEN BY FINDING STRUCTURES ASSOCIATED WITH THESE GOOD ANTIBODIES AND SO STUDYING SURVIVORS IS IMPORTANT BUT IT'S NOT NECESSARILY GOING TO INFORM PREVENTION. >> OTHER COMMENTS FROM THE AUDIENCE? >> I THINK -- I'LL DIRECT THIS TO MIKE LEVINE. WE HEARD EARLIER FROM MIKE CALLAHAN BEFORE YOU GOT HERE, MIKE, HE WAS TALKING ABOUT QUITE A DEAL OF VARIABILITY IN THE SUCCESS, CLINICAL SUCCESS, THE VARIOUS ECUs. I'M WONDERING HOW THAT MIGHT IMPACT CLINICAL TRIALS, QUITE A LOT OF VARIABILITY IN THE CLINICAL CARE ACROSS THESE COUNTRIES. >> YOU MEAN IN TERMS OF FATALITY? THAT'S ALWAYS A PROBLEM, ONE WANTS TO HAVE AS MUCH STANDARDIZATION OF CARE AS POSSIBLE. ON THE OTHER HAND, A LOT DEPENDS ON THE DESIGN, AND IN AN ADEAL DESIGN, WHICH IS DIFFICULT, BUT IF IT WERE A RANDOMIZED AT THE LEVEL OF THE INDIVIDUAL CONTROL, MEANING PLACEBO OR IRRELEVANT VACCINE, THEN BOTH THE VACCINATED AND UNVACCINATED ARE EXPOSED TO THE SAME LEVEL OF CARE AND DEPENDING ON HOW MANY TREATMENT CENTERS THAT SHOULD EVEN OUT. ONE OF THE REAL CHALLENGES OF THIS EBOLA SITUATION THAT THE OTHER SIDE OF THE COIN, BARNEY, OF GOING AHEAD AND DOING PHASE 1 AND 2 TRIALS IN THE MIDST OF EPIDEMIC IS ETHICAL ISSUES OF DOING EFFICACY TRIALS IN THE MIDST, AND SO SOME OF THE TRIALS ARE USING METHODOLOGIES THAT TRY TO ADDRESS THIS AND THEY ARE NOT THE CLASSICAL OR GOLD STANDARD TYPES OF TRIALS, BUT ONE HAS TO GRAPPLE WITH THE REALITY OF ALL THE ETHICAL ISSUES. >> ED NEWSOME, NIAID. I'M GOING TO MAKE A SUGGESTION, ONE IS REPLICATING, THE OTHER WILL BE HETEROLOGOUS PRIME BOOST BUT I DON'T THINK IT'S BEEN LOOKED AT ON CORRELATE OF PROTECTION IF YOU COULD DESIGN NHP STUDIES WITH LOW TO HIGH DOSE OF VACCINE, YET A DOSE DEPENDENT IMMUNE RESPONSE THAT CORRELATES WITH RESPONSE YOU CAN GET VALUABLE SAMPLES TO GO TO ADDRESS THE CORRELATE OF PROTECTION ISSUE WHICH ASSAYS TO USE AND FOR ANTHRAX THAT WAS VALUABLE. THESE VACCINES ARE DIFFERENT BUT IT'S HASN'T BEEN DONE, THE NHP MODEL NEEDS A FURTHER LOOK, I THINK THE CHALLENGE DOSE IS TOO HIGH. WE COULD LOOK AT DIFFERENT ROUTES OF INFECTION, THEY ARE NOT GETTING INFECTED BY THE IM ROUTE SO THERE'S MORE TO DO WITH NHP MODEL THAT MIGHT GIVE US A LOT OF INFORMATION. >> THANK YOU. OTHER COMMENTS? >> COULD I JUST SPEAK TO THAT? STAN IS GONE BUT THIS WAS DISCUSSED, THE ADVISORY WORKING GROUP, TO THE VRC, AND THOSE VERY POINTS WERE MADE AND THE TEAM AT VRC ABSOLUTELY AGREED, THERE'S MUCH MORE TO BE DONE WITH THE NHP MODEL AND THAT MAY BE VERY, VERY IMPORTA. >> TO FOLLOW ON THAT CONCEPT -- >> IDENTIFY YOURSELF. >> WITH THE ANTHRA EXPERIENCE LIKE YOU SAID WE'VE DONE A LOT OF WORK ON THE NHP MODELS AND RABBIT MODELS. MY QUESTION IS IF THE EFFICACY STUDIES ARE NOT POSSIBLE AT THE END OF THE DAY DO WE HAVE A PLAN B? DO WE KNOW WE'RE GOING TO GO WITH ANIMAL RULE, AND SHOULD WE BE DOING EXACTLY WHAT HE SAYS, IN THAT GET THE ANIMAL MODELS WORKED OUT FOR ANIMAL RULES APPROVAL OR LICENSURE STRATEGY AS A PLAN B JUST IN CASE THERE AREN'T ENOUGH CASES IN THE EFFICACY STUDIES. >> I THINK I CAN ADDRESS THAT. IF WE DON'T GET AN EFFICACY RESULT, THE ANIMAL RULE BECOMES THE BACKUP PLAN. IT'S ONE OF THE REASONS WHY RIP BALLOU MENTIONED A 3000 PERSON PHASE 2 TRIALS WILL BE DONE IN NEIGHBORING COUNTRIES SO FAR UNAFFECTED BECAUSE THE SAFETY DATABASE AND MORE ROBUST IMMUNOGENICITY DATABASE WOULD BE NEEDED, WHETHER YOU DO FIELD TRIAL EFFICACY OR ANIMAL RULE EFFICACY, AND ATTEMPTED LICENSURE, SO I THINK THAT STUDY IS CRITICAL BECAUSE IT WILL INFORM EITHER PATHWAY THAT HAS TO BE TAKEN. >> JUST TO ADD THOUGH, THAT IF IT WERE POSSIBLE IN THE COURSE OF THE STUDY TO DEVELOP A CORRELATE OF PROTECTION ACCELERATED APPROVAL WOULD BE AN OPTION UNDER THOSE CIRCUMSTANCES. >> OTHER COMMENTS? >> YOU HUNG IT OUT THERE, SO WHAT EXACTLY DO YOU MEAN BY APPROVAL IN THIS INSTANCE? DO YOU MEAN IT WOULD BE APPROVAL FOR THIS CIRCUMSTANCE? OR WOULD IT BE AN ONGOING -- IT'S A LICENSE THAT WOULD BE IN PERPETUITY UNLESS THE VACCINE DID SOMETHING NASTY IN THE FUTURE? >> IN THE U.S. LICENSES ARE LICENSES, IF LICENSED FOR AN INDICATION, PREVENTION OF EBOLA DISEASE OR INFECTION OR WHATEVER IT WAS. >> ONE QUESTION THAT WENT NOT FULLY EXPLAID, WHY ONE WOULD CHALLENGE 100 DF 50, I.E.E 50, WE KICKED IT AROUND 50 YEARS AGO, DEBATING BETWEEN A HUNDRED AND A THOUSAND, WE WANTED TO BACK TITRATE BECAUSE IT'S SO LETHAL IN MONKEYS IF YOU GO TO LOWER GOES YOU CAN'T BACKTITRATE IT, BUT THAT'S A REALISTIC DOSE BY ANY NEEDLE STICK, AND WE RECKON WHATEVER OUR APPROACH WAS IF IT DIDN'T PROTECT AGAINST 100 OR A THOUSAND PFUs IT AUDIT TO BE LAID DOWN AND PURSUE SOMETHING IT DID. WE WENT PROTECT AGAINST 3 IF WE COULDN'T PROTECT AGAINST A HUNDRED OR A THOUSAND ON THE SAY SAYS, IF A CORE FACILITY THAT COULD DO CORE ASSAYS IT WOULD BE WONDERFUL. >> OTHER COMMENTS? >> IT'S BEEN SAID THERE'S NO CORRELATE OF IMMUNITY, AT LEAST IN THE ANIMALS THAT CORRELATE IS AS GOOD AS WE HAVE FOR SOME LICENSED VACCINES BUT PIE QUESTION IS TO THE FDA WHAT WOULD YOU EXPECT ASSUMES 100 PER CENT PROTECTION IN THE FIELD TRIAL AND NO CHANCE OF MAKING A CORRELATE BECAUSE THERE'S NO FAILURES IF THERE'S EFFICACY, THAT'S A POSSIBTY SINCE WE'RE NOT WORKING WITH A THOUSAND LD 50s, EVEN WHEN PEOPLE ARE DOING BURIAL, I DON'T BELIEVE. SO WHAT WOULD YOU EXPECT FOR CORRELATE OF IMMUNITY IN MONKEYS GIVEN DATA WE HAVE NOW THAT IT LOOKS LIKE A MIX OF ANTIBODY AND CELLULAR IMMUNITY? >> SO THAT'S -- >> AT LEAST FOR THE ADENOMIX PRIME BOOST. >> WHEN YOU ASK A REGULATED QUESTION, THE ANSWER IS ALWAYS IT DEPEND. IT DOES IN THIS CASE. INFORMATION TO SHOW EFFICACY AND SO YOU'LL HAVE BASIC CORE OF THE INFORMATION THAT YOU NEED TO LICENSE THE VACCINE, BUT THEN IT REALLY COMES DOWN TO WHAT IS THE INITIAL USE THAT YOU WANT TO USE THAT CORRELATE FOR? IF IT'S BEING USED FOR -- IF THE IMMUNE MARKER OF PROTECTION IS BEING USED FOR BRIDGING STUDIES FOR INSTANCE IT DOESN'T NEED TO BE AS STRONG AS IF IT WERE SUPPORTING AN ACCELERATED APPROVAL, SO I THINK UNDER THOSE CIRCUMSTANCES WE WOULD LOOK TO THE SCIENTIFIC DATA THAT WERE AVAILABLE AND WOULD MAKE THE BEST JUDGMENT THAT WE COULD. DEPENDING ON THE EXACT PURPOSE THAT THE CORRELATE WAS BEING CONSIDERED FOR. >> IF THAT WAS THE LAST COMMENT, I'M PLEASED TO HAVE HAD THE LAST WORD. I THINK THIS HAS BEEN A FANTASTIC MEETING. WE'VE HAD A SERIES OF OUTSTANDING TALKS, PEOPLE CAME TOGETHER FROM AROUND THE WORLD TO TALK ABOUT A VERY IMPORTANT PUBLIC HEALTH PROBLEM. WE'VE HAD FANTASTIC AND ROBUST DISCUSSIONS INVOLVING INVITED SPEAKERS AS WELL AS THOSE IN THE AUDIENCE. I THINK WE HAVE IDENTIFIED SOME VERY IMPORTANT ISSUES GOING FORWARD. AMONG THEM ONE OF THE MOST IMPORTANT COMMENTS WAS THE NEED SERUM IN A WAY THAT ROBUSTLY CAN BE USED IN THE FUTURE TO DO THE KINDS OF STUDIES WE'RE TALKING ABOUT, TO SUPPORT CORRELATES OF PROTECTION SO THAT'S SOMETHING THAT IT SEEMS REASONABLE FOR SOMEBODY TO FIGURE OUT HOW TO DO. I THINK WE'VE HEARD A LOT ABOUT DIFFERENT ARMS OF THE IMMUNE SYSTEM THAT ARE IMPORTANT BUT I TOOK STANLEY'S POINT AT THE END THAT NOBODY IS ARGUING ANTIBODIES ARE UNIMPORTANT, SO I THINK THAT FOCUSING ON PEOPLE PLACING SO FAR ON ANTIBODY ASSAYS IS TAKING INTO ACCOUNT PRACTICAL ISSUES. THE COMMENT BY BARNEY AT THE END, IT MAY BE WE WON'T YET HAVE THE BEST ASSAYS FOR DEVELOPING THIS CORRELATE OF PROTECTION AND THAT I THINK THE UNANIMOUS AGREEMENT AMONG OUR THREE FINAL PANELISTS TO TRY TO GET AS MANY SAMPLES AS POSSIBLE OUT OF THESE CLINICAL TRIALS IN THE HOPES OF BEING ABLE TO USE THOSE SAMPLES EVEN ON A POST HOC BASIS TO DEVELOP CORRELATES OF PROTECTION AS ASSAYS IMPROVE AND WE WORK THESE THINGS OUT IS REALLY IMPORTANT. I THINK AS WITH EVERYBODY, I WAS STRUCK BY THE SPIRIT OF COLLABORATION AT THIS MEETING AND ALSO STRUCK BY THE WILLINGNESS OF THE PEOPLE AT THE MEETING TO COLLABORATE GOING FORWARD, FOR INSTANCE POTENTIALLY BY PUTTING TOGETHER CLINICAL ASSAYS WORKING GROUP TO ADDRESS ASSAY-RELATED ISSUES. SO WITH THAT, I WOULD LIKE TO REALLY THANK EVERYBODY IN THE ROOM, EVERYONE IN THE OVERFLOW ROOM, ON THE INTERNET WHO HAS BEEN WATCHING THE PROCEEDINGS AND I THINK YOU ALL DESERVE A ROUND OF APPLAUSE. I'M INSTRUCTED TO TELL YOU YOU NEED THIS BADGE TO GET OUT OF THE BUILDING OR YOU'LL BE FORCED TO STAY HERE THE REST OF YOUR LIFE. YOU HAVE TO CHECK OUT WITH SECURITY, WHICH WILL TAKE SOME ADDITIONAL TIME AS YOU LEAVE. SO I WOULD LIKE TO APPLAUD THE ORGANIZING COMMITTEE, SPEAKERS, AUDIENCE, ALL THE PARTICIPANTS AND EVERYBODY INVOLVED IN THE GLOBAL ANTI-EBOLA EFFORT AFTER HAVING HAD VERY PRODUCTIVE DISCUSSIONS TODAY. THANK YOU. [APPLAUSE]