1 00:00:10,227 --> 00:00:15,165 >> I'M DAN ROTROSEN, DIRECTOR OF 2 00:00:15,165 --> 00:00:16,533 THE DIVISION. 3 00:00:16,533 --> 00:00:17,635 IT'S MY PLEASURE TO WELCOME YOU 4 00:00:17,635 --> 00:00:20,304 TO OPEN SESSION OF THE COUNCIL 5 00:00:20,304 --> 00:00:20,871 SUBCOMMITTEE. 6 00:00:20,871 --> 00:00:24,808 WE HAVE FOUR TERRIFIC SPEAKERS 7 00:00:24,808 --> 00:00:30,080 WHO ALL ARE FUNDED BY AND WORK 8 00:00:30,080 --> 00:00:33,584 THROUGH OUR VACCINE ADJUVANT 9 00:00:33,584 --> 00:00:35,753 PROGRAM, SO VERY TIMELY UPDATE 10 00:00:35,753 --> 00:00:36,854 FROM THEM. 11 00:00:36,854 --> 00:00:42,459 BUT BEFORE WE BEGIN WITH THAT, 12 00:00:42,459 --> 00:00:44,094 WOLFGANG LIGHTNER IS GOING TO 13 00:00:44,094 --> 00:00:46,263 GIVE BACKGROUND ON THAT PROGRAM 14 00:00:46,263 --> 00:00:49,333 AND ITS EVOLUTION, AND SOME 15 00:00:49,333 --> 00:00:51,101 THOUGHTS ON NEW OPPORTUNITIES. 16 00:00:51,101 --> 00:00:53,837 WOLFGANG WILL INTRODUCE EACH OF 17 00:00:53,837 --> 00:00:57,675 THE SPEAKERS AND FOLLOWING THOSE 18 00:00:57,675 --> 00:01:00,110 PRESENTATIONS WE WILL HAVE THREE 19 00:01:00,110 --> 00:01:02,279 RESEARCH CONCEPT CLEARANCES FOR 20 00:01:02,279 --> 00:01:02,813 COUNCIL APPROVAL. 21 00:01:02,813 --> 00:01:08,185 AND AS WE ORDINARILY DO, WE 22 00:01:08,185 --> 00:01:10,954 REALLY WELCOME YOUR COMMENTS, 23 00:01:10,954 --> 00:01:14,658 SUGGESTIONS, AND THE LIKE. 24 00:01:14,658 --> 00:01:20,764 AND I HAVE TWO REMINDERS. 25 00:01:20,764 --> 00:01:22,433 ONE IS IF YOU'RE ONLINE DO NOT 26 00:01:22,433 --> 00:01:23,734 USE THE CHAT FUNCTION. 27 00:01:23,734 --> 00:01:26,603 THAT WILL CREATE A FACA 28 00:01:26,603 --> 00:01:27,671 REQUIREMENT, WHICH WE REALLY 29 00:01:27,671 --> 00:01:30,974 DON'T WANT. 30 00:01:30,974 --> 00:01:34,344 AND SECOND, IF YOU ARE SPEAKING 31 00:01:34,344 --> 00:01:37,948 REMEMBER TO USE THE MICS, AND 32 00:01:37,948 --> 00:01:40,584 IDENTIFY YOURSELF SO THE RECORD 33 00:01:40,584 --> 00:01:46,390 CAN BE ACCURATE. 34 00:01:46,390 --> 00:01:50,327 WOLFGANG, IT'S ALL YOURS. 35 00:01:50,327 --> 00:01:54,498 >> GOOD AFTERNOON. 36 00:01:54,498 --> 00:01:58,869 THE MAKE FOCUS WILL BE 37 00:01:58,869 --> 00:02:02,139 ADJUVANTS, I'M THE CHIEF OF THE 38 00:02:02,139 --> 00:02:04,108 SECTION THAT OVERSEES THE 39 00:02:04,108 --> 00:02:04,908 ADJUVANT PROGRAM. 40 00:02:04,908 --> 00:02:09,513 NOW, BEFORE I TELL YOU A LITTLE 41 00:02:09,513 --> 00:02:11,014 MORE ABOUT THE PROGRAM, I WANT 42 00:02:11,014 --> 00:02:12,883 TO GIVE YOU A HISTORIC SUMMARY 43 00:02:12,883 --> 00:02:15,953 OF HOW WE GOT THERE. 44 00:02:15,953 --> 00:02:17,788 DATA HAS BEEN SUPPORTING THE 45 00:02:17,788 --> 00:02:20,991 ADJUVANT RESEARCH FOR TWO 46 00:02:20,991 --> 00:02:28,632 DECADES NOW, AND ACCORDING TO 47 00:02:28,632 --> 00:02:30,267 DR. HACKETT WHO CREDITS THE 48 00:02:30,267 --> 00:02:32,136 PROGRAM HE CREDITS CHARLIE 49 00:02:32,136 --> 00:02:33,036 CHAINWAY WITH INSPIRING THE 50 00:02:33,036 --> 00:02:36,106 PROGRAM, HE PRESENTED THE FIRST 51 00:02:36,106 --> 00:02:39,543 RESULT OF A HUMAN TOLL RECEPTOR 52 00:02:39,543 --> 00:02:42,012 AT ACTUALLY AT AN OPEN COUNCIL 53 00:02:42,012 --> 00:02:45,282 MEETING, THIS FORUM WE'RE HERE 54 00:02:45,282 --> 00:02:48,652 TODAY, IN 1997. 55 00:02:48,652 --> 00:02:51,155 A YEAR LATER, HOSTED AN EXPERT 56 00:02:51,155 --> 00:02:55,125 PANEL ON BASIC IMMUNOLOGY OF 57 00:02:55,125 --> 00:02:59,530 VACCINES, THIS ALSO PROVIDED 58 00:02:59,530 --> 00:03:01,298 FOUNDATIONAL INSIGHT INTO WHAT 59 00:03:01,298 --> 00:03:03,267 LED TO THE FIRST DATE ADJUVANT 60 00:03:03,267 --> 00:03:07,004 PROGRAM, THE FIRST SOLICITED 61 00:03:07,004 --> 00:03:07,638 PROGRAM. 62 00:03:07,638 --> 00:03:11,041 A YEAR LATER ADJUVANT RESEARCH 63 00:03:11,041 --> 00:03:12,676 WAS INCLUDED IN THE NIAID 64 00:03:12,676 --> 00:03:13,644 STRATEGIC PLAN FOR THE FIRST 65 00:03:13,644 --> 00:03:15,746 TIME, AND THE FIRST PROGRAM THAT 66 00:03:15,746 --> 00:03:20,284 WAS THE ADJUVANT DISCOVERY 67 00:03:20,284 --> 00:03:22,953 PROGRAM WAS LAUNCHED IN 2003. 68 00:03:22,953 --> 00:03:24,021 WE'RE NOW STARTING FIFTH 69 00:03:24,021 --> 00:03:28,826 ITERATION OF THAT PROGRAM. 70 00:03:28,826 --> 00:03:30,194 IN 2011, ADJUVANT RESEARCH 71 00:03:30,194 --> 00:03:31,128 BROUGHT ITS OWN STRATEGIC PLAN 72 00:03:31,128 --> 00:03:33,530 FOR THE FIRST TIME, THIS PLAN 73 00:03:33,530 --> 00:03:36,700 WAS RENEWED IN 2019 JUST IN TIME 74 00:03:36,700 --> 00:03:38,001 FOR THE PANDEMIC. 75 00:03:38,001 --> 00:03:39,236 AND THE INVESTIGATORS THAT ARE 76 00:03:39,236 --> 00:03:41,839 SUPPORTED BY THIS PROGRAM HAVE 77 00:03:41,839 --> 00:03:43,607 BEEN EXCEPTIONALLY PRODUCTIVE 78 00:03:43,607 --> 00:03:46,577 AND INNOVATIVE AND THIS PROGRAM 79 00:03:46,577 --> 00:03:49,112 HAS LED TO TWO ADJUVANTS THAT 80 00:03:49,112 --> 00:03:51,181 ARE USED IN LICENSED COVID 81 00:03:51,181 --> 00:03:51,949 VACCINES. 82 00:03:51,949 --> 00:03:54,818 TOGETHER WITH MANY, MANY OTHER 83 00:03:54,818 --> 00:03:58,222 CLINICAL TRIALS OFF VACCINES 84 00:03:58,222 --> 00:03:59,156 INCLUDING ADJUVANTS THAT HAVE 85 00:03:59,156 --> 00:04:00,724 COME OUT OF THE PROGRAM. 86 00:04:00,724 --> 00:04:01,792 NOW, THE PROGRAM STARTED WITH 87 00:04:01,792 --> 00:04:02,860 ADJUVANT DISCOVERY. 88 00:04:02,860 --> 00:04:04,595 IN THE MEANTIME OVER THE LAST 89 00:04:04,595 --> 00:04:06,964 TWO DECADES, A LOT OF ADDITIONAL 90 00:04:06,964 --> 00:04:10,901 SOLICITED PROGRAMS HAVE BEEN 91 00:04:10,901 --> 00:04:13,537 ADDED TO COVER THE RANGE OF 92 00:04:13,537 --> 00:04:16,473 ACTIVITIES NEEDED TO GET NOVEL 93 00:04:16,473 --> 00:04:19,576 ADJUVANTS TOWARDS THE CLINIC. 94 00:04:19,576 --> 00:04:20,878 WE'RE SUPPORTING ADJUVANT 95 00:04:20,878 --> 00:04:21,945 DISCOVERY, RESEARCH ON 96 00:04:21,945 --> 00:04:23,013 COMBINATION ADJUVANTS TO 97 00:04:23,013 --> 00:04:26,984 DETERMINE WHAT'S THE RIGHT 98 00:04:26,984 --> 00:04:27,885 COMBINATION, HOW COMBINATIONS 99 00:04:27,885 --> 00:04:30,487 WORK, AND THERE'S A LOT OF FOCUS 100 00:04:30,487 --> 00:04:31,755 ON BRINGING NOVEL ADJUVANTS 101 00:04:31,755 --> 00:04:34,291 TOWARDS THE FIRST CLINICAL 102 00:04:34,291 --> 00:04:36,727 TRIAL, TOWARDS IND-ENABLING 103 00:04:36,727 --> 00:04:36,960 STUDIES. 104 00:04:36,960 --> 00:04:39,129 SO OUR ADJUVANT DEVELOPMENT 105 00:04:39,129 --> 00:04:41,231 PROGRAM HELPS NOVEL ADJUVANTS 106 00:04:41,231 --> 00:04:43,634 TOWARDS IND-ENABLING STUDIES. 107 00:04:43,634 --> 00:04:46,370 NOW, WHILE THE PROGRAM DOES NOT 108 00:04:46,370 --> 00:04:48,472 DIRECTLY SUPPORT CLINICAL 109 00:04:48,472 --> 00:04:49,773 TRIALS, THESE ARE MANAGED BY 110 00:04:49,773 --> 00:04:55,012 EITHER OTHER DIVISIONS AT NIAID 111 00:04:55,012 --> 00:04:59,449 OR OTHER AGENCIES. 112 00:04:59,449 --> 00:05:02,986 THE ADJUVANT PROGRAM HAS BEEN 113 00:05:02,986 --> 00:05:08,926 INVOLVED IN DEVELOPMENT OF NOVEL 114 00:05:08,926 --> 00:05:12,195 ADJUVANTS FOR OPIOIDS, PART OF 115 00:05:12,195 --> 00:05:14,965 THE NIH "HEAL" PROGRAM. 116 00:05:14,965 --> 00:05:25,008 AS YOU'RE AWARE OF, IT IS NOT IN 117 00:05:25,008 --> 00:05:26,977 THE MISSION TO DEVELOP. 118 00:05:26,977 --> 00:05:32,349 THEY ARE THE MOTE IMPORTANT 119 00:05:32,349 --> 00:05:33,750 COMPONENT OF VACCINES AND THERE 120 00:05:33,750 --> 00:05:35,185 ARE ISSUES WITH RESEARCH, NAMELY 121 00:05:35,185 --> 00:05:40,324 WHAT IS AVAILABLE FOR VACCINE 122 00:05:40,324 --> 00:05:41,091 RESEARCH. 123 00:05:41,091 --> 00:05:43,694 THE NUMBER OF ADJUVANTS THAT ARE 124 00:05:43,694 --> 00:05:45,529 AVAILABLE TO ACTUALLY BE TAKEN 125 00:05:45,529 --> 00:05:46,964 INTO THE CLINIC IS VERY SMALL, 126 00:05:46,964 --> 00:05:51,501 BUT THE NEED CONTINUES TO 127 00:05:51,501 --> 00:05:52,135 INCREASE. 128 00:05:52,135 --> 00:05:53,904 MOST ADJUVANTS OUT THERE ARE 129 00:05:53,904 --> 00:05:56,540 ONLY AVAILABLE FOR PRE-CLINICAL 130 00:05:56,540 --> 00:05:57,174 STUDIES. 131 00:05:57,174 --> 00:05:58,809 ADJUVANTS USED IN LICENSED 132 00:05:58,809 --> 00:06:00,677 VACCINES ARE NOT ACCESSIBLE TO 133 00:06:00,677 --> 00:06:01,345 MOST RESEARCHERS. 134 00:06:01,345 --> 00:06:04,081 SO AS A RESULT, THE WAY ADJUVANT 135 00:06:04,081 --> 00:06:06,583 SELECTION WORKS IN REAL LIFE IS 136 00:06:06,583 --> 00:06:07,784 THE VACCINE DEVELOPERS TEND TO 137 00:06:07,784 --> 00:06:09,753 GO WITH THE ONES THAT ARE 138 00:06:09,753 --> 00:06:12,489 ACCESSIBLE, NOT THE ONES MOST 139 00:06:12,489 --> 00:06:13,256 SUITABLE FOR PARTICULAR VACCINE. 140 00:06:13,256 --> 00:06:16,326 AND SO AS A RESULT YOU MAY END 141 00:06:16,326 --> 00:06:18,061 UP WITH SUBOPTIMAL COMBINATIONS 142 00:06:18,061 --> 00:06:22,733 OF ADJUVANT AND VACCINE. 143 00:06:22,733 --> 00:06:23,867 NOW, CHARLIE CHAINWAY FAMOUSLY 144 00:06:23,867 --> 00:06:26,837 CALLED ADJUVANTS THE DIRTY 145 00:06:26,837 --> 00:06:28,472 LITTLE SECRET OF VACCINES, THAT 146 00:06:28,472 --> 00:06:31,174 REFERS TO THE FACT THAT WE'VE 147 00:06:31,174 --> 00:06:33,176 BEEN ADDING ADJUVANTS OR WITH 148 00:06:33,176 --> 00:06:36,113 KNOWN THAT ADJUVANTS ARE 149 00:06:36,113 --> 00:06:36,980 CRITICAL FOR VACCINES FOR THE 150 00:06:36,980 --> 00:06:38,849 LONGEST TIME WITHOUT 151 00:06:38,849 --> 00:06:39,950 UNDERSTANDING WHY. 152 00:06:39,950 --> 00:06:42,452 THIS WAS CERTAINLY TRUE AT THE 153 00:06:42,452 --> 00:06:42,953 TIME, STILL TRUE. 154 00:06:42,953 --> 00:06:45,389 IF YOU THINK ABOUT ALUM, ADDED 155 00:06:45,389 --> 00:06:48,058 TO HUMAN VACCINES FOR A CENTURY, 156 00:06:48,058 --> 00:06:50,460 WE STILL DON'T UNDERSTAND HOW 157 00:06:50,460 --> 00:06:52,662 ALUM WORKS. 158 00:06:52,662 --> 00:06:54,965 SO VACCINE DEVELOPMENT REALLY 159 00:06:54,965 --> 00:06:59,002 REQUIRES MORE DETAILED INSIGHTS 160 00:06:59,002 --> 00:07:04,574 INTO IMMUNE MECHANISMS, DAIT 161 00:07:04,574 --> 00:07:05,008 SUPPORTS THESE. 162 00:07:05,008 --> 00:07:07,511 SYSTEMATIC SEARCH FOR NOVEL 163 00:07:07,511 --> 00:07:09,179 ADJUVANTS, NOVEL ADJUVANTS THAT 164 00:07:09,179 --> 00:07:11,014 ARE HIGHLY DEFINED, AND I'M NOT 165 00:07:11,014 --> 00:07:14,217 ONLY TALKING ABOUT CHEMICALLY 166 00:07:14,217 --> 00:07:15,519 DEFINED SO VERY SPECIFIC 167 00:07:15,519 --> 00:07:18,255 MOLECULES, NOT JUST MIXTURE OF 168 00:07:18,255 --> 00:07:20,023 MOLECULES, WHOSE FUNCTIONS WE 169 00:07:20,023 --> 00:07:20,590 DON'T UNDERSTAND, BUT ALSO 170 00:07:20,590 --> 00:07:23,727 DEFINED IN TERMS OF THE 171 00:07:23,727 --> 00:07:25,495 MECHANISM OF ACTION. 172 00:07:25,495 --> 00:07:26,129 SIDE-BY-SIDE COMPARISON, GETTING 173 00:07:26,129 --> 00:07:29,966 AT THE PROBLEM I JUST MENTIONED, 174 00:07:29,966 --> 00:07:32,502 THE SELECTION OF ADJUVANT SIMPLY 175 00:07:32,502 --> 00:07:36,440 BASED ON AVAILABILITY, NOT BASED 176 00:07:36,440 --> 00:07:38,742 ON THEIR BEING THE BEST CHOICE 177 00:07:38,742 --> 00:07:40,277 FOR PARTICULAR VACCINE. 178 00:07:40,277 --> 00:07:42,479 WE'RE ABLE TO ADD TWO NEW 179 00:07:42,479 --> 00:07:45,615 PROGRAMS TO THE PORTFOLIO IN 180 00:07:45,615 --> 00:07:47,717 2022, TO LOOK AT DIFFERENT 181 00:07:47,717 --> 00:07:50,854 ADJUVANTS AND ESTABLISH IMMUNE 182 00:07:50,854 --> 00:07:51,555 PROFILES, IMMUNE FINGERPRINTS OF 183 00:07:51,555 --> 00:07:54,157 DIFFERENT ADJUVANTS THAT WILL 184 00:07:54,157 --> 00:07:56,893 HELP US GET AT -- GAIN 185 00:07:56,893 --> 00:07:57,527 MECHANISTIC INSIGHTS INTO 186 00:07:57,527 --> 00:07:59,729 CORRELATES OF PROTECTION. 187 00:07:59,729 --> 00:08:02,032 THE ULTIMATE GOAL OF THE PROGRAM 188 00:08:02,032 --> 00:08:06,203 IS TO CREATE A COMPREHENSIVE 189 00:08:06,203 --> 00:08:08,472 TOOLBOX OF NOVEL ADJUVANTS 190 00:08:08,472 --> 00:08:09,806 AVAILABLE FOR VACCINE 191 00:08:09,806 --> 00:08:10,107 DEVELOPMENT. 192 00:08:10,107 --> 00:08:13,210 NOW, GETTING BACK TO THE THEME 193 00:08:13,210 --> 00:08:15,479 OF THIS AFTERNOON, OPPORTUNITIES 194 00:08:15,479 --> 00:08:16,379 AND NEW DIRECTIONS, WE COULD 195 00:08:16,379 --> 00:08:18,148 SPEND A LOT OF TIME TALKING 196 00:08:18,148 --> 00:08:19,983 ABOUT NEW DIRECTIONS, A LOT HAS 197 00:08:19,983 --> 00:08:21,318 HAPPENED IN THE ADJUVANT 198 00:08:21,318 --> 00:08:22,719 RESEARCH FIELD, ESPECIALLY IN 199 00:08:22,719 --> 00:08:24,888 THE LAST COUPLE YEARS. 200 00:08:24,888 --> 00:08:26,957 NOW, THE FOUR TOPICS I WANT TO 201 00:08:26,957 --> 00:08:29,292 ADDRESS, THOSE WILL BE COVERED 202 00:08:29,292 --> 00:08:32,996 BY THE SPEAKERS, FIRST OF ALL 203 00:08:32,996 --> 00:08:40,103 WHAT IS AN ADJUVANT. 204 00:08:40,103 --> 00:08:42,205 TRADITIONALLY AGONISTS OF IT 205 00:08:42,205 --> 00:08:44,808 NATURE IMMUNE RECEPTORS BUT SO 206 00:08:44,808 --> 00:08:48,879 MANY MORE MOLECULES CAN GIVE 207 00:08:48,879 --> 00:08:49,646 ADJUVANT EFFECT. 208 00:08:49,646 --> 00:08:51,414 FROM THE UNIVERSITY OF CHICAGO, 209 00:08:51,414 --> 00:08:54,918 HE'S BEEN WORKING ON IDENTIFYING 210 00:08:54,918 --> 00:08:57,988 NOT ACTIVATORS BUT INHIBITORS, 211 00:08:57,988 --> 00:09:00,257 SPECIFICALLY INHIBITORS OF 212 00:09:00,257 --> 00:09:03,660 SELECTIVE OF NF-kappaB, AS 213 00:09:03,660 --> 00:09:04,661 CO-ADJUVANTS, CHALLENGING THIS 214 00:09:04,661 --> 00:09:09,432 NOTION OF INFLAMMATION HAS TO BE 215 00:09:09,432 --> 00:09:13,637 ASSOCIATED WITH IMMUNITY, AND IN 216 00:09:13,637 --> 00:09:17,774 ORDER TO BE EFFECTIVE. 217 00:09:17,774 --> 00:09:20,177 ONE OF THE OBSTACLES IN THE 218 00:09:20,177 --> 00:09:22,045 FIELD HAS BEEN THE READOUTS. 219 00:09:22,045 --> 00:09:23,513 SO IF YOU'RE LOOKING AT 220 00:09:23,513 --> 00:09:27,717 INDIVIDUAL IMMUNE PARAMETERS, IT 221 00:09:27,717 --> 00:09:29,686 IS VERY HARD TO UNDERSTAND HOW 222 00:09:29,686 --> 00:09:31,121 AND ADJUVANT WORKS, WHAT IS 223 00:09:31,121 --> 00:09:36,693 REQUIRED IS A BROAD LOOK AT THE 224 00:09:36,693 --> 00:09:42,499 PROFILE IMMUNE RESPONSE INDUCES, 225 00:09:42,499 --> 00:09:43,900 AND DR. PULENDRAN WILL TALK 226 00:09:43,900 --> 00:09:49,172 ABOUT SYSTEMS IMMUNOLOGY TO 227 00:09:49,172 --> 00:09:50,974 UNDERSTAND HOW ADJUVANTS WORK. 228 00:09:50,974 --> 00:09:52,209 HOW TO USE THE RIGHT ADJUVANT 229 00:09:52,209 --> 00:09:53,643 FOR THE JOB. 230 00:09:53,643 --> 00:09:58,248 WE'VE BEEN THINKING OF ADJUVANTS 231 00:09:58,248 --> 00:10:00,116 AS ENHANCERS, INCREASING IMMUNE 232 00:10:00,116 --> 00:10:00,417 RESPONSE. 233 00:10:00,417 --> 00:10:01,952 BUT ADJUVANTS DO MUCH MORE. 234 00:10:01,952 --> 00:10:04,254 THEY ARE NOT JUST RAMPING UP 235 00:10:04,254 --> 00:10:04,921 IMMUNE RESPONSES BUT ALSO 236 00:10:04,921 --> 00:10:07,324 DRIVING IN A CERTAIN DIRECTION, 237 00:10:07,324 --> 00:10:10,393 THEY ACT AS IMMUNE MODULATORS. 238 00:10:10,393 --> 00:10:13,463 DR. JAY EVANS FROM UNIVERSITY OF 239 00:10:13,463 --> 00:10:16,166 MONTANA WILL BE JOINING US 240 00:10:16,166 --> 00:10:17,267 ONLINE. 241 00:10:17,267 --> 00:10:19,336 HE'S BEEN PART OF -- HIS TEAM 242 00:10:19,336 --> 00:10:21,771 HAS BEEN PART OF THE PROGRAM 243 00:10:21,771 --> 00:10:24,140 SINCE THE BEGINNING, SINCE 2003. 244 00:10:24,140 --> 00:10:33,717 HE WILL BE TALKING ABOUT A NOVEL 245 00:10:33,717 --> 00:10:36,119 SYNTHETIC TLR 4 AGONIST AS 246 00:10:36,119 --> 00:10:38,288 IMMUNE MODULATOR TO ALTER 247 00:10:38,288 --> 00:10:46,429 EXISTING ALLERGIC RESPONSE TO IN 248 00:10:46,429 --> 00:10:47,664 THIS CASE (INDISCERNIBLE) 249 00:10:47,664 --> 00:10:49,266 ADJUVANTS, DELIVERY THROUGH THE 250 00:10:49,266 --> 00:10:52,535 NASAL ROUTE. 251 00:10:52,535 --> 00:10:54,638 AND FINALLY, ONE OF THE 252 00:10:54,638 --> 00:10:56,172 RECOGNITIONS IN THE FIELD HAS 253 00:10:56,172 --> 00:10:59,209 BEEN THE TARGETING A SINGLE 254 00:10:59,209 --> 00:11:01,778 PATHWAY, SINGLE RECEPTOR, SIMPLY 255 00:11:01,778 --> 00:11:02,879 NOT ENOUGH TO GET AN OPTIMAL 256 00:11:02,879 --> 00:11:04,180 IMMUNE RESPONSE TO VACCINE, MAY 257 00:11:04,180 --> 00:11:06,249 BE NECESSARY TO COMBINE MULTIPLE 258 00:11:06,249 --> 00:11:08,685 PATHWAYS AND TO DEVELOP 259 00:11:08,685 --> 00:11:09,786 COMBINATION ADJUVANTS. 260 00:11:09,786 --> 00:11:12,489 THERE ARE AT LEAST TWO MAJOR 261 00:11:12,489 --> 00:11:14,157 CHALLENGES WHEN COMBINING IMMUNE 262 00:11:14,157 --> 00:11:14,457 MODULATORS. 263 00:11:14,457 --> 00:11:16,526 NUMBER ONE, WHAT'S THE RIGHT 264 00:11:16,526 --> 00:11:17,294 COMBINATION? 265 00:11:17,294 --> 00:11:21,031 WHICH ONES ARE ACTING 266 00:11:21,031 --> 00:11:21,998 SYNERGISTICALLY, TRULY, WHICH 267 00:11:21,998 --> 00:11:23,533 ARE ONLY ADDITIVE, AND WHICH 268 00:11:23,533 --> 00:11:26,169 ONES MAY ACTUALLY INTERFERE WITH 269 00:11:26,169 --> 00:11:27,003 EACH OTHER. 270 00:11:27,003 --> 00:11:30,874 THAT'S CHALLENGE NUMBER 1. 271 00:11:30,874 --> 00:11:32,175 NUMBER TWO, HOW DO YOU DELIVER 272 00:11:32,175 --> 00:11:38,982 IN ORDER TO GET OPTIMAL EFFECT. 273 00:11:38,982 --> 00:11:40,517 DR. NICOLAS CHEVRIE FROM 274 00:11:40,517 --> 00:11:41,584 UNIVERSITY OF CHICAGO WILL TALK 275 00:11:41,584 --> 00:11:45,088 ABOUT THAT PROBLEM AND HOW TO 276 00:11:45,088 --> 00:11:50,794 SOLVE THIS ISSUE OF DEVELOPING 277 00:11:50,794 --> 00:11:52,062 OPTIMAL COMBINATION ADJUVANTS. 278 00:11:52,062 --> 00:11:58,902 I'LL HAND OVER TO THE FIRST 279 00:11:58,902 --> 00:12:01,071 SPEAKER, AND I'LL FINISH WITH A 280 00:12:01,071 --> 00:12:11,581 SNAPSHOT OF THE DAIT ADJUVANT 281 00:12:14,818 --> 00:12:15,552 WEBSITE. 282 00:12:15,552 --> 00:12:19,489 HERE WE GO. 283 00:12:19,489 --> 00:12:19,789 >> GREAT. 284 00:12:19,789 --> 00:12:22,192 I'LL JUST START TALKING WHILE MY 285 00:12:22,192 --> 00:12:23,193 TITLE -- THERE IT GOES. 286 00:12:23,193 --> 00:12:26,196 THANK YOU FOR THE INVITATION TO 287 00:12:26,196 --> 00:12:27,430 COME TALK, THANK YOU, WOLFGANG, 288 00:12:27,430 --> 00:12:28,865 FOR THE INTRODUCTION AND SUPPORT 289 00:12:28,865 --> 00:12:31,301 OF THIS WORK FOR MANY YEARS. 290 00:12:31,301 --> 00:12:32,502 SO, IT'S REALLY MY PLEASURE TO 291 00:12:32,502 --> 00:12:34,671 COME AND TALK TO YOU GUYS ABOUT 292 00:12:34,671 --> 00:12:35,238 THIS. 293 00:12:35,238 --> 00:12:36,973 I THOUGHT I WOULD -- YOU 294 00:12:36,973 --> 00:12:38,274 MENTIONED THAT WE'RE FROM 295 00:12:38,274 --> 00:12:41,878 CHICAGO, YOU'RE GETTING A 296 00:12:41,878 --> 00:12:42,545 CHICAGO SANDWICH TODAY. 297 00:12:42,545 --> 00:12:46,916 AS YOU'RE SORT OF MAYBE YOU'VE 298 00:12:46,916 --> 00:12:49,552 SEEN, YOU KNOW, THE ITALIAN BEEF 299 00:12:49,552 --> 00:12:51,187 SITUATION HERE, I WANTED TO 300 00:12:51,187 --> 00:12:53,390 EXPLAIN THE PROGRAM WE'RE FROM, 301 00:12:53,390 --> 00:12:56,993 IT'S A UNIQUE THING, PRITZKER 302 00:12:56,993 --> 00:12:59,396 SCHOOL OF MOLECULAR ENGINEERING, 303 00:12:59,396 --> 00:13:00,397 FOCUSED IN IMMUNOENGINEERING 304 00:13:00,397 --> 00:13:03,433 AREA ON SOCIETAL PROBLEMS BUT 305 00:13:03,433 --> 00:13:04,868 BRINGING VERY BASIC TECHNOLOGY 306 00:13:04,868 --> 00:13:06,169 IN ENGINEERING TO SOCIETAL 307 00:13:06,169 --> 00:13:07,036 PROBLEMS. 308 00:13:07,036 --> 00:13:08,671 SO VACCINES AND ADJUVANTS SIT 309 00:13:08,671 --> 00:13:12,876 SQUARELY IN THIS AREA, THERE'S 310 00:13:12,876 --> 00:13:14,277 WHY THERE'S TWO OF US IN THE 311 00:13:14,277 --> 00:13:16,012 ROOM FOCUSED ON THIS TOPIC. 312 00:13:16,012 --> 00:13:17,881 IN PARTICULAR I'M INTERESTED IN 313 00:13:17,881 --> 00:13:21,818 THIS IDEA OF UNDERSTANDING HOW 314 00:13:21,818 --> 00:13:29,159 TO BALANCE KIND OF 315 00:13:29,159 --> 00:13:29,626 REACTOGENICITY. 316 00:13:29,626 --> 00:13:30,927 THE PANDEMIC BROUGHT THIS TO A 317 00:13:30,927 --> 00:13:33,229 FORE, AND THERE'S THAT GREAT 318 00:13:33,229 --> 00:13:37,066 QUOTE FROM PHIL DORMIZZER 319 00:13:37,066 --> 00:13:38,968 TALKING ABOUT CHALLENGES OF 320 00:13:38,968 --> 00:13:42,539 PICKING A DOSE VERSUS RESULTING 321 00:13:42,539 --> 00:13:44,941 AT VERSE EVENTS THAT MIGHT CROP 322 00:13:44,941 --> 00:13:46,709 UP, THE QUIET PART SAID OUT 323 00:13:46,709 --> 00:13:48,711 LOUD, THE WAY VACCINES GET 324 00:13:48,711 --> 00:13:49,212 DEVELOPED. 325 00:13:49,212 --> 00:13:51,581 AND SO THIS IS -- I MADE THIS 326 00:13:51,581 --> 00:13:54,350 FOR A VARIETY OF REASONS, 327 00:13:54,350 --> 00:13:55,985 THERE'S A HERO'S JOURNALY WHEN 328 00:13:55,985 --> 00:13:57,520 YOU TRY AND DEVELOP A VACCINE, 329 00:13:57,520 --> 00:14:01,791 FROM A CORE NEW IDEA, TRY AND 330 00:14:01,791 --> 00:14:05,495 GET EFFICACY, TRY TO BATTLE 331 00:14:05,495 --> 00:14:06,963 REACTIVE GENICITY, THERE'S ALL 332 00:14:06,963 --> 00:14:08,565 THESE THINGS YOU HAVE TO 333 00:14:08,565 --> 00:14:10,967 CONSIDER, DIFFERENT AREAS THAT 334 00:14:10,967 --> 00:14:11,301 COME TOGETHER. 335 00:14:11,301 --> 00:14:15,138 PART IS THAT WE SORT OF LACK A 336 00:14:15,138 --> 00:14:17,974 NUMBER OF TOOLS TO NAVIGATE THE 337 00:14:17,974 --> 00:14:18,208 SPACE. 338 00:14:18,208 --> 00:14:21,144 WE DON'T HAVE A WAY TO BALANCE 339 00:14:21,144 --> 00:14:22,545 OUT ALL THESE AREAS. 340 00:14:22,545 --> 00:14:24,113 WE HAVE THINGS WE'D LIKE TO 341 00:14:24,113 --> 00:14:26,950 ACHIEVE, AND YET WE DON'T HAVE A 342 00:14:26,950 --> 00:14:32,622 LOT OF THE TOOLS WE NEED MY 343 00:14:32,622 --> 00:14:34,824 GROUP IS INTERESTED IN BRINGING 344 00:14:34,824 --> 00:14:37,327 NEW TOOLS, BETTER FRONT ENDS TO 345 00:14:37,327 --> 00:14:41,164 THE INNATE IMMUNE SYSTEM, THE 346 00:14:41,164 --> 00:14:43,566 THING WE'RE FOCUSED ON. 347 00:14:43,566 --> 00:14:45,869 ADJUVANTS ARE A FUNDAMENTAL TOOL 348 00:14:45,869 --> 00:14:47,971 FOR INNATE IMMUNE MANIPULATION, 349 00:14:47,971 --> 00:14:49,639 FRONT END TO THE BACK END 350 00:14:49,639 --> 00:14:51,341 DEVELOPING OVER A FEW YEARS TO 351 00:14:51,341 --> 00:14:52,308 STUDY AND CHARACTERIZE IMMUNE 352 00:14:52,308 --> 00:14:54,511 SYSTEM IN GREAT DETAIL. 353 00:14:54,511 --> 00:14:58,114 WE HAVE INCREDIBLE ADVANCES IN 354 00:14:58,114 --> 00:14:59,749 SYSTEMS IMMUNOLOGY WHICH DR. 355 00:14:59,749 --> 00:15:00,550 PULENDRAN WILL TELL US A 356 00:15:00,550 --> 00:15:02,151 FRACTION OF. 357 00:15:02,151 --> 00:15:03,686 WE HAVE INSIGHTS INTO 358 00:15:03,686 --> 00:15:04,587 COMPUTATIONAL IMMUNOLOGY. 359 00:15:04,587 --> 00:15:06,890 WE HAVE ALL THIS ABILITY TO 360 00:15:06,890 --> 00:15:10,393 STUDY EVERY CELL IN IMMUNE 361 00:15:10,393 --> 00:15:12,896 RESPONSE, YET HAVE FEW TOOLS FOR 362 00:15:12,896 --> 00:15:13,663 MANIPULATING AND CHANGING THE 363 00:15:13,663 --> 00:15:16,165 RESPONSE ON THE FRONT END. 364 00:15:16,165 --> 00:15:19,035 I SEE ADJUVANTS AS A BASIC TOOL 365 00:15:19,035 --> 00:15:20,537 FOR PUTTING INPUTS IN AND 366 00:15:20,537 --> 00:15:21,871 CHANGING THEM IN DIFFERENT WAYS. 367 00:15:21,871 --> 00:15:23,606 I WANTED TO HIGHLIGHT ONE OF THE 368 00:15:23,606 --> 00:15:26,476 THINGS THAT WE GLOSS OVER ABOUT 369 00:15:26,476 --> 00:15:30,547 THE NOBEL PRIZE FROM LAST YEAR 370 00:15:30,547 --> 00:15:31,414 MORE mRNA TECHNOLOGY WASN'T 371 00:15:31,414 --> 00:15:33,049 GIVEN FOR THE mRNA TECHNOLOGY 372 00:15:33,049 --> 00:15:42,358 ITSELF, IT WAS FOR ABILITY TO 373 00:15:42,358 --> 00:15:43,526 REDUCE INFLAMMATION FROM mRNA 374 00:15:43,526 --> 00:15:45,194 VACCINE, THE MANIPULATION OF THE 375 00:15:45,194 --> 00:15:45,562 IMMUNE RESPONSE. 376 00:15:45,562 --> 00:15:47,964 IT'S A GOOD IDEA TO DELIVER 377 00:15:47,964 --> 00:15:52,635 mRNA, GREAT IDEA IN THE '90s, 378 00:15:52,635 --> 00:15:56,573 BUT ABILITY TO MODIFY INNATE 379 00:15:56,573 --> 00:15:58,875 IMMUNE RESPONSE THAT WAS GAME 380 00:15:58,875 --> 00:15:59,142 CHANGING. 381 00:15:59,142 --> 00:16:00,710 A LESSON TO LEARN. 382 00:16:00,710 --> 00:16:02,979 WHAT CAUSES EFFECTS, THE HOST OF 383 00:16:02,979 --> 00:16:06,849 THINGS THAT OCCUR WHEN YOU 384 00:16:06,849 --> 00:16:08,818 INJECT VACCINE INTO -- DO AN 385 00:16:08,818 --> 00:16:12,121 I.M. INJECTION INTO A MUSCLE. 386 00:16:12,121 --> 00:16:14,390 I CALLED THESE THINGS THE DIRTY 387 00:16:14,390 --> 00:16:16,526 HALF DOZEN, THE THREE CYTOKINES 388 00:16:16,526 --> 00:16:22,498 THAT SHOW UP IN PARTICULAR TNF, 389 00:16:22,498 --> 00:16:28,738 ILL 390 00:16:28,738 --> 00:16:32,875 IL-AND IL-1 BETA, WHEN WE'RE 391 00:16:32,875 --> 00:16:34,744 HAVING HOW TO MODIFY A RESPONSE. 392 00:16:34,744 --> 00:16:36,813 WHEN CONSIDERING BALANCING 393 00:16:36,813 --> 00:16:41,851 ADVERSE EVENTS BETWEEN ABILITY 394 00:16:41,851 --> 00:16:44,287 TO BOOST ADJUVANTICITY AND 395 00:16:44,287 --> 00:16:44,921 REMOVE INFLAMMATION, DIFFERENCE 396 00:16:44,921 --> 00:16:46,923 BETWEEN A NORMAL DRUG WITH 397 00:16:46,923 --> 00:16:48,591 BALANCE BETWEEN ABILITY TO DOSE 398 00:16:48,591 --> 00:16:51,661 AND THE ABILITY TO INDUCE 399 00:16:51,661 --> 00:16:53,162 ADVERSE EVENT, LET ME HIGHLIGHT 400 00:16:53,162 --> 00:16:54,497 THIS, VERSUS THE WAY A VACCINE 401 00:16:54,497 --> 00:16:57,367 WORKS WHERE YOU NORMALLY HAVE AN 402 00:16:57,367 --> 00:16:59,202 INCREASING DOSE, SIDE EFFECTS, 403 00:16:59,202 --> 00:17:01,037 AND EFFICACY, AND THESE TWO ARE 404 00:17:01,037 --> 00:17:01,804 COUPLED. 405 00:17:01,804 --> 00:17:06,409 THIS IDEA WE COULD UNCOUPLE, 406 00:17:06,409 --> 00:17:08,611 HAVE INDEPENDENT CONTROL OVER 407 00:17:08,611 --> 00:17:09,779 INFLAMMATION WHILE MAINTAINING 408 00:17:09,779 --> 00:17:11,881 ABILITY TO DOSE. 409 00:17:11,881 --> 00:17:17,487 WE COULD CREATE TYPES OF CURVES 410 00:17:17,487 --> 00:17:20,423 WHERE TNF, IL-6, IL-1 BETA, 411 00:17:20,423 --> 00:17:22,592 MAINTAIN ABILITY TO INDUCE 412 00:17:22,592 --> 00:17:24,127 DIFFERENT RESPONSES. 413 00:17:24,127 --> 00:17:25,995 I MADE THIS METAPHOR, THAT WHEN 414 00:17:25,995 --> 00:17:27,964 WE ADD A TRADITIONAL VACCINE TO 415 00:17:27,964 --> 00:17:30,233 A SYSTEM, IT'S LIKE SHOUTING 416 00:17:30,233 --> 00:17:31,567 INTO A MEGAPHONE. 417 00:17:31,567 --> 00:17:32,435 ALL OF THE SIGNALS INCREASE AT 418 00:17:32,435 --> 00:17:35,405 THE SAME VOLUME. 419 00:17:35,405 --> 00:17:37,607 YOU HAVE TNF IL-6, GO UP AT SAME 420 00:17:37,607 --> 00:17:39,909 RATE, DON'T HAVE ROLE OVER THE 421 00:17:39,909 --> 00:17:40,143 PROCESS. 422 00:17:40,143 --> 00:17:42,779 THIS IS JUST THE WAY YOU THINK 423 00:17:42,779 --> 00:17:44,280 ABOUT TRADITIONALLY, YOU 424 00:17:44,280 --> 00:17:47,050 ACTIVATE A SIGNAL THROUGH 425 00:17:47,050 --> 00:17:49,652 NORMALLY TOLL LIKE RECEPTOR OR 426 00:17:49,652 --> 00:17:50,553 PATTERN RECOGNITION RECEPTOR, 427 00:17:50,553 --> 00:17:51,954 GOES DOWNSTREAM, THE CELL DOES 428 00:17:51,954 --> 00:17:52,622 WHAT IT DOES. 429 00:17:52,622 --> 00:17:54,357 MY KIDS WERE IN KINDERGARTEN 430 00:17:54,357 --> 00:17:55,725 WHEN WE STARTED THIS PROJECT, 431 00:17:55,725 --> 00:17:56,559 THE KINDERGARTEN TEACH HER A 432 00:17:56,559 --> 00:17:57,093 GREAT LINE. 433 00:17:57,093 --> 00:17:59,062 YOU GET WHAT YOU GET, YOU DON'T 434 00:17:59,062 --> 00:18:01,130 GET UPSET. 435 00:18:01,130 --> 00:18:03,766 THIS IS EXACTLY HOW VACCINATION 436 00:18:03,766 --> 00:18:04,867 WORKS, RIGHT? 437 00:18:04,867 --> 00:18:06,636 AND SO WE WERE THINKING, YOU 438 00:18:06,636 --> 00:18:10,873 KNOW, OUR IDEA IS CAN WE KIND OF 439 00:18:10,873 --> 00:18:12,108 CREATE SIX-BAND EQUALIZER FOR 440 00:18:12,108 --> 00:18:14,944 THIS SYSTEM, BE ABLE TO TUNE OR 441 00:18:14,944 --> 00:18:16,546 MODIFY VERY SPECIFIC PARTS OF 442 00:18:16,546 --> 00:18:19,716 THE RESPONSE SO WE CAN CHANGE 443 00:18:19,716 --> 00:18:21,584 THE SIGNAL IN A DESIRED FASHION. 444 00:18:21,584 --> 00:18:23,252 AND SO WHAT IF WE COULD MAKE 445 00:18:23,252 --> 00:18:28,257 SOMETHING THAT LOOKED LIKE THIS 446 00:18:28,257 --> 00:18:28,825 I'M IN AN ENGINEERING 447 00:18:28,825 --> 00:18:31,461 DEPARTMENT, WHAT IF WE COULD 448 00:18:31,461 --> 00:18:34,397 MAKE A HIGH PASS/LOW PASS 449 00:18:34,397 --> 00:18:39,602 FILTER, ABLE TO TUNE DOWN N TNF 450 00:18:39,602 --> 00:18:42,271 AND IL-6, AND CONTROL FACTORS 451 00:18:42,271 --> 00:18:43,139 WITHIN THE CELL. 452 00:18:43,139 --> 00:18:45,441 WHAT IF WE COULD DO THAT FOR 453 00:18:45,441 --> 00:18:46,109 INNATE SIGNALING? 454 00:18:46,109 --> 00:18:48,711 THE APPROACH WAS TO ALTER THE 455 00:18:48,711 --> 00:18:50,813 SIGNAL BY ALTERING THE SIGNAL 456 00:18:50,813 --> 00:18:52,348 PROCESSING WITHIN THE CELL. 457 00:18:52,348 --> 00:18:53,983 RATHER THAN ACTIVATE RECEPTOR ON 458 00:18:53,983 --> 00:18:56,486 THE OUTSIDE WE TOOK THIS IDEA OF 459 00:18:56,486 --> 00:18:58,588 CHANGING THE SIGNALING WITHIN 460 00:18:58,588 --> 00:19:00,857 THE CELL, SO THERE'S A LOT KNOWN 461 00:19:00,857 --> 00:19:01,958 ABOUT WHAT TARGETS, WHAT CAN YOU 462 00:19:01,958 --> 00:19:03,926 DO TO CHANGE RESPONSE. 463 00:19:03,926 --> 00:19:08,431 THE FACT THAT OF NF-kappaB IS 464 00:19:08,431 --> 00:19:11,601 HUNDREDS OF PROTEINS TALKING TO 465 00:19:11,601 --> 00:19:14,337 EACH OTHER, CORE TRANSCRIPTION 466 00:19:14,337 --> 00:19:16,405 FACTOR, SIMPLIFYING THIS ARROW 467 00:19:16,405 --> 00:19:20,777 WITH HUNDREDS OF PROTEINS THAT 468 00:19:20,777 --> 00:19:22,211 PERFORM THIS PROCESS DECIDING 469 00:19:22,211 --> 00:19:28,885 HOW MUCH TNF OR MHC TO PRODUCE 470 00:19:28,885 --> 00:19:30,953 AND HOW TO TRANSCRIBE THEM. 471 00:19:30,953 --> 00:19:36,759 THEN YOU CONTROL WITH A SECOND 472 00:19:36,759 --> 00:19:38,961 MOLECULE THAT GOES IN THE 473 00:19:38,961 --> 00:19:40,263 INHIBITION PROCESS, WE STARTED 474 00:19:40,263 --> 00:19:42,331 AS THE PANDEMIC WAS BEGINNING 475 00:19:42,331 --> 00:19:44,667 BUT DID THIS HIGH-THROUGHPUT 476 00:19:44,667 --> 00:19:47,503 SCREEN, TOOK 15 PRR AGONISTS, 477 00:19:47,503 --> 00:19:49,372 EVERYTHING THAT WOULD ACTIVATE 478 00:19:49,372 --> 00:19:51,541 INNATE IMMUNE SYSTEM CROSSED 479 00:19:51,541 --> 00:19:55,378 WITH 4,000 OR 5,000 DIFFERENT 480 00:19:55,378 --> 00:19:56,012 SIGNAL-MODIFYING MOLECULES KNOWN 481 00:19:56,012 --> 00:19:58,848 TO INTERACT WITH THE NETWORK, 482 00:19:58,848 --> 00:20:00,616 FIRST LOOKED FOR ANYTHING THAT 483 00:20:00,616 --> 00:20:02,151 WOULD MODIFY THE SIGNAL, 484 00:20:02,151 --> 00:20:03,586 DOWN-SELECTED IN A CRITERIA I'LL 485 00:20:03,586 --> 00:20:05,988 EXPLAIN, AND EVENTUALLY ENDED UP 486 00:20:05,988 --> 00:20:08,291 WITH VERY SPECIFIC COMPOUNDS 487 00:20:08,291 --> 00:20:09,592 THAT WE KNEW MODIFIED THE 488 00:20:09,592 --> 00:20:12,028 NF-kappaB SIGNAL IN A SPECIFIC 489 00:20:12,028 --> 00:20:14,964 WAY. 490 00:20:14,964 --> 00:20:17,366 HOW DO YOU FIND AN IDEAL 491 00:20:17,366 --> 00:20:18,801 MOLECULE AMONGST MANY THINGS 492 00:20:18,801 --> 00:20:19,669 THAT LOOK SIMILAR? 493 00:20:19,669 --> 00:20:20,903 I'LL MAKE THIS ANALOGY AGAIN, 494 00:20:20,903 --> 00:20:22,972 YOU CAN TELL I HAVE CHILDREN. 495 00:20:22,972 --> 00:20:24,173 IT'S LIKE DOING WHERE'S WALDO, 496 00:20:24,173 --> 00:20:26,542 YOU HAVE THIS BIG CHALLENGE, 497 00:20:26,542 --> 00:20:28,010 EVERYTHING LOOKS SIMILAR BUT 498 00:20:28,010 --> 00:20:29,645 SOMEWHERE IN THE GIANT FIELD OF 499 00:20:29,645 --> 00:20:31,848 SIMILAR THINGS IS ONE THING YOU 500 00:20:31,848 --> 00:20:32,181 WANT. 501 00:20:32,181 --> 00:20:34,584 I WON'T TELL YOU WHERE HE IS YET 502 00:20:34,584 --> 00:20:36,986 BUT I'LL SHOW YOU BY THE END OF 503 00:20:36,986 --> 00:20:39,155 THE PRESENTATION WHERE WALDO IS. 504 00:20:39,155 --> 00:20:42,959 THIS WAS THE CHALLENGE, A HUGE 505 00:20:42,959 --> 00:20:47,797 LIBRARY OF MOLECULES, WE WERE 506 00:20:47,797 --> 00:20:48,798 LOOKING FOR DO THESE MOLECULES 507 00:20:48,798 --> 00:20:50,766 JUST CHANGE THE WAY THESE THINGS 508 00:20:50,766 --> 00:20:52,835 WORK, THEN WE ASKED DO THEY 509 00:20:52,835 --> 00:20:56,138 CHANGE THE SPECIFIC CYTOKINES, 510 00:20:56,138 --> 00:21:00,376 DO THEY CHANGE TNF, IL-6, IL-1 511 00:21:00,376 --> 00:21:03,012 BETA, AND HOW MUCH DO THEY 512 00:21:03,012 --> 00:21:05,314 CHANGE CELL SURFACE MARKERS, WE 513 00:21:05,314 --> 00:21:06,949 CREATED THIS INDEPENDENTLY 514 00:21:06,949 --> 00:21:09,118 WEIGHTED SCORE WE CALL A VACCINE 515 00:21:09,118 --> 00:21:10,119 SCORE TO PICK THOSE MOLECULES, 516 00:21:10,119 --> 00:21:11,654 TESTED ON HUMAN CELL LINES TO 517 00:21:11,654 --> 00:21:13,956 MAKE SURE WE COULD VALIDATE THEY 518 00:21:13,956 --> 00:21:15,258 WOULD WORK IN A PERSON AT SOME 519 00:21:15,258 --> 00:21:15,458 POINT. 520 00:21:15,458 --> 00:21:16,559 WE'RE BEGINNING TO TEST ON 521 00:21:16,559 --> 00:21:17,760 SPECIFIC PATIENTS AND THEN 522 00:21:17,760 --> 00:21:19,862 LOOKING FOR ONES THAT WORK VERY 523 00:21:19,862 --> 00:21:26,002 WELL WITH DIFFERENT INDIVIDUAL 524 00:21:26,002 --> 00:21:26,669 SYSTEMS, mRNA VACCINES, 525 00:21:26,669 --> 00:21:27,436 COMMERCIAL VACCINES. 526 00:21:27,436 --> 00:21:29,605 I'LL SHOW YOU THE VACCINE SCORE 527 00:21:29,605 --> 00:21:30,506 IN MORE DETAIL. 528 00:21:30,506 --> 00:21:34,343 THIS IS ONE AXIS. 529 00:21:34,343 --> 00:21:36,746 TWO AXES, YOU CAN SEE IMPROVED 530 00:21:36,746 --> 00:21:38,948 PERFORMANCE, BETTER AT ANTIGEN 531 00:21:38,948 --> 00:21:42,318 PRESENTATION AND REDUCE TNF AND 532 00:21:42,318 --> 00:21:44,287 IL-6 BUT MAINTAIN CYTOKINES THAT 533 00:21:44,287 --> 00:21:46,255 CAUSE CELL MIGRATION AND 534 00:21:46,255 --> 00:21:46,589 INTERFERENCE. 535 00:21:46,589 --> 00:21:50,826 THERE'S A SWEET SPOT IN BETWEEN 536 00:21:50,826 --> 00:21:51,627 THE TWO. 537 00:21:51,627 --> 00:21:53,562 THIS MOLECULE, PME-564, IS LEAD 538 00:21:53,562 --> 00:21:54,130 CANDIDATE, BALANCING THE TWO 539 00:21:54,130 --> 00:21:55,798 PERFECTLY WHERE IT'S ABLE TO 540 00:21:55,798 --> 00:21:57,767 INCREASE ABILITY TO PRESENT 541 00:21:57,767 --> 00:21:59,302 ANTIGENS WHILE MINIMIZING THE 542 00:21:59,302 --> 00:22:07,510 AMOUNT OF THOSE CYTOKINES 543 00:22:07,510 --> 00:22:09,345 INVOLVED IN REACTOGENICITY, TO 544 00:22:09,345 --> 00:22:14,951 TUNE DOWN REACTIVE CYTOKINES AND 545 00:22:14,951 --> 00:22:16,052 INCREASE REACTOGENICITY. 546 00:22:16,052 --> 00:22:17,353 THIS SHOWS THE POINT WE 547 00:22:17,353 --> 00:22:18,688 CORRELATED ALL OF THESE THINGS 548 00:22:18,688 --> 00:22:21,390 TOGETHER AND WHEN YOU HAVE A 549 00:22:21,390 --> 00:22:23,025 TRADITIONAL VACCINE YOU HAVE 550 00:22:23,025 --> 00:22:23,926 INHERENT CONTRAST BETWEEN WHERE 551 00:22:23,926 --> 00:22:27,630 WHEN YOU ADD MORE VACCINE, YOU 552 00:22:27,630 --> 00:22:28,831 GET MORE PROTECTION, BUT WHEN 553 00:22:28,831 --> 00:22:30,599 YOU -- THEN YOU HAVE A DROP IN 554 00:22:30,599 --> 00:22:32,001 THE TOLERABILITY SCORE. 555 00:22:32,001 --> 00:22:35,738 THERE'S AN AN AXIS. 556 00:22:35,738 --> 00:22:36,472 WHEN YOU ADD MODIFYING COMPOUNDS 557 00:22:36,472 --> 00:22:39,809 YOU MOVE TO THE AREA MORE SAFE 558 00:22:39,809 --> 00:22:41,644 AND MORE PROTECTIVE 559 00:22:41,644 --> 00:22:42,144 SIMULTANEOUSLY. 560 00:22:42,144 --> 00:22:43,612 THAT'S WHAT WE'VE BEEN LOOKING 561 00:22:43,612 --> 00:22:43,779 FOR. 562 00:22:43,779 --> 00:22:45,014 I WANTED TO HIGHLIGHT SOME OF 563 00:22:45,014 --> 00:22:46,549 THE OTHER THINGS WE'VE BEEN 564 00:22:46,549 --> 00:22:48,317 DOING IN THIS SPACE, TRYING TO 565 00:22:48,317 --> 00:22:50,186 APPLY NEW METHODS OF SIFTING 566 00:22:50,186 --> 00:22:50,619 THROUGH THE DATA. 567 00:22:50,619 --> 00:22:52,822 AND SO ONE OF THE THINGS WE PUT 568 00:22:52,822 --> 00:22:54,957 IN THIS PROPOSAL WAS USING 569 00:22:54,957 --> 00:23:01,130 MACHINE LEARNING AS A WAY TO 570 00:23:01,130 --> 00:23:03,332 PRIORITIZE AND OPTIMIZE. 571 00:23:03,332 --> 00:23:04,400 THE OTHER QUESTIONS PEOPLE SEEM 572 00:23:04,400 --> 00:23:05,401 TO HAVE A LOT OF DISCUSSION 573 00:23:05,401 --> 00:23:07,069 WHETHER A.I. IS GOING TO BE A 574 00:23:07,069 --> 00:23:10,373 USEFUL TOOL, I WANT TO HIGHLIGHT 575 00:23:10,373 --> 00:23:11,741 AND EMPHASIZED AT THE WORLD 576 00:23:11,741 --> 00:23:14,477 VACCINE CONGRESS IT WON'T TAKE 577 00:23:14,477 --> 00:23:16,012 ANYBODY'S JOB, JUST A BETTER 578 00:23:16,012 --> 00:23:17,446 VERSION OF A TOASTER, AN 579 00:23:17,446 --> 00:23:18,748 APPLIANCE YOU PLUG IN AND LEARN 580 00:23:18,748 --> 00:23:19,648 HOW TO USE IT. 581 00:23:19,648 --> 00:23:21,150 SO THINK ABOUT IT THAT WAY WHEN 582 00:23:21,150 --> 00:23:22,485 YOU'RE THINKING ABOUT A.I., NOT 583 00:23:22,485 --> 00:23:23,919 AS SORT OF THIS THING THAT'S 584 00:23:23,919 --> 00:23:27,423 GOING TO RISE UP AND, YOU KNOW, 585 00:23:27,423 --> 00:23:28,924 MAKE EVERYBODY'S LIVES MORE 586 00:23:28,924 --> 00:23:29,191 DIFFICULT. 587 00:23:29,191 --> 00:23:30,593 THE REASON IT MIGHT BE VALUABLE, 588 00:23:30,593 --> 00:23:32,128 WHY WE THOUGHT IT WOULD BE WORTH 589 00:23:32,128 --> 00:23:33,863 CONSIDERING, IS THAT IN A 590 00:23:33,863 --> 00:23:34,463 TRADITIONAL DISCOVERY PROJECT 591 00:23:34,463 --> 00:23:37,033 YOU GO FROM THIS HUGE NUMBER OF 592 00:23:37,033 --> 00:23:38,801 COMPOUNDS, WINNOWING DOWN LIKE I 593 00:23:38,801 --> 00:23:41,170 SHOWED, ALL THESE SELECTION 594 00:23:41,170 --> 00:23:41,437 CRITERIA. 595 00:23:41,437 --> 00:23:43,506 AND WHAT THE MACHINE SYSTEMS CAN 596 00:23:43,506 --> 00:23:44,907 DO IS GIVE THEM INFORMATION 597 00:23:44,907 --> 00:23:47,410 ABOUT HOW TO SUBSELECT FROM THAT 598 00:23:47,410 --> 00:23:49,812 MUCH LARGER LIBRARY, AND THEN 599 00:23:49,812 --> 00:23:51,047 THEY CAN MAKE INFORMED GUESSES 600 00:23:51,047 --> 00:23:52,581 BY JUMPING ALL OVER THIS SPACE. 601 00:23:52,581 --> 00:23:54,984 I'LL SHOW AN EXAMPLE OF THAT. 602 00:23:54,984 --> 00:23:57,386 AND THEN THEY CAN FORECAST MORE 603 00:23:57,386 --> 00:23:58,487 ACCURATELY THE MORE INFORMATION 604 00:23:58,487 --> 00:24:00,356 THEY HAVE TO UNDERSTAND HOW TO 605 00:24:00,356 --> 00:24:01,791 REDUCE THAT DOWN AND GIVE YOU 606 00:24:01,791 --> 00:24:03,626 SORT OF MORE HITS WITH LESS 607 00:24:03,626 --> 00:24:03,959 INFORMATION. 608 00:24:03,959 --> 00:24:05,828 AND I'M GOING TO SHOW YOU AN 609 00:24:05,828 --> 00:24:07,563 EXAMPLE OF HOW THAT MIGHT WORK 610 00:24:07,563 --> 00:24:09,632 WITH SORT OF CARTOON FROM THE 611 00:24:09,632 --> 00:24:10,199 WHERE'S WALDO. 612 00:24:10,199 --> 00:24:13,269 WE USE THIS VERSION OF MACHINE 613 00:24:13,269 --> 00:24:14,804 LEARNING, BAYESIAN OPTIMIZATION. 614 00:24:14,804 --> 00:24:16,872 WHICH IS WE FED THE DATA FROM 615 00:24:16,872 --> 00:24:18,874 THAT ORIGINAL SCREEN AND THEN 616 00:24:18,874 --> 00:24:25,347 THE BAYESIAN OPTIMIZER BUILDS A 617 00:24:25,347 --> 00:24:26,315 SURROGATE MODEL, CREATES 618 00:24:26,315 --> 00:24:27,950 INFERENCE, ORIGIN FRIENDS MODEL, 619 00:24:27,950 --> 00:24:30,052 A FUNCTION THAT BASES OFF OF ALL 620 00:24:30,052 --> 00:24:31,687 THE DATA BEFORE, MAKES GUESSES 621 00:24:31,687 --> 00:24:32,655 AND THEN TRIES AGAIN. 622 00:24:32,655 --> 00:24:34,723 WE GAVE IT ANOTHER ROUND OF DATA 623 00:24:34,723 --> 00:24:36,192 TO TRY AGAIN. 624 00:24:36,192 --> 00:24:37,493 IT KEEPS ITERATING THIS PROCESS. 625 00:24:37,493 --> 00:24:39,161 THIS IS WHERE THE WHERE'S WALDO 626 00:24:39,161 --> 00:24:40,663 CARTOON COMES BACK IN BECAUSE 627 00:24:40,663 --> 00:24:43,399 WHAT WE DID IS BASICALLY WHAT 628 00:24:43,399 --> 00:24:44,433 THE BAYESIAN OPTIMIZER DOES IS 629 00:24:44,433 --> 00:24:46,168 LOOKS AT THIS PICTURE AND PUTS 630 00:24:46,168 --> 00:24:48,904 RANDOM SPOTS DOWN AND SAYS, 631 00:24:48,904 --> 00:24:50,339 OKAY, ARE THESE RANDOM SPOTS 632 00:24:50,339 --> 00:24:52,308 WALDO OR NOT WALDO? 633 00:24:52,308 --> 00:24:53,275 THAT'S ALL IT KNOWS, CREATES A 634 00:24:53,275 --> 00:24:55,478 FUNCTION, THIS IS WHAT A 635 00:24:55,478 --> 00:24:56,345 BAYESIAN OPTIMIZER DOES, CREATES 636 00:24:56,345 --> 00:24:58,314 A FUNCTION AND THESE ARE THE 637 00:24:58,314 --> 00:24:59,415 RANDOM POINTS ALONG THE 638 00:24:59,415 --> 00:24:59,682 FUNCTION. 639 00:24:59,682 --> 00:25:01,283 OKAY, I'VE LEARNED FROM THESE 640 00:25:01,283 --> 00:25:02,985 OBSERVED DATA THAT THESE ARE 641 00:25:02,985 --> 00:25:04,553 EITHER CLOSE TO WALDO OR THEY 642 00:25:04,553 --> 00:25:06,622 ARE NOT WALDO. 643 00:25:06,622 --> 00:25:08,157 AND THEN IT REVISES THAT DATA, 644 00:25:08,157 --> 00:25:11,026 SECOND TIME, THAT'S A WALL, 645 00:25:11,026 --> 00:25:12,962 THAT'S THE SKY, THOSE ARE NOT 646 00:25:12,962 --> 00:25:14,296 WALDO, THESE DON'T LOOK LIKE 647 00:25:14,296 --> 00:25:15,631 WALDO, ET CETERA. 648 00:25:15,631 --> 00:25:17,900 IT CAN BLOT OUT PORTIONS OF THE 649 00:25:17,900 --> 00:25:19,869 DATA VERY QUICKLY BECAUSE IT CAN 650 00:25:19,869 --> 00:25:21,737 MAKE INFERENCES ABOUT WHAT'S 651 00:25:21,737 --> 00:25:22,838 AROUND THERE USING STATISTICAL 652 00:25:22,838 --> 00:25:24,707 PROBABILITY TO GUESS WHAT IS OR 653 00:25:24,707 --> 00:25:26,775 ISN'T IN THAT SPACE. 654 00:25:26,775 --> 00:25:31,580 IT DOES IT AGAIN, SECOND GUESS, 655 00:25:31,580 --> 00:25:33,782 SAMPLES AGAINST, REVISES ITS 656 00:25:33,782 --> 00:25:35,217 FUNCTIONAL GUESS, USES 657 00:25:35,217 --> 00:25:35,885 ACQUISITION FUNCTION, KEEPS 658 00:25:35,885 --> 00:25:37,286 ROUNDING THE CURVE DOWN TO GET 659 00:25:37,286 --> 00:25:39,255 CLOSER TO WHAT MIGHT BE WHAT WE 660 00:25:39,255 --> 00:25:41,090 CALL THE TRUE FUNCTION, WHAT THE 661 00:25:41,090 --> 00:25:42,091 OPTIMIZED VERSION OF THE 662 00:25:42,091 --> 00:25:43,926 FUNCTION WOULD LOOK LIKE. 663 00:25:43,926 --> 00:25:47,563 IT'S BOUNDING IT WITH CONFIDENCE 664 00:25:47,563 --> 00:25:48,731 INTERVAL EACH TIME. 665 00:25:48,731 --> 00:25:50,232 WE DON'T KNOW WHERE WALDO IS YET 666 00:25:50,232 --> 00:25:54,003 BUT WE KNOW WHERE HE ISN'T IN 667 00:25:54,003 --> 00:25:54,603 THIS EXAMPLE. 668 00:25:54,603 --> 00:25:56,071 IT KEEPS DOING THIS. 669 00:25:56,071 --> 00:25:57,640 I'M NOT GOING TO BELABOR THE 670 00:25:57,640 --> 00:25:59,608 POINT MUCH BUT YOU CAN KEEP 671 00:25:59,608 --> 00:26:01,777 REFINING YOUR FUNCTION, KEEP 672 00:26:01,777 --> 00:26:02,044 GUESSING. 673 00:26:02,044 --> 00:26:03,646 AND SO EVENTUALLY YOU GET CLOSER 674 00:26:03,646 --> 00:26:04,513 TO THE GUESS WITH EACH GUESS 675 00:26:04,513 --> 00:26:05,481 THAT YOU GET. 676 00:26:05,481 --> 00:26:07,683 I'LL JUST SHOW YOU HE'S DOWN 677 00:26:07,683 --> 00:26:10,085 HERE IN THIS LITTLE CORNER HERE, 678 00:26:10,085 --> 00:26:11,287 FOR EVERYBODY'S SATISFACTION. 679 00:26:11,287 --> 00:26:13,189 BUT HE'S HIDING IN THIS YELLOW 680 00:26:13,189 --> 00:26:13,422 POCKET. 681 00:26:13,422 --> 00:26:16,525 THIS IS WHAT WE DID WITH THE 682 00:26:16,525 --> 00:26:19,395 MOLECULES, WE TOOK THIS LARGE 683 00:26:19,395 --> 00:26:20,963 TRAINING SCREEN AND THEN SET OF 684 00:26:20,963 --> 00:26:26,068 DATA, FED IT TO THE BAYESIAN 685 00:26:26,068 --> 00:26:28,671 OPTIMIZER, IT ITERATED AND WENT 686 00:26:28,671 --> 00:26:30,039 OVER A LIBRARY OF 140,000 687 00:26:30,039 --> 00:26:31,574 MOLECULES AND SAID I HAVE A 688 00:26:31,574 --> 00:26:32,741 GUESS OF 720 MOLECULES. 689 00:26:32,741 --> 00:26:34,510 AND WE DID THAT EXPERIMENT. 690 00:26:34,510 --> 00:26:38,047 AND GUESSED AGAIN. 691 00:26:38,047 --> 00:26:40,549 DID ANOTHER 720 MOLECULES, 692 00:26:40,549 --> 00:26:41,317 GUESSED AGAIN, REPEATED SEVERAL 693 00:26:41,317 --> 00:26:41,517 TIMES. 694 00:26:41,517 --> 00:26:43,319 YOU CAN SEE HOW IT'S MOVING 695 00:26:43,319 --> 00:26:45,588 AROUND THIS ENTIRE LARGE SPACE 696 00:26:45,588 --> 00:26:46,822 OF MOLECULES AS IT TRIES TO FIND 697 00:26:46,822 --> 00:26:48,891 NEW THINGS THAT IT CAN LOOK FOR. 698 00:26:48,891 --> 00:26:52,061 THIS IS HOW WE REPRESENT THAT IN 699 00:26:52,061 --> 00:26:54,129 THIS SPACE, AND YOU'LL SEE IT'S 700 00:26:54,129 --> 00:26:56,532 COVERING THAT SPACE RELATIVELY 701 00:26:56,532 --> 00:26:58,934 EFFECTIVELY BUT ENDS UP WITH 702 00:26:58,934 --> 00:27:01,370 SETTLING ON VERY SPECIFIC AREAS, 703 00:27:01,370 --> 00:27:03,806 THESE HIGH RED POINTS, LOG FOLD 704 00:27:03,806 --> 00:27:05,941 CHANGE WHERE IT'S WORKING WELL. 705 00:27:05,941 --> 00:27:07,309 TURNS OUT IN PARTICULAR IT FOUND 706 00:27:07,309 --> 00:27:10,913 REALLY GOOD HITS FOR THINGS THAT 707 00:27:10,913 --> 00:27:15,184 WERE GOOD AND MODIFYING C DAMPER 708 00:27:15,184 --> 00:27:17,586 OR STING, ITS BEST HITS. 709 00:27:17,586 --> 00:27:19,021 I WANT TO HIGHLIGHT ONE, AN 710 00:27:19,021 --> 00:27:20,556 INTERESTING STORY. 711 00:27:20,556 --> 00:27:25,160 WE FOUND THIS MOLECULE THAT VERY 712 00:27:25,160 --> 00:27:28,530 SMALL MOLECULE WORKING IN 713 00:27:28,530 --> 00:27:30,733 COMBINATION WITH TRADITIONAL 714 00:27:30,733 --> 00:27:33,235 AGONIST WAS ABLE TO BOOST 715 00:27:33,235 --> 00:27:35,437 INTERFERON ALMOST TO THE SAME 716 00:27:35,437 --> 00:27:37,206 LEVEL AS THIS COMPOUND MERCK 717 00:27:37,206 --> 00:27:40,609 DISCOVERED, AND TRIED TO 718 00:27:40,609 --> 00:27:43,012 HIGHLIGHT THE FACT MERCK'S 719 00:27:43,012 --> 00:27:43,912 LIBRARY WAS 204 MILLION 720 00:27:43,912 --> 00:27:45,381 COMPOUNDS IN SIZE, WE ONLY HAD 721 00:27:45,381 --> 00:27:47,783 TO DO 2,000 COMPOUNDS, TRYING TO 722 00:27:47,783 --> 00:27:48,817 HIGHLIGHT THE CONTRAST IN TERMS 723 00:27:48,817 --> 00:27:50,352 OF THE AMOUNT OF SIZE OF A 724 00:27:50,352 --> 00:27:53,856 LIBRARY SPACE YOU WOULD HAVE TO 725 00:27:53,856 --> 00:27:54,490 EXPLORE. 726 00:27:54,490 --> 00:27:56,625 s SO WHAT DO WE DO WITH THESE 727 00:27:56,625 --> 00:27:58,227 MOLECULES ONCE WE FIND THEM? 728 00:27:58,227 --> 00:27:59,161 WHAT'S THE POINT OF SEARCHING 729 00:27:59,161 --> 00:28:00,863 AND LOOKING IF YOU'RE GOING TO 730 00:28:00,863 --> 00:28:01,263 EXPLORE? 731 00:28:01,263 --> 00:28:02,298 I WANT TO HIGHLIGHT THINGS YOU 732 00:28:02,298 --> 00:28:04,066 CAN DO WITH THESE AFTERWARDS. 733 00:28:04,066 --> 00:28:07,303 THIS WAS A COVID VACCINATION 734 00:28:07,303 --> 00:28:08,737 EXPERIMENT IN SYRIAN GOLDEN 735 00:28:08,737 --> 00:28:13,976 HAMSTERS, A PRIME AND BOOST, 736 00:28:13,976 --> 00:28:15,978 WE'RE USING CpG AS ADJUVANT, 737 00:28:15,978 --> 00:28:18,347 PROTEIN BASED EXPERIMENT, 738 00:28:18,347 --> 00:28:20,349 CHALLENGE ON DAY 42 WITH THE 739 00:28:20,349 --> 00:28:22,184 ACTUAL VIRUS, AND I'M GOING TO 740 00:28:22,184 --> 00:28:23,519 HIGHLIGHT THE MOST RELEVANT DATA 741 00:28:23,519 --> 00:28:26,555 HERE WHICH IS THAT WHEN WE TOOK 742 00:28:26,555 --> 00:28:28,223 THE NASAL WASH FROM THIS, FOR 743 00:28:28,223 --> 00:28:30,592 THOSE NOT FAMILIAR, THAT'S THE 744 00:28:30,592 --> 00:28:32,928 NASAL CAVITY OF A HUMAN, THE 745 00:28:32,928 --> 00:28:35,130 CAVITY OF THE HAMSTER IS SMALLER 746 00:28:35,130 --> 00:28:35,864 OF COURSE. 747 00:28:35,864 --> 00:28:37,099 YOU'RE LOOKING FOR AMOUNT OF 748 00:28:37,099 --> 00:28:38,634 VIRUS STILL IN THAT CAVITY AFTER 749 00:28:38,634 --> 00:28:40,202 A DAY OR TWO POST-INFECTION 750 00:28:40,202 --> 00:28:42,037 BECAUSE YOU CARE MOST ABOUT HOW 751 00:28:42,037 --> 00:28:43,806 MUCH THAT VIRUS RESIDES THERE, 752 00:28:43,806 --> 00:28:46,075 THAT'S HOW RELATED IT IS TO 753 00:28:46,075 --> 00:28:46,475 INFECTIVITY. 754 00:28:46,475 --> 00:28:49,244 YOU'LL SEE THAT HERE WITH THE 755 00:28:49,244 --> 00:28:51,880 FULL S PROTEIN WE HAVE CpG, 756 00:28:51,880 --> 00:28:53,716 NORMAL ADJUVANT, OR OUR MOLECULE 757 00:28:53,716 --> 00:28:56,118 ON DAY 2, ALREADY HALF OF THE 758 00:28:56,118 --> 00:28:57,219 HAMSTERS HAVE NO DETECTABLE 759 00:28:57,219 --> 00:29:01,490 VIRUS IN THE NASAL WASHES. 760 00:29:01,490 --> 00:29:03,592 BY DAY 3 ALMOST ALL COMPLETELY 761 00:29:03,592 --> 00:29:04,893 CLEARED, IN TRADITIONAL VIRUS 762 00:29:04,893 --> 00:29:07,296 MORE THAN HALF STILL HAVE VIRUS 763 00:29:07,296 --> 00:29:08,497 RESIDING IN THEIR NASAL PHARYNX. 764 00:29:08,497 --> 00:29:10,933 SO THE POINT IS THAT, YOU KNOW, 765 00:29:10,933 --> 00:29:13,001 WITH THE MODULATORS YOU CAN WORK 766 00:29:13,001 --> 00:29:14,403 QUICKLY, DECREASE AMOUNT OF 767 00:29:14,403 --> 00:29:17,106 VIRUS, SOME HAD COMPLETE 768 00:29:17,106 --> 00:29:17,806 STERILIZING IMMUNITY TO THE 769 00:29:17,806 --> 00:29:20,242 INFECTION AS FAR AS WE CAN 770 00:29:20,242 --> 00:29:20,476 DETECT. 771 00:29:20,476 --> 00:29:22,211 THESE ARE THE THINGS YOU CAN 772 00:29:22,211 --> 00:29:23,379 ACHIEVE BY TWEAKING AND 773 00:29:23,379 --> 00:29:27,583 ADJUSTING THE RESPONSE. 774 00:29:27,583 --> 00:29:31,954 IT DOESN'T JUST REDUCE 775 00:29:31,954 --> 00:29:32,588 REACTOGENICITY, AFFECTS POTENCY 776 00:29:32,588 --> 00:29:33,155 OF THE VACCINE. 777 00:29:33,155 --> 00:29:36,458 THE OTHER THING PEOPLE ARE 778 00:29:36,458 --> 00:29:37,893 INTERESTED IN INCREASING 779 00:29:37,893 --> 00:29:38,761 DURABILITY OF IMMUNE RESPONSE, 780 00:29:38,761 --> 00:29:40,329 PLEASED TO SEE THIS WAS THE 781 00:29:40,329 --> 00:29:42,064 OTHER EFFECT COMPOUNDS HAD. 782 00:29:42,064 --> 00:29:45,033 WE TOOK THE SEASONAL FLU 783 00:29:45,033 --> 00:29:47,236 VACCINE, IN THIS CASE THE 784 00:29:47,236 --> 00:29:50,739 PRODUCT FROM SANOFI, THIS HAS NO 785 00:29:50,739 --> 00:29:53,375 ADJUVANTED MOLECULE ON ITS OWN, 786 00:29:53,375 --> 00:29:55,010 BECAUSE IT'S AN INACTIVATED FLU 787 00:29:55,010 --> 00:30:03,986 VIRUS THERE ARE SEVERAL PRRs 788 00:30:03,986 --> 00:30:05,053 INSIDE, SELF-ADJUVATING VIRUS. 789 00:30:05,053 --> 00:30:11,126 WHAT IT'S GOOD AT ACCEPTING 790 00:30:11,126 --> 00:30:13,629 INPUTS IN A GENERAL FASHION. 791 00:30:13,629 --> 00:30:15,898 WE DID A SIMILAR EXPERIMENT, 792 00:30:15,898 --> 00:30:20,269 BOOST AND PRIME, BOOST TO DAY 793 00:30:20,269 --> 00:30:21,236 21, MEASURE HOW MANY ANTIBODIES, 794 00:30:21,236 --> 00:30:23,105 AND DO A CHALLENGE ON DAY 35. 795 00:30:23,105 --> 00:30:24,973 I'M NOT GOING TO SHOW YOU ALL OF 796 00:30:24,973 --> 00:30:26,408 THE DATA BECAUSE IT'S A LOT. 797 00:30:26,408 --> 00:30:27,943 WE DON'T HAVE THAT MUCH TIME BUT 798 00:30:27,943 --> 00:30:29,778 THE MOST IMPORTANT AND RELEVANT 799 00:30:29,778 --> 00:30:32,080 FACT WAS THAT EVEN AS WE TRACK 800 00:30:32,080 --> 00:30:34,483 THESE ANIMALS OVER TIME, WE SAW 801 00:30:34,483 --> 00:30:36,351 AT THAT EARLY TIME POINT THEY 802 00:30:36,351 --> 00:30:38,754 HAD MUCH HIGHER LEVELS OF 803 00:30:38,754 --> 00:30:41,590 ANTIBODY, WHEN WE ADDED THIS PME 804 00:30:41,590 --> 00:30:44,693 564, AND TRUE FOR LOTS OF 805 00:30:44,693 --> 00:30:45,494 COMPOUNDS, HIGH LEVELS OF 806 00:30:45,494 --> 00:30:47,296 ANTIBODIES STAYED OVER A LONG 807 00:30:47,296 --> 00:30:48,630 PERIOD OF TIME, MAINTAINED THIS 808 00:30:48,630 --> 00:30:52,000 KIND OF MUCH HIGHER LEVEL OF 809 00:30:52,000 --> 00:30:53,101 DURABLE RESPONSE, AND WE LEVEL 810 00:30:53,101 --> 00:30:54,870 SET THEM AT HIGHER LEVEL, THEY 811 00:30:54,870 --> 00:30:57,172 CONTINUED TO HAVE THAT HIGHER 812 00:30:57,172 --> 00:31:00,576 LEVEL BASICALLY UNTIL WE FACT 813 00:31:00,576 --> 00:31:03,011 THEM OUT AT DAY 110. 814 00:31:03,011 --> 00:31:05,814 SO, AND THEN WE DID A CHALLENGE. 815 00:31:05,814 --> 00:31:09,985 THIS WAS KIND OF AN INTERESTING 816 00:31:09,985 --> 00:31:11,954 IDEA, TYPICALLY THIS STRANGE OF 817 00:31:11,954 --> 00:31:14,990 2019 IS NOT LETHAL, BUT WE 818 00:31:14,990 --> 00:31:16,625 WANTED TO SEE HOW EFFECTIVE IT 819 00:31:16,625 --> 00:31:20,295 WAS AT PROTECTION AND SO WHAT WE 820 00:31:20,295 --> 00:31:22,264 DID WAS ADDED REGULAR FLU ZONE 821 00:31:22,264 --> 00:31:27,536 AND MODULATORS AND GAVE THEM 822 00:31:27,536 --> 00:31:32,908 JUST INCREDIBLY HIGH DOSE OF 823 00:31:32,908 --> 00:31:34,209 VICTORIA 2019. 824 00:31:34,209 --> 00:31:37,713 YOU'LL SEE THE MICE PARTICULARLY 825 00:31:37,713 --> 00:31:39,481 ONES JUST INOCULATED WITH FLU 826 00:31:39,481 --> 00:31:44,052 ZONE ABOUT SUCCUMB, TO 827 00:31:44,052 --> 00:31:45,687 INFECTION, SOME. 828 00:31:45,687 --> 00:31:46,788 AND MICE WITH COMPOUND WILL 829 00:31:46,788 --> 00:31:48,524 BOTH, YOU KNOW, EXPERIENCE SOME 830 00:31:48,524 --> 00:31:50,492 BODY WEIGHT LOSS AND THEN 831 00:31:50,492 --> 00:31:52,027 EVENTUALLY REBOUND AND SO THEY 832 00:31:52,027 --> 00:31:54,696 WILL ALL SURVIVE EVEN AT THIS 833 00:31:54,696 --> 00:31:56,732 HIGH LEVEL OF VIRUS. 834 00:31:56,732 --> 00:31:58,500 AND THEN DO MUCH BETTER. 835 00:31:58,500 --> 00:31:59,801 WE DO SEE INTERESTING THINGS 836 00:31:59,801 --> 00:32:02,304 WHERE THERE'S A SPLIT BETWEEN 837 00:32:02,304 --> 00:32:04,072 THE NUMBER OF MICE THAT ARE SORT 838 00:32:04,072 --> 00:32:06,375 OF EXPERIENCING NO EFFECT AT 839 00:32:06,375 --> 00:32:07,242 ALL, BASICALLY STERILIZED FROM 840 00:32:07,242 --> 00:32:09,211 THE VERY BEGINNING, SOME MICE 841 00:32:09,211 --> 00:32:10,612 ARE EXPERIENCING INFECTION MORE 842 00:32:10,612 --> 00:32:10,879 SEVERELY. 843 00:32:10,879 --> 00:32:13,382 SO WE'RE STILL LOOKING AT HOW 844 00:32:13,382 --> 00:32:14,917 THAT WORKS RIGHT NOW. 845 00:32:14,917 --> 00:32:16,685 SO WITH THAT, I'VE TOLD YOU A 846 00:32:16,685 --> 00:32:18,420 LITTLE BIT ABOUT THIS KIND OF 847 00:32:18,420 --> 00:32:20,756 AREA THAT WE'RE WORKING IN, SO 848 00:32:20,756 --> 00:32:22,424 TO SUMMARIZE, YOU KNOW, 849 00:32:22,424 --> 00:32:25,827 ADJUVANTS ARE THIS I THINK VERY 850 00:32:25,827 --> 00:32:26,495 PROBLEM-DRIVEN TECHNOLOGY, 851 00:32:26,495 --> 00:32:28,897 ULTIMATELY THIS FRONT END FOR 852 00:32:28,897 --> 00:32:30,465 INNATE IMMUNE SYSTEM, A THING 853 00:32:30,465 --> 00:32:36,038 WE'RE REALLY STUDYING SO WE CAN 854 00:32:36,038 --> 00:32:37,139 UNDERSTAND HOW TO BETTER 855 00:32:37,139 --> 00:32:38,774 MANIPULATE INNATE IMMUNITY. 856 00:32:38,774 --> 00:32:41,276 I TALKED ABOUT POTENTIATORS AND 857 00:32:41,276 --> 00:32:44,012 IMMUNE MODULATORS THAT ALLOW YOU 858 00:32:44,012 --> 00:32:45,681 TO TUNE AND TWEAK IMMUNE 859 00:32:45,681 --> 00:32:47,316 RESPONSE, MACHINE LEARNING AS A 860 00:32:47,316 --> 00:32:49,084 DIFFERENT WAY TO SUBSELECT AND 861 00:32:49,084 --> 00:32:49,952 MOVE THROUGH HIGH-THROUGHPUT 862 00:32:49,952 --> 00:32:51,253 SCREEN MORE EFFICIENTLY. 863 00:32:51,253 --> 00:32:53,455 AND COOL THINGS THESE MOLECULES 864 00:32:53,455 --> 00:32:56,925 CAN DO ONCE YOU FIND THEM, PLUG 865 00:32:56,925 --> 00:32:57,726 THEM INTO COMMERCIAL PRODUCTS, 866 00:32:57,726 --> 00:32:58,827 IMPROVE COMMERCIAL PRODUCTS. 867 00:32:58,827 --> 00:33:00,362 WE'RE BEGINNING TO EXPLORE HOW 868 00:33:00,362 --> 00:33:01,863 TO MAKE A COMPANY AROUND THIS 869 00:33:01,863 --> 00:33:04,399 IDEA SO WE CAN TRANSITION THAT 870 00:33:04,399 --> 00:33:05,701 OUT INTO THE REAL WORLD, 871 00:33:05,701 --> 00:33:05,968 HOPEFULLY. 872 00:33:05,968 --> 00:33:07,436 WITH THAT I WANT TO ACKNOWLEDGE 873 00:33:07,436 --> 00:33:10,038 ALL THE PEOPLE WHO HAVE DONE ALL 874 00:33:10,038 --> 00:33:13,809 THIS HARD WORK, IN PARTICULAR 875 00:33:13,809 --> 00:33:15,944 JEREMIAH AND MATT, LEADS ON THE 876 00:33:15,944 --> 00:33:18,180 DISCOVERY PROJECT, DROVE A LOT 877 00:33:18,180 --> 00:33:21,283 OF THIS WORK, █AND THEN OLIVER 878 00:33:21,283 --> 00:33:24,219 LED THE MACHINE LEARNING WORK, 879 00:33:24,219 --> 00:33:25,754 AND ANDY FERGUSON, MY PARTNER IN 880 00:33:25,754 --> 00:33:26,822 DOING THE MACHINE LEARNING WORK 881 00:33:26,822 --> 00:33:28,056 AS WELL. 882 00:33:28,056 --> 00:33:33,629 OF COURSE, I'D LIKE TO THANK 883 00:33:33,629 --> 00:33:34,329 WOLFGANG AND KENTNER, 884 00:33:34,329 --> 00:33:35,263 INSTRUMENTAL IN SUPPORTING THIS 885 00:33:35,263 --> 00:33:35,497 WORK. 886 00:33:35,497 --> 00:33:36,898 I'D BE HAPPY TO ANSWER QUESTIONS 887 00:33:36,898 --> 00:33:37,866 AND THANK YOU VERY MUCH FOR THE 888 00:33:37,866 --> 00:33:40,402 OPPORTUNITY TO TALK. 889 00:33:40,402 --> 00:33:50,445 890 00:33:57,452 --> 00:33:58,687 >> YOU INCREASE ANTIGEN 891 00:33:58,687 --> 00:34:00,322 PRESENTATION, DOWNREGULATE THE 892 00:34:00,322 --> 00:34:01,390 TNF AND IL-6. 893 00:34:01,390 --> 00:34:04,359 BUT IF YOU LOWER THAT TOO MUCH 894 00:34:04,359 --> 00:34:07,095 THEN YOU SKEW IMMUNE RESPONSE 895 00:34:07,095 --> 00:34:09,064 FROM CELL-MEDIATED IMMUNITY MORE 896 00:34:09,064 --> 00:34:13,335 TOWARD PERHAPS Th2 IMMUNITY. 897 00:34:13,335 --> 00:34:15,203 DO YOU SEE THAT WHEN YOU USE 898 00:34:15,203 --> 00:34:17,906 YOUR LEVERS TO THE POINT WHERE 899 00:34:17,906 --> 00:34:20,108 IF YOU DOWNREGULATE THE TNF AND 900 00:34:20,108 --> 00:34:22,811 IL-6 TOO MUCH YOU SEE A Th2 901 00:34:22,811 --> 00:34:24,479 RESPONSE OR HAVE YOU LOOKED AT 902 00:34:24,479 --> 00:34:25,347 THAT YET? 903 00:34:25,347 --> 00:34:25,781 >> WE HAVE. 904 00:34:25,781 --> 00:34:29,418 SO I THINK THIS IS OFTEN THE 905 00:34:29,418 --> 00:34:31,486 INTERESTING THING THINKING ABOUT 906 00:34:31,486 --> 00:34:34,990 CYTOKINES, THERE'S A DIFFERENCE 907 00:34:34,990 --> 00:34:36,858 BETWEEN SYSTEMIC LEVELS OF 908 00:34:36,858 --> 00:34:38,060 CYTOKINES AND WHAT YOU NEED IN 909 00:34:38,060 --> 00:34:41,663 THE LYMPH NODE FOR INDUCING 910 00:34:41,663 --> 00:34:42,764 Th1 AND Th2 RESPONSE. 911 00:34:42,764 --> 00:34:45,000 WHEN WE DO THIS WE'RE MEASURING 912 00:34:45,000 --> 00:34:47,035 SYSTEMIC CYTOKINES IN THE BLOOD, 913 00:34:47,035 --> 00:34:49,104 WHAT CAUSES REACTOGENICITY AND 914 00:34:49,104 --> 00:34:50,205 SIDE EFFECTS. 915 00:34:50,205 --> 00:34:51,940 WE'RE TRYING TO LOWER ENOUGH SO 916 00:34:51,940 --> 00:34:53,809 YOU DON'T DETECT THEM IN THE 917 00:34:53,809 --> 00:34:56,678 BLOOD BUT THE CELLS PRODUCE TNF 918 00:34:56,678 --> 00:34:57,879 AND IL-6, NOT ENOUGH TO DUMP 919 00:34:57,879 --> 00:35:01,583 THEM INTO THE BLOOD IF THAT 920 00:35:01,583 --> 00:35:02,584 MAKES SENSE. 921 00:35:02,584 --> 00:35:05,554 >> THE QUESTION IS RECHALLENGE, 922 00:35:05,554 --> 00:35:08,256 AT THE RECHALLENGE STAGE, WHEN 923 00:35:08,256 --> 00:35:09,825 YOU TOGGLE DOWN, WHEN YOU 924 00:35:09,825 --> 00:35:11,560 RECHALLENGE TO WHATEVER YOUR 925 00:35:11,560 --> 00:35:14,329 TARGET IS, THAT YOU SEE Th2 926 00:35:14,329 --> 00:35:17,432 IMMUNITY IN WE SAW WITH THE 927 00:35:17,432 --> 00:35:20,969 FIRST RSV VACCINE IN THE 928 00:35:20,969 --> 00:35:23,271 1960s, YOU SAW THIS THC 929 00:35:23,271 --> 00:35:24,372 RESPONSE, THAT WOULD KILL KIDS 930 00:35:24,372 --> 00:35:25,874 RATHER THAN PROTECT THEM. 931 00:35:25,874 --> 00:35:27,209 >> WHEN WE LOOK AT BOTH THE 932 00:35:27,209 --> 00:35:28,977 ANTIBODY SUBTYPES AND LOOK AT 933 00:35:28,977 --> 00:35:30,612 THE RATIOS, THEY BASICALLY 934 00:35:30,612 --> 00:35:32,214 MAINTAIN THE SAME LEVEL, WHEN WE 935 00:35:32,214 --> 00:35:34,883 LOOK AT THE T CELLS THEY DON'T 936 00:35:34,883 --> 00:35:35,884 APPEAR VERY DIFFERENT. 937 00:35:35,884 --> 00:35:38,720 SO, AGAIN, THERE'S KIND OF THE 938 00:35:38,720 --> 00:35:42,424 ABILITY TO MODULATE ALLOWS YOU 939 00:35:42,424 --> 00:35:43,859 TO INTERMEDIATE BETWEEN THINGS. 940 00:35:43,859 --> 00:35:45,293 IF WE DID ADD TOO MUCH OF THIS 941 00:35:45,293 --> 00:35:47,996 WE WOULD END UP IN THAT 942 00:35:47,996 --> 00:35:48,797 SITUATION, BUT THERE'S THE 943 00:35:48,797 --> 00:35:49,798 ABILITY TO DOSE. 944 00:35:49,798 --> 00:35:52,067 SO WE'VE DONE A DOSE CURVE WHERE 945 00:35:52,067 --> 00:35:54,603 YOU CAN SORT OF ADD JUST ENOUGH 946 00:35:54,603 --> 00:35:56,538 TO START SEEING TNF AND IL-6 947 00:35:56,538 --> 00:35:59,941 COME BACK IN THE BLOODSTREAM AS 948 00:35:59,941 --> 00:36:01,009 WELL AS CONTINUING DOWN THAT 949 00:36:01,009 --> 00:36:01,610 PATH. 950 00:36:01,610 --> 00:36:03,779 IN THE LYMPH NODE YOU SEE THEY 951 00:36:03,779 --> 00:36:05,547 ARE STILL PRODUCING CYTOKINES 952 00:36:05,547 --> 00:36:07,849 AND INDUCING A DIFFERENT -- A 953 00:36:07,849 --> 00:36:08,917 SORT OF REGULAR T-CELL RESPONSE. 954 00:36:08,917 --> 00:36:10,886 BUT TO ANSWER THE LARGER 955 00:36:10,886 --> 00:36:13,088 QUESTION AS WELL, WE'RE VERY 956 00:36:13,088 --> 00:36:15,824 INTERESTED IN BEING ABLE TO 957 00:36:15,824 --> 00:36:17,592 DIRECTLY FORECAST, PREDICT, AND 958 00:36:17,592 --> 00:36:18,960 THEN CONTROL T-CELL RESPONSE AS 959 00:36:18,960 --> 00:36:20,762 WELL, THAT'S THE NEXT PHASE OF 960 00:36:20,762 --> 00:36:21,863 THIS, WE'RE HOPING WE GET THE 961 00:36:21,863 --> 00:36:23,932 CHANCE TO KIND OF DO THAT AND 962 00:36:23,932 --> 00:36:25,801 DESIGN THINGS THAT WILL GIVE YOU 963 00:36:25,801 --> 00:36:27,202 EXACTLY THE TYPE OF T-CELL 964 00:36:27,202 --> 00:36:27,869 RESPONSE YOU WANT. 965 00:36:27,869 --> 00:36:33,775 AND SO THAT'S WHAT WE'RE LOOKING 966 00:36:33,775 --> 00:36:34,109 FOR. 967 00:36:34,109 --> 00:36:35,777 >> A FOLLOW-UP FROM YOUR 968 00:36:35,777 --> 00:36:38,213 QUESTION, IN YOUR TARGETS, YOUR 969 00:36:38,213 --> 00:36:40,482 SCREENS, YOU IDENTIFIED 970 00:36:40,482 --> 00:36:42,818 NF-kappaB AND MENTIONED LIN AS 971 00:36:42,818 --> 00:36:44,252 TARGET MOLECULES. 972 00:36:44,252 --> 00:36:46,521 >> IN OUR EARLIER CONVERSATION. 973 00:36:46,521 --> 00:36:47,789 >> SHOULD I HAVE SAID THAT BUT 974 00:36:47,789 --> 00:36:50,125 BOTH OF THEM ARE TERRIFIC 975 00:36:50,125 --> 00:36:51,326 TARGETS. 976 00:36:51,326 --> 00:36:52,093 YOU'VE SHOWN NICE DATA. 977 00:36:52,093 --> 00:36:54,462 THEY ARE ALSO SO IMPORTANT IN 978 00:36:54,462 --> 00:36:56,364 ADAPTIVE IMMUNE RESPONSE SO THAT 979 00:36:56,364 --> 00:36:58,567 IF YOU INHIBIT THEM, IT GOES 980 00:36:58,567 --> 00:37:00,769 BACK TO THRESHOLD AT WHICH YOU 981 00:37:00,769 --> 00:37:02,470 WOULD LIKE TO INHIBIT THEM. 982 00:37:02,470 --> 00:37:05,006 IN YOUR SCREEN HAVE YOU BEEN 983 00:37:05,006 --> 00:37:11,012 ABLE TO IDENTIFY A TARGET THAT 984 00:37:11,012 --> 00:37:13,748 PLAYS NO ROLE BUT SEEMS TO BE 985 00:37:13,748 --> 00:37:15,383 SOLELY MEDIATING THE EARLY 986 00:37:15,383 --> 00:37:16,218 INFLAMMATORY RESPONSE, BECAUSE 987 00:37:16,218 --> 00:37:18,019 THAT WOULD BE A MORE -- THAT 988 00:37:18,019 --> 00:37:21,423 WOULD ADDRESS THIS ISSUE OF 989 00:37:21,423 --> 00:37:22,624 COMPROMISING IMMUNOGENICITY BY 990 00:37:22,624 --> 00:37:22,924 INHIBITING. 991 00:37:22,924 --> 00:37:24,059 >> THIS WAS A REALLY GOOD 992 00:37:24,059 --> 00:37:24,326 QUESTION. 993 00:37:24,326 --> 00:37:25,794 ONE THAT WE HAVEN'T 994 00:37:25,794 --> 00:37:29,097 INTENTIONALLY SEARCHED FOR WHERE 995 00:37:29,097 --> 00:37:30,732 WE SORT OF HAVE DONE EXCLUSION 996 00:37:30,732 --> 00:37:31,833 CRITERIA AND NOW WE COULD LOOK 997 00:37:31,833 --> 00:37:34,369 AT NOW THAT WE LOOKED AT TARGETS 998 00:37:34,369 --> 00:37:34,669 MORE. 999 00:37:34,669 --> 00:37:36,671 WHAT I'LL EXPLAIN, THAT'S 1000 00:37:36,671 --> 00:37:38,106 HELPFUL FOR CONTEXT, BECAUSE 1001 00:37:38,106 --> 00:37:40,609 THESE ARE ADMINISTERED AT THE 1002 00:37:40,609 --> 00:37:42,143 SITE OF INJECTION, ALL SMALL 1003 00:37:42,143 --> 00:37:49,217 MOLECULES, WE ALSO MODIFY THE 1004 00:37:49,217 --> 00:37:50,185 MOLECULES TO BE LOCALIZED, THEY 1005 00:37:50,185 --> 00:37:52,087 ARE NOT MOVING INTO THE REST OF 1006 00:37:52,087 --> 00:37:54,356 THE SYSTEM, SO BY LOCALIZING IT 1007 00:37:54,356 --> 00:37:59,127 WE CAN SEE THEY ARE ONLY 1008 00:37:59,127 --> 00:38:02,831 INHIBITING INNATE RESPONSE AND 1009 00:38:02,831 --> 00:38:03,999 NOT AFFECTING. 1010 00:38:03,999 --> 00:38:06,201 UNDERSTANDING HOW TO MANIPULATE 1011 00:38:06,201 --> 00:38:07,402 ONLY THE INNATE RESPONSE IS 1012 00:38:07,402 --> 00:38:08,403 FUNDAMENTALLY INTERESTING 1013 00:38:08,403 --> 00:38:09,404 QUESTION BECAUSE WE'D LIKE TO 1014 00:38:09,404 --> 00:38:11,606 SEE HOW THE TWO SYSTEMS OPERATE 1015 00:38:11,606 --> 00:38:12,040 DIFFERENTLY, RIGHT? 1016 00:38:12,040 --> 00:38:13,642 I THINK WE HAVE THE OPPORTUNITY 1017 00:38:13,642 --> 00:38:15,076 TO MINE THE DATASET FOR THAT, 1018 00:38:15,076 --> 00:38:19,681 FOR SURE. 1019 00:38:19,681 --> 00:38:19,814 1020 00:38:19,814 --> 00:38:20,048 >> HI. 1021 00:38:20,048 --> 00:38:20,982 JIM BURN, UNIVERSITY OF 1022 00:38:20,982 --> 00:38:21,483 WISCONSIN. 1023 00:38:21,483 --> 00:38:24,953 I HOPE YOU CAN HEAR ME. 1024 00:38:24,953 --> 00:38:25,687 >> YES. 1025 00:38:25,687 --> 00:38:26,888 >> TERRIFIC TALK. 1026 00:38:26,888 --> 00:38:31,059 WHEN YOU STARTED OFF WITH WHAT 1027 00:38:31,059 --> 00:38:33,795 LOOKS LIKES EXPERIMENTS USING 1028 00:38:33,795 --> 00:38:34,663 DIFFERENT COMBINATION OF SMALL 1029 00:38:34,663 --> 00:38:36,097 MOLECULES TO FIND OUT HOW THEY 1030 00:38:36,097 --> 00:38:38,500 WORK TOGETHER AND SO FORTH, AND 1031 00:38:38,500 --> 00:38:40,502 YOU'VE DONE WORK WITH INJECTED 1032 00:38:40,502 --> 00:38:44,739 VACCINES, BUT ALSO SHOWED WORK 1033 00:38:44,739 --> 00:38:47,375 WITH MUCOSAL VACCINES LIKE FLU 1034 00:38:47,375 --> 00:38:52,414 ZONE OR I THINK IT WAS MUCOSALLY 1035 00:38:52,414 --> 00:38:53,915 APPLIED FLU VACCINE YOU SHOWED. 1036 00:38:53,915 --> 00:38:55,517 WHEN YOU DO THAT IS IT IMPORTANT 1037 00:38:55,517 --> 00:38:56,985 TO CONSIDER WHAT SMALL MOLECULES 1038 00:38:56,985 --> 00:38:57,986 ARE DOING TO EPITHELIAL CELLS 1039 00:38:57,986 --> 00:39:00,722 AND DO YOU HAVE A PARALLEL 1040 00:39:00,722 --> 00:39:03,658 DATASET WHERE YOU'VE DONE ALL 1041 00:39:03,658 --> 00:39:04,659 DIFFERENT COMBINATIONS TO SEE 1042 00:39:04,659 --> 00:39:06,828 WHAT THAT DOES TO EPITHELIAL 1043 00:39:06,828 --> 00:39:09,497 CELL RESPONSES? 1044 00:39:09,497 --> 00:39:10,732 >> THAT'S A GREAT QUESTION. 1045 00:39:10,732 --> 00:39:13,435 WE -- JUST TO BE CLEAR THAT WAS 1046 00:39:13,435 --> 00:39:15,804 DONE WITH AN I.M. INJECTION. 1047 00:39:15,804 --> 00:39:18,239 BUT WE'RE ACTIVELY IN THE 1048 00:39:18,239 --> 00:39:19,441 PROCESS OF DOING MUCOSAL 1049 00:39:19,441 --> 00:39:20,342 VACCINATION, AND SO THAT'S 1050 00:39:20,342 --> 00:39:26,681 SOMETHING WE CAN LOOK AT IN MORE 1051 00:39:26,681 --> 00:39:27,015 DETAIL. 1052 00:39:27,015 --> 00:39:28,850 SO ASAKÉ'S LAB REACHED OUT, TO 1053 00:39:28,850 --> 00:39:30,185 THE SURPRISE OF NOBODY, RUNNING 1054 00:39:30,185 --> 00:39:31,453 INTO THE SAME PROBLEM THAT 1055 00:39:31,453 --> 00:39:32,253 EVERYBODY ELSE IN THE 1056 00:39:32,253 --> 00:39:33,688 VACCINATION WORLD IS RUNNING 1057 00:39:33,688 --> 00:39:36,324 INTO, WHICH IS IT'S NOT SO EASY 1058 00:39:36,324 --> 00:39:37,359 TO ADMINISTER ADJUVANTS TO THE 1059 00:39:37,359 --> 00:39:39,661 LONG, SO THEY ARE LOOKING FOR 1060 00:39:39,661 --> 00:39:41,029 SIMILAR SOLUTIONS. 1061 00:39:41,029 --> 00:39:44,632 I THINK WE CAN START EARLY IN 1062 00:39:44,632 --> 00:39:46,968 THAT PROCESS LOOKING AT 1063 00:39:46,968 --> 00:39:49,771 EPITHELIAL RESPONSE. 1064 00:39:49,771 --> 00:39:51,773 WE'VE ADMINISTERED COMPOUNDS 1065 00:39:51,773 --> 00:39:52,507 INTRANASALLY, INTRATRACHEALLY, 1066 00:39:52,507 --> 00:39:54,142 BOTH. 1067 00:39:54,142 --> 00:39:55,443 WHEN WE LOOK AT INNATE RESPONSE 1068 00:39:55,443 --> 00:39:58,880 IN THE LUNG WE DON'T SEE MASSIVE 1069 00:39:58,880 --> 00:40:00,081 CHANGE WITH MODULATOR OR THE 1070 00:40:00,081 --> 00:40:01,916 ADJUVANT ON ITS OWN BUT WE'VE 1071 00:40:01,916 --> 00:40:03,351 NEVER LOOKED AT THE EPITHELIAL 1072 00:40:03,351 --> 00:40:04,019 RESPONSES. 1073 00:40:04,019 --> 00:40:05,653 THAT'S A REALLY INTERESTING 1074 00:40:05,653 --> 00:40:13,294 QUESTION THAT WE SHOULD DIVE 1075 00:40:13,294 --> 00:40:13,928 INTO. 1076 00:40:13,928 --> 00:40:16,264 >> THANK YOU. 1077 00:40:16,264 --> 00:40:17,465 >> THANK YOU VERY MUCH. 1078 00:40:17,465 --> 00:40:18,900 >> OH, YES. 1079 00:40:18,900 --> 00:40:20,535 >> SORRY, ONE MORE QUESTION. 1080 00:40:20,535 --> 00:40:22,737 >> ONE QUICK QUESTION ABOUT THE 1081 00:40:22,737 --> 00:40:24,472 TRAINING FOR YOUR IN SILICO 1082 00:40:24,472 --> 00:40:28,309 EXPERIMENTS, SO USING YOUR WALDO 1083 00:40:28,309 --> 00:40:29,744 ANALOGY, WHAT IF WALDO CHANGES 1084 00:40:29,744 --> 00:40:30,712 CLOTHES, FOR EXAMPLE MOLECULE 1085 00:40:30,712 --> 00:40:34,315 YOU'RE LOOKING FOR WHAT ABOUT 1086 00:40:34,315 --> 00:40:35,517 POST TRANSCRIPTIONAL CHANGES, 1087 00:40:35,517 --> 00:40:36,251 FOR EXAMPLE GLYCOSYLATION, ET 1088 00:40:36,251 --> 00:40:37,819 CETERA, WHAT IF THE PARAMETERS 1089 00:40:37,819 --> 00:40:41,222 THAT YOU ARE TRAINING THE SYSTEM 1090 00:40:41,222 --> 00:40:42,424 WITH ARE DIFFERENT? 1091 00:40:42,424 --> 00:40:45,393 >> YEAH, SO I THINK THIS IS THE 1092 00:40:45,393 --> 00:40:46,594 SORT OF CAUTIONARY TALE ABOUT 1093 00:40:46,594 --> 00:40:49,064 USING A.I. AND MACHINE LEARNING 1094 00:40:49,064 --> 00:40:51,733 APPROACHES, YOU HAVE TO BE VERY 1095 00:40:51,733 --> 00:40:54,002 CLEAR ABOUT EXACTLY WHAT YOU 1096 00:40:54,002 --> 00:40:55,637 WANT FROM THE TRAINING AND THE 1097 00:40:55,637 --> 00:40:56,037 SCREENING SYSTEM. 1098 00:40:56,037 --> 00:40:57,405 SO WHAT I'VE BEEN TRYING TO 1099 00:40:57,405 --> 00:40:59,374 EMPHASIZE AS WE GO INTO THIS 1100 00:40:59,374 --> 00:41:01,576 PROCESS IS THAT, YOU KNOW, YOU 1101 00:41:01,576 --> 00:41:02,877 CAN'T JUST SET THE MACHINE OFF 1102 00:41:02,877 --> 00:41:04,379 AND LET IT GO SEARCH FOR 1103 00:41:04,379 --> 00:41:04,846 SOMETHING. 1104 00:41:04,846 --> 00:41:06,614 YOU HAVE TO HAVE AN EXPERT THAT 1105 00:41:06,614 --> 00:41:07,816 UNDERSTANDS EVERY PART OF THE 1106 00:41:07,816 --> 00:41:08,049 PROCESS. 1107 00:41:08,049 --> 00:41:10,118 SO THAT YOU KNOW EXACTLY WHAT 1108 00:41:10,118 --> 00:41:11,086 PARAMETER TO OPTIMIZE FOR. 1109 00:41:11,086 --> 00:41:12,954 AND THEN YOU HAVE TO HAVE A LOT 1110 00:41:12,954 --> 00:41:14,489 OF SANITY CHECKS ALONG THE WAY. 1111 00:41:14,489 --> 00:41:16,891 SO EACH TIME WE DID THIS WE WERE 1112 00:41:16,891 --> 00:41:18,960 SORT OF LOOKING FOR MAKING SURE 1113 00:41:18,960 --> 00:41:20,728 THE MOLECULES MADE SENSE, MAKING 1114 00:41:20,728 --> 00:41:23,798 SURE THEY WERE REASONABLE, IT 1115 00:41:23,798 --> 00:41:25,834 WASN'T OPTIMIZING FOR SOMETHING 1116 00:41:25,834 --> 00:41:27,635 KILLING THE CELL, FOR INSTANCE. 1117 00:41:27,635 --> 00:41:29,037 SO WHENEVER YOU GIVE A SYSTEM 1118 00:41:29,037 --> 00:41:33,408 THE CHANCE TO OPTIMIZE A 1119 00:41:33,408 --> 00:41:34,409 PARAMETERS IT WILL ALWAYS FIND 1120 00:41:34,409 --> 00:41:35,477 THE EASIEST SOLUTION, MAYBE NOT 1121 00:41:35,477 --> 00:41:36,644 THE SOLUTION YOU WANT. 1122 00:41:36,644 --> 00:41:38,713 YOU HAVE TO BE THOUGHTFUL IN 1123 00:41:38,713 --> 00:41:40,014 THAT PROCESS MAKING SURE YOU'RE 1124 00:41:40,014 --> 00:41:41,015 DOING THAT CORRECTLY. 1125 00:41:41,015 --> 00:41:42,617 THAT'S THE ANSWER. 1126 00:41:42,617 --> 00:41:45,386 IT REQUIRES HUMAN EYE TO KIND OF 1127 00:41:45,386 --> 00:41:46,988 MAKE SURE THAT IT'S GOING IN THE 1128 00:41:46,988 --> 00:41:49,224 PATH YOU WANT, IF THAT MAKES 1129 00:41:49,224 --> 00:41:53,361 SENSE. 1130 00:41:53,361 --> 00:41:53,495 1131 00:41:53,495 --> 00:41:59,167 >> THANK YOU VERY MUCH. 1132 00:41:59,167 --> 00:42:00,602 WE'LL TRANSITION FROM A 1133 00:42:00,602 --> 00:42:03,104 DISCUSSION OF BIG DATA FOCUSED 1134 00:42:03,104 --> 00:42:05,073 ON MOLECULES THAT INDUCE IMMUNE 1135 00:42:05,073 --> 00:42:07,375 RESPONSES TO THE BIG DATA OF THE 1136 00:42:07,375 --> 00:42:09,344 MOLECULES THAT ARE INDUCED BY 1137 00:42:09,344 --> 00:42:10,545 THESE IMMUNE RESPONSES. 1138 00:42:10,545 --> 00:42:11,546 DR. PULENDRAN? 1139 00:42:11,546 --> 00:42:12,747 >> THANK YOU, WOLFGANG. 1140 00:42:12,747 --> 00:42:14,449 I THANK YOU FOR INVITING ME. 1141 00:42:14,449 --> 00:42:16,918 IT'S A PLEASURE TO BE HERE. 1142 00:42:16,918 --> 00:42:18,920 THE NEXT 20 MINUTES OR SO I'D 1143 00:42:18,920 --> 00:42:21,122 LIKE TO TALK WITH YOU ABOUT SOME 1144 00:42:21,122 --> 00:42:22,857 WORK WE'RE DOING TO UNDERSTAND 1145 00:42:22,857 --> 00:42:25,593 MECHANISMS OF ACTION OF 1146 00:42:25,593 --> 00:42:26,227 ADJUVANTS USING SYSTEMS 1147 00:42:26,227 --> 00:42:27,829 IMMUNOLOGY APPROACH. 1148 00:42:27,829 --> 00:42:31,166 THE MODEL SYSTEMS WE'RE USING 1149 00:42:31,166 --> 00:42:35,203 HUMANS, NON-HUMAN PRIMATES AND 1150 00:42:35,203 --> 00:42:37,172 MICE TO DO SYSTEMATIC COMPARISON 1151 00:42:37,172 --> 00:42:39,040 HOW IMMUNE SYSTEMS SENSES 1152 00:42:39,040 --> 00:42:40,808 ADJUVANTS IN RESPONSE IN THREE 1153 00:42:40,808 --> 00:42:44,646 SPECIES, IT'S IMPORTANT TO DO 1154 00:42:44,646 --> 00:42:45,547 SIDE-BY-SIDE COMPARISON BECAUSE 1155 00:42:45,547 --> 00:42:48,917 CLINICAL VACCINE FOLLOW THE 1156 00:42:48,917 --> 00:42:50,218 WELL-TRODDEN PATH OF MICE TO 1157 00:42:50,218 --> 00:42:52,020 MONKEYS TO HUMAN, GREAT 1158 00:42:52,020 --> 00:42:53,755 ATTRITION RATE WITH THIS, VERY 1159 00:42:53,755 --> 00:42:54,789 FEW THINGS WORK BEAUTIFULLY IN 1160 00:42:54,789 --> 00:42:56,824 MICE SEEM TO WORK WELL IN 1161 00:42:56,824 --> 00:42:58,560 MONKEYS AND THEN EVEN FEWER IN 1162 00:42:58,560 --> 00:42:58,793 HUMANS. 1163 00:42:58,793 --> 00:43:02,297 WE'D LIKE TO UNDERSTAND WHY THIS 1164 00:43:02,297 --> 00:43:09,337 IS THE CASE. 1165 00:43:09,337 --> 00:43:11,406 SO, ALL RIGHT. 1166 00:43:11,406 --> 00:43:13,708 OKAY, GOOD. 1167 00:43:13,708 --> 00:43:15,043 THIS SLIDE NEEDS NO INTRODUCTION 1168 00:43:15,043 --> 00:43:18,846 BUT TO REMIND YOU ADJUVANTS 1169 00:43:18,846 --> 00:43:20,615 STIMULATE INNATE AND ADAPTIVE 1170 00:43:20,615 --> 00:43:29,023 IMMUNE RESPONSES, INNATE WORKS 1171 00:43:29,023 --> 00:43:30,892 QUICKLY, AND THIS IS THE BASIS 1172 00:43:30,892 --> 00:43:33,628 OF VACCINATION. 1173 00:43:33,628 --> 00:43:35,163 NOW, ADJUVANTS, CURRENT THINKING 1174 00:43:35,163 --> 00:43:38,566 IS THEY TARGET INNATE IMMUNE 1175 00:43:38,566 --> 00:43:40,768 SYSTEM, TO STIMULATE THESE 1176 00:43:40,768 --> 00:43:43,071 EVENTS THAT HAPPEN DURING IMMUNE 1177 00:43:43,071 --> 00:43:43,738 RESPONSE. 1178 00:43:43,738 --> 00:43:45,273 THE OTHER IMPORTANT THING TO 1179 00:43:45,273 --> 00:43:47,442 REALIZE, AARON TOUCHED UPON 1180 00:43:47,442 --> 00:43:48,543 THIS, ADJUVANTS ARE WONDERFUL, 1181 00:43:48,543 --> 00:43:51,379 YOU MIGHT WONDER WHY WE EVEN ARE 1182 00:43:51,379 --> 00:43:52,914 DISCUSSING ADJUVANTS. 1183 00:43:52,914 --> 00:43:54,649 WELL, BECAUSE ADJUVANTS BRING TO 1184 00:43:54,649 --> 00:43:56,084 THE TABLE MANY INTERESTING 1185 00:43:56,084 --> 00:44:00,555 FEATURES SUCH AS ENHANCING 1186 00:44:00,555 --> 00:44:01,222 MAGNITUDE, BREADTH, AND 1187 00:44:01,222 --> 00:44:04,292 DURABILITY OF IMMUNE RESPONSES. 1188 00:44:04,292 --> 00:44:05,827 WE'VE BEEN INTERESTED, HERE'S A 1189 00:44:05,827 --> 00:44:06,961 PAPER THAT CAME OUT FROM OUR 1190 00:44:06,961 --> 00:44:09,230 GROUP TWO WEEKS AGO, A HUMAN 1191 00:44:09,230 --> 00:44:14,369 STUDY IN WHICH HUMANS WHO 1192 00:44:14,369 --> 00:44:16,771 RECEIVED A RECOMBINANT SPIKE 1193 00:44:16,771 --> 00:44:20,375 PROTEIN FOR COVID WITHOUT OR 1194 00:44:20,375 --> 00:44:28,716 WITH ADJUVANT, ASO3 DEVELOPED BY 1195 00:44:28,716 --> 00:44:31,986 GLAXOSMITHKLINE, A SQUALINE OIL, 1196 00:44:31,986 --> 00:44:34,289 THE IMMUNE RESPONSE INDUCED WITH 1197 00:44:34,289 --> 00:44:35,390 ADJUVANT WAS MUCH HIGHER IN 1198 00:44:35,390 --> 00:44:37,358 TERMS OF THE LEVEL OF 1199 00:44:37,358 --> 00:44:39,894 ANTIBODIES, BUT THE BREADTH OF 1200 00:44:39,894 --> 00:44:41,729 ANTIBODIES AND THEIR CAPACITY TO 1201 00:44:41,729 --> 00:44:45,333 NEUTRALIZE NOT JUST THE PARENT 1202 00:44:45,333 --> 00:44:47,535 WUHAN STRAIN BUT ALSO VARIANTS 1203 00:44:47,535 --> 00:44:48,836 WAS SUBSTANTIALLY HIGHER. 1204 00:44:48,836 --> 00:44:50,605 MECHANISM BY WHICH THIS HAPPENED 1205 00:44:50,605 --> 00:44:52,473 WAS TO REPROGRAM MEMORY B CELLS 1206 00:44:52,473 --> 00:44:56,944 SO YOU WOULD NOW ILLICIT MEMORY 1207 00:44:56,944 --> 00:44:58,479 B CELLS THAT EXPRESSED 1208 00:44:58,479 --> 00:44:59,380 IMMUNOGLOBULIN PROTEINS FAR 1209 00:44:59,380 --> 00:45:01,215 BROADER IN THEIR CAPACITY TO 1210 00:45:01,215 --> 00:45:01,849 NEUTRALIZE. 1211 00:45:01,849 --> 00:45:06,921 SO THAT WAS AN EXAMPLE OF HOW 1212 00:45:06,921 --> 00:45:07,722 ADJUVANTS CAN INDUCE ENHANCED 1213 00:45:07,722 --> 00:45:09,891 BREADTH BUT AT CLONAL LEVEL. 1214 00:45:09,891 --> 00:45:11,192 THEY CAN INDUCE HIGHLY DURABLE 1215 00:45:11,192 --> 00:45:11,726 RESPONSE. 1216 00:45:11,726 --> 00:45:14,362 THIS IS A STUDY PUBLISHED A 1217 00:45:14,362 --> 00:45:15,229 COUPLE YEARS AGO, NON-HUMAN 1218 00:45:15,229 --> 00:45:18,733 PRIMATE STUDY IN WHICH WE WORKED 1219 00:45:18,733 --> 00:45:23,004 WITH THE SYNTHETIC PLR 7 LIGAND, 1220 00:45:23,004 --> 00:45:25,506 DEVELOPED BY 3M. 1221 00:45:25,506 --> 00:45:28,042 WE FOUND THAT THIS HAD A 1222 00:45:28,042 --> 00:45:29,777 REMARKABLE PROPERTY TO ENHANCE 1223 00:45:29,777 --> 00:45:33,981 DURABILITY OF ANTIBODY RESPONSE 1224 00:45:33,981 --> 00:45:35,917 AND LONG LIVED PLASMA BONE 1225 00:45:35,917 --> 00:45:36,584 MARROW CELLS IN MONKEYS LASTING 1226 00:45:36,584 --> 00:45:39,754 MORE THAN A YEAR. 1227 00:45:39,754 --> 00:45:41,856 ALONG WITH THIS WE SHOWED HIGHLY 1228 00:45:41,856 --> 00:45:44,726 DURABLE IMMUNE RESPONSES WERE 1229 00:45:44,726 --> 00:45:46,160 EFFICIENT AT PROTECTING A YEAR 1230 00:45:46,160 --> 00:45:50,298 LATER WHEN THESE ANIMALS WERE 1231 00:45:50,298 --> 00:45:52,400 CHALLENGED WITH THE SARS-COV-2 1232 00:45:52,400 --> 00:45:52,867 STRAIN. 1233 00:45:52,867 --> 00:45:54,369 ADJUVANTS ARE EXTREMELY 1234 00:45:54,369 --> 00:45:56,003 IMPORTANT, THEY INCREASE 1235 00:45:56,003 --> 00:45:56,971 MAGNITUDE, DURABILITY, AND 1236 00:45:56,971 --> 00:45:58,339 BREADTH OF IMMUNE RESPONSES. 1237 00:45:58,339 --> 00:45:59,674 SO IT IS EXTREMELY IMPORTANT 1238 00:45:59,674 --> 00:46:01,509 THAT WE DEVELOP NEW ADJUVANTS 1239 00:46:01,509 --> 00:46:04,345 AND UNDERSTAND THE MECHANISMS OF 1240 00:46:04,345 --> 00:46:06,314 HOW SOME EXISTING ADJUVANTS 1241 00:46:06,314 --> 00:46:06,581 WORK. 1242 00:46:06,581 --> 00:46:09,717 SPEAKING OF MECHANISMS, YOU 1243 00:46:09,717 --> 00:46:13,654 HEARD FROM WOLFGANG AND CHUCK, 1244 00:46:13,654 --> 00:46:18,459 BASED ON THE PIONEERING WORK 1245 00:46:18,459 --> 00:46:21,095 CHARLIE JANEWAY AND OTHERS IN 1246 00:46:21,095 --> 00:46:21,963 THE FIELD WHO CONTRIBUTED SO 1247 00:46:21,963 --> 00:46:26,601 MUCH IN TERMS OF HOW ANCIENT 1248 00:46:26,601 --> 00:46:29,537 INNATE SYSTEM WE ALL HAVE CAN 1249 00:46:29,537 --> 00:46:31,606 SENSE A VIRUS OR MICROBE OR 1250 00:46:31,606 --> 00:46:32,240 ADJUVANTS. 1251 00:46:32,240 --> 00:46:39,247 THE DISCOVERY OF TOLL-LIKE WE 1252 00:46:39,247 --> 00:46:40,915 RECEPTORS GIVEN THE NOBEL PRIZE 1253 00:46:40,915 --> 00:46:43,851 HIGHLIGHTED THIS. 1254 00:46:43,851 --> 00:46:46,921 MANY ADJUVANTS IN THE CLINIC, 1255 00:46:46,921 --> 00:46:48,389 I'VE HIGHLIGHTED A FEW THERE, 1256 00:46:48,389 --> 00:46:53,094 THESE ARE ADJUVANTS DEVELOPED BY 1257 00:46:53,094 --> 00:46:54,061 GLAXO SMITHLINE, CONTAIN 1258 00:46:54,061 --> 00:46:58,232 COMPONENTS THAT ARE TRIGGERING 1259 00:46:58,232 --> 00:47:02,170 TOLLLIKE RECEPTOR 4. 1260 00:47:02,170 --> 00:47:05,907 THERE'S A DIFFERENT ADJUVANT 1261 00:47:05,907 --> 00:47:16,317 CpG 1018 IN HEPATITIS B 1262 00:47:19,787 --> 00:47:20,822 VACCINE BY DYNAVAX, AND ANOTHER 1263 00:47:20,822 --> 00:47:22,690 USED IN THE CONTEXT OF COVID 1264 00:47:22,690 --> 00:47:25,426 VACCINE IN INDIA. 1265 00:47:25,426 --> 00:47:27,929 SO, CLEARLY ADVANCING KNOWLEDGE 1266 00:47:27,929 --> 00:47:29,997 OF INNATE IMMUNITY HAS BEEN 1267 00:47:29,997 --> 00:47:31,332 FUNDAMENTAL IN CATALYZING 1268 00:47:31,332 --> 00:47:34,402 DEVELOPMENT OF NEW ADJUVANTS 1269 00:47:34,402 --> 00:47:36,804 THAT TARGET THESE INNATE 1270 00:47:36,804 --> 00:47:37,071 RECEPTORS. 1271 00:47:37,071 --> 00:47:38,773 BUT I SHOULDN'T LEAVE YOU WITH 1272 00:47:38,773 --> 00:47:40,975 THE IMPRESSION THAT WE NOW 1273 00:47:40,975 --> 00:47:43,444 UNDERSTAND EVERYTHING ABOUT HOW 1274 00:47:43,444 --> 00:47:46,514 ADJUVANTS WORK BECAUSE OF THE 1275 00:47:46,514 --> 00:47:48,149 HANDFUL OF ADJUVANTS WE 1276 00:47:48,149 --> 00:47:49,750 CURRENTLY HAVE, ALUM THE MOST 1277 00:47:49,750 --> 00:47:52,253 PROMINENT EXAMPLE IN USE FOR 1278 00:47:52,253 --> 00:47:54,655 DECADES, NEARLY 100 YEARS OR SO, 1279 00:47:54,655 --> 00:48:03,197 IF YOU ASK AN IMMUNOLOGIES DO E 1280 00:48:03,197 --> 00:48:06,801 UNDERSTAND THE MOLECULAR 1281 00:48:06,801 --> 00:48:08,870 PATHWAYS, NOT AT ALL. 1282 00:48:08,870 --> 00:48:12,707 ANOTHER LICENSED IN EUROPE, NOW 1283 00:48:12,707 --> 00:48:23,217 IN THIS VACCINE FOR FLU IN THE 1284 00:48:23,718 --> 00:48:28,689 ELDERLY, MF59, AGAIN SQUALINE 1285 00:48:28,689 --> 00:48:39,200 BASED, AND ASO3, USED WITH THE 1286 00:48:40,668 --> 00:48:45,873 H1N1, ANOTHER SQUALINE BASED, 1287 00:48:45,873 --> 00:48:49,043 AND ANOTHER ONE ASO1 IN 1288 00:48:49,043 --> 00:48:50,344 SHINGRIX, WE DON'T HAVE A FULL 1289 00:48:50,344 --> 00:48:54,081 UNDERSTANDING HOW IT WORKS. 1290 00:48:54,081 --> 00:49:01,055 IT'S USED IN THE RTS MALARIA 1291 00:49:01,055 --> 00:49:03,824 SCREEN, AND MATRIX M, USED BY 1292 00:49:03,824 --> 00:49:04,992 NOVAVAX IN THE COVID VACCINE WE 1293 00:49:04,992 --> 00:49:09,397 DON'T KNOW HOW IT WORKS. 1294 00:49:09,397 --> 00:49:10,264 I'M AN IMMUNOLOGIST STANDING IN 1295 00:49:10,264 --> 00:49:12,133 FRONT OF YOU, THE FIELD 1296 00:49:12,133 --> 00:49:14,969 DISCOVERED TOLLLIKE RECEPTORS 1297 00:49:14,969 --> 00:49:16,837 AND THEY HAVE CATALYZED 1298 00:49:16,837 --> 00:49:18,139 ADVANCEMENTS, BUT ALL THESE 1299 00:49:18,139 --> 00:49:19,140 WONDERFUL ADJUVANTS MILLIONS OF 1300 00:49:19,140 --> 00:49:20,441 PEOPLE HAVE BEEN IMMUNIZED WITH 1301 00:49:20,441 --> 00:49:21,642 WE DON'T REALLY UNDERSTAND HOW 1302 00:49:21,642 --> 00:49:22,843 THEY WORK, OKAY? 1303 00:49:22,843 --> 00:49:24,145 THE REASON YOU MIGHT THINK, WHY 1304 00:49:24,145 --> 00:49:25,313 IS IT IMPORTANT TO UNDERSTAND, 1305 00:49:25,313 --> 00:49:29,417 SO THAT WE COULD HAVE A MORE 1306 00:49:29,417 --> 00:49:30,484 RATIONAL UNDERSTANDING OF INNATE 1307 00:49:30,484 --> 00:49:31,919 IMMUNITY SO LIKE WHAT AARON 1308 00:49:31,919 --> 00:49:33,788 MENTIONED YOU COULD USE THOSE 1309 00:49:33,788 --> 00:49:36,857 SAME PATHWAYS TO DESIGN NEW 1310 00:49:36,857 --> 00:49:37,291 ADJUVANTS. 1311 00:49:37,291 --> 00:49:43,631 NOW, THIS TREE IS WHAT'S CALLED 1312 00:49:43,631 --> 00:49:48,102 THE QUILLAJA SAPONAA FOUND IN 1313 00:49:48,102 --> 00:49:48,436 CHILE ONLY. 1314 00:49:48,436 --> 00:49:49,737 ASO1 IS ESSENTIALLY THIS WITH A 1315 00:49:49,737 --> 00:49:51,606 LITTLE BIT OF CHOLESTEROL. 1316 00:49:51,606 --> 00:49:54,041 IT'S BEEN THIS VERY EMPIRICAL 1317 00:49:54,041 --> 00:49:56,978 PROCESS BY WHICH ADJUVANTS HAVE 1318 00:49:56,978 --> 00:49:57,912 BEEN DEVELOPED. 1319 00:49:57,912 --> 00:50:01,582 THIS CAME OUT IN "SCIENCE," THE 1320 00:50:01,582 --> 00:50:04,218 OTHER IN "NATURE BIOTECHNOLOGY," 1321 00:50:04,218 --> 00:50:06,954 CHEMICALLY ABLE TO SYNTHESIZE, 1322 00:50:06,954 --> 00:50:09,590 ELUCIDATE PATHWAY FOR THE 1323 00:50:09,590 --> 00:50:11,892 BIOSYNTHESIS OF THESE MYSTERIOUS 1324 00:50:11,892 --> 00:50:13,194 ADJUVANTS, VERY EXCITING BECAUSE 1325 00:50:13,194 --> 00:50:15,896 FOR THE FIRST TIME BY 1326 00:50:15,896 --> 00:50:20,101 UNDERSTANDING THE CHEMICAL BASIS 1327 00:50:20,101 --> 00:50:21,602 OF THIS SAPONIN ADJUVANT, COME 1328 00:50:21,602 --> 00:50:23,137 UP WITH SMALL MOLECULE THAT 1329 00:50:23,137 --> 00:50:24,805 COULD SERVE POTENTIALLY AS NEXT 1330 00:50:24,805 --> 00:50:26,073 GENERATION OF ADJUVANTS. 1331 00:50:26,073 --> 00:50:27,308 THE OTHER PROBLEM IN THE FIELD 1332 00:50:27,308 --> 00:50:28,943 AS I MENTIONED EARLIER ON IS 1333 00:50:28,943 --> 00:50:30,845 THAT LOTS AND LOTS OF ETHICS 1334 00:50:30,845 --> 00:50:33,447 THAT WORK AMAZINGLY WELL IN MICE 1335 00:50:33,447 --> 00:50:37,084 SIMPLY DO NOT TRANSLATE INTO 1336 00:50:37,084 --> 00:50:37,485 HUMANS. 1337 00:50:37,485 --> 00:50:40,454 THE REASON FOR THAT IS MICE, AND 1338 00:50:40,454 --> 00:50:43,224 WE HUMANS, HAVE EVOLVED IN A 1339 00:50:43,224 --> 00:50:44,959 DIVERGENT WAY FROM 100 MILLION 1340 00:50:44,959 --> 00:50:45,526 YEARS AGO. 1341 00:50:45,526 --> 00:50:47,461 SO ALTHOUGH IN BROAD PRINCIPLES, 1342 00:50:47,461 --> 00:50:49,764 THE IMMUNE SYSTEMS IN MICE AND 1343 00:50:49,764 --> 00:50:50,798 HUMANS ARE QUITE SIMILAR, WE 1344 00:50:50,798 --> 00:50:53,267 BOTH HAVE T CELLS AND B CELLS 1345 00:50:53,267 --> 00:50:55,469 AND DENDRITIC CELLS AND 1346 00:50:55,469 --> 00:50:56,971 MACROPHAGES, THERE'S VERY 1347 00:50:56,971 --> 00:50:57,872 IMPORTANT DETAILS THAT ARE 1348 00:50:57,872 --> 00:50:58,973 DIFFERENT. 1349 00:50:58,973 --> 00:51:00,374 YOU MIGHT BE WONDERING WHY 1350 00:51:00,374 --> 00:51:02,977 SHOULD ONE WORRY ABOUT MINOR 1351 00:51:02,977 --> 00:51:03,210 DETAILS? 1352 00:51:03,210 --> 00:51:05,946 WELL, IT COMES INTO PLAY IF YOU 1353 00:51:05,946 --> 00:51:08,149 INJECT AN ADJUVANT THAT TRIGGERS 1354 00:51:08,149 --> 00:51:10,551 A CERTAIN RECEPTOR, LET'S SAY 1355 00:51:10,551 --> 00:51:11,752 TOLL-LIKE RECEPTOR 7, AND IN 1356 00:51:11,752 --> 00:51:14,055 HUMANS WE KNOW THAT THIS IS 1357 00:51:14,055 --> 00:51:19,293 HIGHLY RESTRICTED TO ONE TYPE OF 1358 00:51:19,293 --> 00:51:20,294 DENDRITIC CELL, PLASMACYTOID, 1359 00:51:20,294 --> 00:51:22,697 BUT IN MICE IT'S MORE BROADLY 1360 00:51:22,697 --> 00:51:24,298 EXPRESSED IN MANY TYPES OF 1361 00:51:24,298 --> 00:51:25,232 DENDRITIC CELLS. 1362 00:51:25,232 --> 00:51:28,536 WHEN YOU INJECT A MOLECULE THAT 1363 00:51:28,536 --> 00:51:29,637 ACTIVATES ONE RECEPTOR YOU'LL 1364 00:51:29,637 --> 00:51:30,905 GET DIFFERENT RESPONSES IN MICE 1365 00:51:30,905 --> 00:51:34,775 AND HUMANS, THAT'S ONE EXAMPLE 1366 00:51:34,775 --> 00:51:36,410 BUT THERE ARE COUNTLESS OTHERS. 1367 00:51:36,410 --> 00:51:37,945 HOW ABOUT MONKEYS? 1368 00:51:37,945 --> 00:51:39,980 MONKEYS ARE CLOSER TO HUMANS BUT 1369 00:51:39,980 --> 00:51:42,950 ARE STILL 35 MILLION YEARS AWAY, 1370 00:51:42,950 --> 00:51:43,150 OKAY? 1371 00:51:43,150 --> 00:51:44,485 SO, THIS HIGHLIGHTS THE NEED FOR 1372 00:51:44,485 --> 00:51:46,787 US TO DO A COMPARATIVE ANALYSIS 1373 00:51:46,787 --> 00:51:48,756 IN THESE THREE DIFFERENT SPECIES 1374 00:51:48,756 --> 00:51:51,625 TO SEE WHAT WORKS, WHAT'S 1375 00:51:51,625 --> 00:51:52,293 COMMON, WHAT'S DIFFERENT. 1376 00:51:52,293 --> 00:51:55,129 AND SO HOW MIGHT YOU LOOK AT 1377 00:51:55,129 --> 00:51:56,864 THIS IMMUNE RESPONSE AND I THINK 1378 00:51:56,864 --> 00:51:58,399 AARON MENTIONED THIS BRIEFLY IN 1379 00:51:58,399 --> 00:51:59,700 HIS TALK. 1380 00:51:59,700 --> 00:52:00,468 TRADITIONALLY WE'VE ALWAYS 1381 00:52:00,468 --> 00:52:02,336 MEASURED ONE MEASURE OF THE 1382 00:52:02,336 --> 00:52:03,771 IMMUNE RESPONSE, ANTIBODY LEVELS 1383 00:52:03,771 --> 00:52:05,306 OR T CELL LEVELS. 1384 00:52:05,306 --> 00:52:06,307 THAT SERVED US WELL. 1385 00:52:06,307 --> 00:52:08,042 THAT'S A VERY GOOD FIRST STEP. 1386 00:52:08,042 --> 00:52:10,311 BUT YOU KNOW THE IMMUNE SYSTEM 1387 00:52:10,311 --> 00:52:12,079 IS SO MUCH MORE COMPLICATED THAN 1388 00:52:12,079 --> 00:52:13,614 JUST ANTIBODIES AND T CELLS. 1389 00:52:13,614 --> 00:52:19,320 THERE'S ALL THESE SUBSETS OF 1390 00:52:19,320 --> 00:52:20,254 DENDRITIC CELLS, MACROPHAGES, 1391 00:52:20,254 --> 00:52:20,521 MONOCYTES. 1392 00:52:20,521 --> 00:52:21,856 HOW DO YOU GET A COMPREHENSIVE 1393 00:52:21,856 --> 00:52:24,325 LOOK AT HOW THE IMMUNE SYSTEM IS 1394 00:52:24,325 --> 00:52:25,659 RESPONDING TO ADJUVANT OR 1395 00:52:25,659 --> 00:52:26,527 VACCINE? 1396 00:52:26,527 --> 00:52:28,529 SO HERE'S WHERE THE FIELD OF 1397 00:52:28,529 --> 00:52:29,730 SYSTEMS IMMUNOLOGY COMES IN 1398 00:52:29,730 --> 00:52:31,799 BECAUSE IT IS A SYSTEMATIC WAY 1399 00:52:31,799 --> 00:52:33,334 OF LOOKING AT IMMUNE SYSTEM. 1400 00:52:33,334 --> 00:52:42,076 THAT'S AN EXAMPLE WHERE A HUMAN 1401 00:52:42,076 --> 00:52:43,978 CANP BE IMMUNIZED HAVE ADJUVANT 1402 00:52:43,978 --> 00:52:46,781 OR VACCINES, COLLECT LYMPH NODE 1403 00:52:46,781 --> 00:52:50,918 SAMPLES, OTHER TISSUES, YOU 1404 00:52:50,918 --> 00:52:55,756 COULD USE TOOLS OF EPIGENOMICS, 1405 00:52:55,756 --> 00:52:56,857 TRANSCRIPTOMICS, METABOLOMICS, 1406 00:52:56,857 --> 00:52:59,260 SO FORTH TO LOOK AT CHANGES IN 1407 00:52:59,260 --> 00:53:00,694 RESPONSE TO VACCINATION. 1408 00:53:00,694 --> 00:53:02,563 AND REALLY THE FIRST EXAMPLE OF 1409 00:53:02,563 --> 00:53:04,465 THAT CAME FROM A STUDY WE HAD 1410 00:53:04,465 --> 00:53:06,200 DONE ABOUT 15 YEARS AGO, WHERE 1411 00:53:06,200 --> 00:53:08,502 WE DECIDED THAT WE WOULD TAKE A 1412 00:53:08,502 --> 00:53:11,105 VACCINE WHICH WAS REALLY A 1413 00:53:11,105 --> 00:53:12,740 TERRIFIC VACCINE, HAD BEEN IN 1414 00:53:12,740 --> 00:53:15,176 USE IN HUMANS FOR DECADES, AND 1415 00:53:15,176 --> 00:53:17,111 600 MILLION PEOPLE HAD RECEIVED 1416 00:53:17,111 --> 00:53:17,678 THIS VACCINE. 1417 00:53:17,678 --> 00:53:20,514 IT'S A SORT OF GOLD STANDARD 1418 00:53:20,514 --> 00:53:22,950 VACCINE BECAUSE ONE SHOT OF THIS 1419 00:53:22,950 --> 00:53:25,486 VACCINE GIVES YOU LIFELONG 1420 00:53:25,486 --> 00:53:25,886 IMMUNITY. 1421 00:53:25,886 --> 00:53:26,987 YET WE DIDN'T REALLY UNDERSTAND 1422 00:53:26,987 --> 00:53:29,723 THE BASIS OF HOW THIS VACCINE IS 1423 00:53:29,723 --> 00:53:29,957 WORKING. 1424 00:53:29,957 --> 00:53:33,227 WELL, I HAVE TO BE PRECISE HERE. 1425 00:53:33,227 --> 00:53:35,229 WE DO UNDERSTAND THAT IT USES 1426 00:53:35,229 --> 00:53:38,165 ANTIBODIES AND T CELLS BUT THESE 1427 00:53:38,165 --> 00:53:39,934 MOLECULAR MECHANISMS BY WHICH 1428 00:53:39,934 --> 00:53:42,670 THIS VACCINE WAS TARGETING THE 1429 00:53:42,670 --> 00:53:44,405 IMMUNE SYSTEM WAS SHROUDED IN 1430 00:53:44,405 --> 00:53:44,638 MYSTERY. 1431 00:53:44,638 --> 00:53:49,009 WHAT WE DID WAS A STUDY IN 1432 00:53:49,009 --> 00:53:50,211 HUMANS, IMMUNIZED WITH VACCINE, 1433 00:53:50,211 --> 00:53:52,646 COLLECTED BLOOD SAMPLES AT ALL 1434 00:53:52,646 --> 00:53:54,815 TIME POINTS, AND APPLIED THE 1435 00:53:54,815 --> 00:53:57,318 TOOLS OF GENOMICS OR 1436 00:53:57,318 --> 00:53:58,319 TRANSCRIPTOMICS TO MEASURE THE 1437 00:53:58,319 --> 00:53:59,620 CHANGE IN THE EXPRESSION OF 1438 00:53:59,620 --> 00:54:02,022 GENES IN THE BLOOD OF THESE 1439 00:54:02,022 --> 00:54:03,958 PEOPLE IN RESPONSE TO 1440 00:54:03,958 --> 00:54:04,258 VACCINATION. 1441 00:54:04,258 --> 00:54:04,992 AND THEN USING MACHINE LEARNING 1442 00:54:04,992 --> 00:54:08,495 TOOLS WE WERE ABLE TO COME UP 1443 00:54:08,495 --> 00:54:11,198 WITH A GENE LIST, A PREDICTIVE 1444 00:54:11,198 --> 00:54:13,434 SIGNATURE, THAT COULD PREDICT IN 1445 00:54:13,434 --> 00:54:14,702 A COMPLETELY INDEPENDENT TRIAL 1446 00:54:14,702 --> 00:54:15,736 THE STRENGTH OF THE T-CELL 1447 00:54:15,736 --> 00:54:17,204 RESPONSE AND STRENGTH OF THE 1448 00:54:17,204 --> 00:54:18,105 ANTIBODY RESPONSE. 1449 00:54:18,105 --> 00:54:20,207 THIS WAS THE FIRST EXAMPLE OF A 1450 00:54:20,207 --> 00:54:23,811 STUDY IN WHICH WE CAN LOOK 1451 00:54:23,811 --> 00:54:24,545 BROADLY, COMPREHENSIVELY, AT 1452 00:54:24,545 --> 00:54:26,447 IMMUNE RESPONSE TO VACCINE USING 1453 00:54:26,447 --> 00:54:28,716 TOOLS OF SYSTEMS BIOLOGY AND 1454 00:54:28,716 --> 00:54:30,918 IMPORTANTLY TO USE THE TOOLS OF 1455 00:54:30,918 --> 00:54:32,019 MACHINE LEARNING TO PREDICT 1456 00:54:32,019 --> 00:54:33,420 VACCINE IMMUNITY. 1457 00:54:33,420 --> 00:54:35,823 SO, THERE'S NO QUESTION WE WERE 1458 00:54:35,823 --> 00:54:38,359 GENERATING LOTS OF DATA. 1459 00:54:38,359 --> 00:54:41,662 THE QUESTION WAS WHAT PARTICULAR 1460 00:54:41,662 --> 00:54:43,197 INSIGHT ABOUT THE PATHWAYS THIS 1461 00:54:43,197 --> 00:54:44,932 VACCINE WAS TRIGGERING COULD WE 1462 00:54:44,932 --> 00:54:46,033 DISCERN FROM THIS VOLUMES OF 1463 00:54:46,033 --> 00:54:46,533 DATA. 1464 00:54:46,533 --> 00:54:48,435 OF COURSE IT'S IMPORTANT IN 1465 00:54:48,435 --> 00:54:50,204 BIOLOGY TO GO FROM 1466 00:54:50,204 --> 00:54:50,905 DATA-TO-KNOWLEDGE TO 1467 00:54:50,905 --> 00:54:51,272 UNDERSTANDING. 1468 00:54:51,272 --> 00:54:55,075 I'LL JUST GIVE YOU ONE EXAMPLE. 1469 00:54:55,075 --> 00:54:56,110 HERE'S THE EXAMPLE I'D LIKE TO 1470 00:54:56,110 --> 00:54:58,078 MENTION, YOU CAN SEE ON THE LEFT 1471 00:54:58,078 --> 00:55:01,282 THE HEAT MAP, ON THE TOP YOU CAN 1472 00:55:01,282 --> 00:55:03,017 SEE THE T-CELL RESPONSE ACROSS 1473 00:55:03,017 --> 00:55:04,451 15 OR 20 VOLUNTEERS. 1474 00:55:04,451 --> 00:55:07,388 THESE ARE PEOPLE WHO HAVE THE 1475 00:55:07,388 --> 00:55:08,822 YELLOW FEVER VACCINE BUT ALL 1476 00:55:08,822 --> 00:55:09,957 RESPOND DIFFERENTLY. 1477 00:55:09,957 --> 00:55:12,092 SOME HAVE VERY LOW LEVELS OF T 1478 00:55:12,092 --> 00:55:14,728 CELLS, OTHERS HAVE VERY HIGH 1479 00:55:14,728 --> 00:55:15,729 LEVELS OF T CELL. 1480 00:55:15,729 --> 00:55:17,665 WE ASK A SIMPLE QUESTION, WHAT 1481 00:55:17,665 --> 00:55:19,133 IS PATTERN OF GENE EXPRESSION IN 1482 00:55:19,133 --> 00:55:21,869 USE IN A DAY OR THREE DAYS OR 1483 00:55:21,869 --> 00:55:24,038 SEVEN DAYS, VERY EARLY AFTER 1484 00:55:24,038 --> 00:55:25,205 VACCINATION, THAT WOULD 1485 00:55:25,205 --> 00:55:27,107 CORRELATE WITH THE LEVEL OF T 1486 00:55:27,107 --> 00:55:27,308 CELLS. 1487 00:55:27,308 --> 00:55:28,642 YOU CAN SEE THERE WERE GENES 1488 00:55:28,642 --> 00:55:30,044 THAT POPPED OUT, AND I WAS 1489 00:55:30,044 --> 00:55:33,013 STRUCK BY THE FACT THAT ALL OF 1490 00:55:33,013 --> 00:55:35,983 THESE GENES BELONG TO WHAT WE 1491 00:55:35,983 --> 00:55:37,618 CALL THE INTEGRATED STRESS 1492 00:55:37,618 --> 00:55:38,585 RESPONSE. 1493 00:55:38,585 --> 00:55:40,988 THIS IS ANOTHER ANCIENT SYSTEM, 1494 00:55:40,988 --> 00:55:42,423 A HOMEOSTATIC SYSTEM THAT 1495 00:55:42,423 --> 00:55:43,958 MAMMALIAN CELLS EVOLVED TO SENSE 1496 00:55:43,958 --> 00:55:46,026 ALL KINDS OF STRESSES. 1497 00:55:46,026 --> 00:55:49,663 YOU SEE FOUR MAJOR PROTEINS, 1498 00:55:49,663 --> 00:55:53,334 KNOWN THERE, GCN 2, HRI, PERK, 1499 00:55:53,334 --> 00:55:53,500 PKR. 1500 00:55:53,500 --> 00:55:57,738 GCN 2 IS KNOWN AS EIF 2AK 4 IN 1501 00:55:57,738 --> 00:55:58,372 RED. 1502 00:55:58,372 --> 00:56:00,240 THAT IS A MOLECULE THAT WE ALL 1503 00:56:00,240 --> 00:56:02,876 HAVE IN OUR BODIES, INSIDE 1504 00:56:02,876 --> 00:56:05,279 CELLS, THAT CAN SENSE AMINO ACID 1505 00:56:05,279 --> 00:56:05,980 CHANGES. 1506 00:56:05,980 --> 00:56:07,381 WHEN INSIDE YOUR BODY, IN YOUR 1507 00:56:07,381 --> 00:56:10,551 CELL, THE LEVEL OF AMINO ACID 1508 00:56:10,551 --> 00:56:13,620 DROPS DOWN, THIS GCN 2 MOLECULE 1509 00:56:13,620 --> 00:56:15,055 BECOMES ACTIVATED, THEN IT SENDS 1510 00:56:15,055 --> 00:56:18,425 A SIGNAL TO THE RIBOSOMES WHICH 1511 00:56:18,425 --> 00:56:20,427 ARE THE PROTEIN TRANSLATION 1512 00:56:20,427 --> 00:56:24,465 MACHINERY, TO STOP MAKING ANY 1513 00:56:24,465 --> 00:56:27,001 MORE PROTEIN. 1514 00:56:27,001 --> 00:56:27,201 OKAY? 1515 00:56:27,201 --> 00:56:29,503 WE WERE AMAZED HOW WOULD THE 1516 00:56:29,503 --> 00:56:30,270 ANCIENT STRESS RESPONSE PATHWAY 1517 00:56:30,270 --> 00:56:31,705 BE LINKED TO VACCINE IMMUNITY? 1518 00:56:31,705 --> 00:56:33,474 WHAT HAPPENED IN THE ENSUING FEW 1519 00:56:33,474 --> 00:56:34,641 YEARS WHICH I'M SUMMARIZING IN 1520 00:56:34,641 --> 00:56:37,077 ONE SLIDE IS WE WERE ABLE TO 1521 00:56:37,077 --> 00:56:38,379 WORK OUT MOLECULAR DETAILS OF 1522 00:56:38,379 --> 00:56:41,415 THE PATHWAY AND SHOW THAT IN 1523 00:56:41,415 --> 00:56:43,951 FACT THIS VIRAL VACCINE, YELLOW 1524 00:56:43,951 --> 00:56:45,252 FEVER VACCINE, WAS TRIGGERING 1525 00:56:45,252 --> 00:56:48,522 GCN 2 PATHWAY THROUGH PROCESS 1526 00:56:48,522 --> 00:56:50,424 KNOWN AS AUTOPHAGY IN DENDRITIC 1527 00:56:50,424 --> 00:56:51,158 CELLS, ENHANCING PRESENTATION TO 1528 00:56:51,158 --> 00:56:52,059 T CELLS. 1529 00:56:52,059 --> 00:56:54,795 I MENTION THIS TO YOU BECAUSE 1530 00:56:54,795 --> 00:56:58,198 ORDINARILY, NEITHER WE, NONE OF 1531 00:56:58,198 --> 00:56:59,700 MY COLLEAGUES, WERE JUXTAPOSING 1532 00:56:59,700 --> 00:57:02,002 VACCINE IMMUNITY WITH INTEGRATED 1533 00:57:02,002 --> 00:57:02,436 STRESS RESPONSE. 1534 00:57:02,436 --> 00:57:04,071 TWO COMPLETELY DISPARATE THREADS 1535 00:57:04,071 --> 00:57:05,839 OF BIOLOGY COULD NOW BE UNITED 1536 00:57:05,839 --> 00:57:08,108 THROUGH DEEP MINING OF THE DATA 1537 00:57:08,108 --> 00:57:10,210 AND COMING UP WITH NEW 1538 00:57:10,210 --> 00:57:12,946 BIOLOGICAL HYPOTHESES WHICH YOU 1539 00:57:12,946 --> 00:57:14,181 COULD MECHANISTICALLY DISSECT. 1540 00:57:14,181 --> 00:57:17,117 SO, THIS REALLY LEADS ME TO THIS 1541 00:57:17,117 --> 00:57:18,318 PARTICULAR ADJUVANT CONTRACT 1542 00:57:18,318 --> 00:57:20,521 THAT WOLFGANG MENTIONED WE'RE 1543 00:57:20,521 --> 00:57:20,721 SO 1544 00:57:20,721 --> 00:57:22,256 THRILLED TO BE PART OF. 1545 00:57:22,256 --> 00:57:25,092 I'D LIKE TO SHOW SOME EARLY 1546 00:57:25,092 --> 00:57:28,695 RESULTS THAT WE'RE GETTING WITH 1547 00:57:28,695 --> 00:57:32,099 THIS KIND OF SYSTEMS APPROACH. 1548 00:57:32,099 --> 00:57:33,734 OUR ADJUVANT COMPARISON AND 1549 00:57:33,734 --> 00:57:34,835 CHARACTERIZATION ACC PROGRAM, AT 1550 00:57:34,835 --> 00:57:38,238 STANFORD, GOALS TO USE SYSTEMS 1551 00:57:38,238 --> 00:57:40,307 BIOLOGY APPROACH TO PRE-FILE 1552 00:57:40,307 --> 00:57:43,577 INNATE AND ADAPTIVE IMMUNE 1553 00:57:43,577 --> 00:57:46,880 RESPONSE INTRODUCED BY 1554 00:57:46,880 --> 00:57:48,282 ADJUVANTATED SUBUNIT VACCINES, 1555 00:57:48,282 --> 00:57:52,352 IN MICE, MONKEYS, HUMANS. 1556 00:57:52,352 --> 00:57:53,654 A COLLABORATION WITH MARK AND 1557 00:57:53,654 --> 00:57:57,925 HIS LAB. 1558 00:57:57,925 --> 00:58:01,095 WE'D LIKE TO ESTABLISH 1559 00:58:01,095 --> 00:58:04,264 COMPARATIVE IMMUNE FINGERPRINT 1560 00:58:04,264 --> 00:58:06,033 OF EACH ADJUVANT. 1561 00:58:06,033 --> 00:58:07,000 WHY? 1562 00:58:07,000 --> 00:58:11,105 WE'D LIKE TO DEFINE MOLECULAR 1563 00:58:11,105 --> 00:58:15,776 TICKETS, -- SIGNATURES, GENERAE 1564 00:58:15,776 --> 00:58:17,544 MOLECULAR ATLAS OF ADJUVANT. 1565 00:58:17,544 --> 00:58:19,480 IF YOU HAVE ABCD, EACH ADJUVANT 1566 00:58:19,480 --> 00:58:23,884 HAS A CERTAIN MOLECULAR ATLAS. 1567 00:58:23,884 --> 00:58:24,184 WHO CARES? 1568 00:58:24,184 --> 00:58:26,720 WELL, I THINK THIS WOULD BE 1569 00:58:26,720 --> 00:58:28,021 HELPFUL IN BENCHMARKING NEW 1570 00:58:28,021 --> 00:58:30,224 ADJUVANTS SO WHEN AARON COMES UP 1571 00:58:30,224 --> 00:58:32,226 WITH THIS NEW ADJUVANT OR IMMUNE 1572 00:58:32,226 --> 00:58:34,561 REGULATOR, HE WOULD BE ABLE TO 1573 00:58:34,561 --> 00:58:39,566 LOG INTO THE AT ATLAS, AH, THIS 1574 00:58:39,566 --> 00:58:41,735 LOOKS LIKE SOMETHING ELSE, AND 1575 00:58:41,735 --> 00:58:43,804 COULD CLASSIFY ADJUVANTS. 1576 00:58:43,804 --> 00:58:45,172 I THINK THIS IMPORTANTLY FOR 1577 00:58:45,172 --> 00:58:47,541 BIOLOGISTS IS A GUIDE POST FOR 1578 00:58:47,541 --> 00:58:48,542 HYPOTHESIS-DRIVEN RESEARCH INTO 1579 00:58:48,542 --> 00:58:50,177 THE MECHANISMS OF ACTION OF 1580 00:58:50,177 --> 00:58:50,711 ADJUVANTS. 1581 00:58:50,711 --> 00:58:52,679 SO, LET ME SHARE WITH YOU A FEW 1582 00:58:52,679 --> 00:58:54,348 SLIDES ON WHERE WE ARE WITH 1583 00:58:54,348 --> 00:58:54,948 THIS. 1584 00:58:54,948 --> 00:58:57,584 AND THE SORT OF FOUNDATIONAL 1585 00:58:57,584 --> 00:58:58,619 STUDY FOR THIS PROGRAM COMES 1586 00:58:58,619 --> 00:59:01,455 FROM A STUDY THAT WE HAD DONE A 1587 00:59:01,455 --> 00:59:04,625 FEW YEARS AGO BACK IN 2020, 1588 00:59:04,625 --> 00:59:06,260 DURING THE COVID HAND WHEN WE 1589 00:59:06,260 --> 00:59:11,732 WORKED WITH DR. NEIL KING AND 1590 00:59:11,732 --> 00:59:14,568 DR. DAVID BUTLI AT UNIVERSITY OF 1591 00:59:14,568 --> 00:59:16,770 WASHINGTON. 1592 00:59:16,770 --> 00:59:20,807 THEY DESIGNED THIS, THIS IS NOW 1593 00:59:20,807 --> 00:59:23,977 APPROVED FOR USE IN CLINIC SOUTH 1594 00:59:23,977 --> 00:59:24,178 KOREA. 1595 00:59:24,178 --> 00:59:26,813 WE WORKED WITH THEM AND WITH A 1596 00:59:26,813 --> 00:59:28,882 NUMBER OF DIFFERENT VACCINE AND 1597 00:59:28,882 --> 00:59:34,021 ADJUVANTS MANUFACTURERS THAT ARE 1598 00:59:34,021 --> 00:59:38,091 SHOWN HERE WITH GLAXOSMITHKLINE, 1599 00:59:38,091 --> 00:59:44,998 DYNAVAX AND THIS COMPANY SEPPIC 1600 00:59:44,998 --> 00:59:49,703 TO TEST FIVE ADJUVANTS. 1601 00:59:49,703 --> 00:59:54,508 ASO 3 IS A SQUALINE BASED, 1602 00:59:54,508 --> 00:59:57,578 ANOTHER IS SQUALINE BASED, AS37, 1603 00:59:57,578 --> 01:00:02,049 IT'S BASICALLY A TLR7 LIGAND 1604 01:00:02,049 --> 01:00:02,482 WITH ALUM. 1605 01:00:02,482 --> 01:00:07,054 CPC 1058 MIXED WITH ALUM, AND 1606 01:00:07,054 --> 01:00:07,988 STANDARD ALUM. 1607 01:00:07,988 --> 01:00:10,023 IN THE CONTEXT OF THAT STUDY 1608 01:00:10,023 --> 01:00:11,892 WHERE WE'RE DOING IS EXTENSIVE 1609 01:00:11,892 --> 01:00:14,127 IMMUNE PROFILING TO BEGIN TO 1610 01:00:14,127 --> 01:00:21,268 DEFINE THE MOLECULAR 1611 01:00:21,268 --> 01:00:22,970 FINGERPRINTS OF EACH ADJUVANT. 1612 01:00:22,970 --> 01:00:24,938 WE'RE LOOKING AT SINGLE CELL RNA 1613 01:00:24,938 --> 01:00:26,073 SEQUENCING, EVERY CELL IN THE 1614 01:00:26,073 --> 01:00:28,141 BLOOD IN A DROP OF BLOOD OF A 1615 01:00:28,141 --> 01:00:31,111 MONKEY BEFORE IT GOT THE 1616 01:00:31,111 --> 01:00:32,646 IMMUNIZATION, ONE DAY AFTER, 1617 01:00:32,646 --> 01:00:34,948 SEVEN DAYS, SO ON, YOU CAN ASK 1618 01:00:34,948 --> 01:00:37,684 EVERY SINGLE CELL IN ITS GENOME, 1619 01:00:37,684 --> 01:00:38,552 THERE ARE SOME 30,000 GENES, 1620 01:00:38,552 --> 01:00:40,087 WHAT ARE THEY DOING, GOING UP, 1621 01:00:40,087 --> 01:00:41,622 COMING DOWN? 1622 01:00:41,622 --> 01:00:45,025 AND YOU CAN THEN MAP THE 1623 01:00:45,025 --> 01:00:46,760 TRAJECTORY. 1624 01:00:46,760 --> 01:00:47,961 IN THE BEAUTIFUL U-MAP CLUSTER 1625 01:00:47,961 --> 01:00:49,263 YOU CAN SEE MAJOR CELL TIMES YOU 1626 01:00:49,263 --> 01:00:59,773 CAN DEFINE IN A DROP OF MONKEY 1627 01:01:00,941 --> 01:01:01,308 BLOOD. 1628 01:01:01,308 --> 01:01:05,345 YOU CAN SEE DIFFERENT TYPES OF 1629 01:01:05,345 --> 01:01:07,447 MONOCYTES AND SO ON. 1630 01:01:07,447 --> 01:01:08,982 WITH THE FIVE ADJUVANTS, WHAT 1631 01:01:08,982 --> 01:01:10,617 HAPPENS WITH TIME? 1632 01:01:10,617 --> 01:01:13,353 WHEN YOU IMMUNIZE THESE MONKEYS? 1633 01:01:13,353 --> 01:01:15,956 AND YOU CAN SEE HERE IN RED I'M 1634 01:01:15,956 --> 01:01:18,058 POINTING TO THESE CLUSTERS WHERE 1635 01:01:18,058 --> 01:01:21,094 THERE'S SOME GREEN COMING UP. 1636 01:01:21,094 --> 01:01:24,264 SO, THOSE ARE -- ON THE FOCUS ON 1637 01:01:24,264 --> 01:01:27,034 THE TREE, THE ALUM, THE ONE 1638 01:01:27,034 --> 01:01:28,669 BELOW THE PENULTIMATE ROW, DAY 1 1639 01:01:28,669 --> 01:01:31,071 YOU CAN SEE LOTS OF INTERFERON 1640 01:01:31,071 --> 01:01:34,474 STIMULATED GENES THAT ARE BEING 1641 01:01:34,474 --> 01:01:34,908 STIMULATED. 1642 01:01:34,908 --> 01:01:37,210 AND THIS PERSISTS FOR DAY 7. 1643 01:01:37,210 --> 01:01:39,613 LOOK AT DAY 22, ONE DAY AFTER 1644 01:01:39,613 --> 01:01:42,249 THE SECOND REIMMUNIZATION. 1645 01:01:42,249 --> 01:01:44,751 AGAIN, YOU SEE BURST OF GENE 1646 01:01:44,751 --> 01:01:46,520 ACTIVITY, PERHAPS NOT 1647 01:01:46,520 --> 01:01:47,220 SURPRISING, THAT'S WHAT 1648 01:01:47,220 --> 01:01:48,388 ADJUVANTS DO. 1649 01:01:48,388 --> 01:01:50,991 BUT WHAT WAS VERY INTERESTING 1650 01:01:50,991 --> 01:01:52,659 WHEN YOU ZOOMED INTO THE 1651 01:01:52,659 --> 01:01:54,961 MONOCYTE POPULATION ON THE RIGHT 1652 01:01:54,961 --> 01:01:56,830 THERE, YOU SEE MANY, MANY 1653 01:01:56,830 --> 01:01:59,666 DIFFERENT CLUSTERS OF MONOCYTES. 1654 01:01:59,666 --> 01:02:00,600 TRADITIONALLY IF YOU ASK HOW 1655 01:02:00,600 --> 01:02:03,704 MANY TYPES DO YOU KNOW? 1656 01:02:03,704 --> 01:02:06,873 THE IMMUNOLOGIST WOULD SAY 1657 01:02:06,873 --> 01:02:07,541 CLASSICAL, INFLAMMATORY 1658 01:02:07,541 --> 01:02:08,942 MONOCYTES, PATROLLING MONOCYTES. 1659 01:02:08,942 --> 01:02:10,010 SURE ENOUGH WE CAN SEE THEM. 1660 01:02:10,010 --> 01:02:12,579 WE CAN SEE AT THE BOTTOM IN 1661 01:02:12,579 --> 01:02:15,215 BROWN ARE THE PATROLLING OR 1662 01:02:15,215 --> 01:02:15,649 NON-CLASSICAL. 1663 01:02:15,649 --> 01:02:20,320 IN THE MIDDLE IN PINK ARE 1664 01:02:20,320 --> 01:02:20,687 INFLAMMATORY. 1665 01:02:20,687 --> 01:02:22,723 AT THE TOP YOU SEE ALL THOSE 1666 01:02:22,723 --> 01:02:22,956 COLORS. 1667 01:02:22,956 --> 01:02:25,926 THOSE ARE ALL DIFFERENT TYPES OF 1668 01:02:25,926 --> 01:02:27,227 MONOCYTES, CLASSICAL MONOCYTES. 1669 01:02:27,227 --> 01:02:28,662 WHAT ARE THOSE DIFFERENT TYPES? 1670 01:02:28,662 --> 01:02:32,499 YOU CAN SEE IN ORANGE THOSE ARE 1671 01:02:32,499 --> 01:02:34,701 MONOCYTES OF CLUSTER 1, ISG. 1672 01:02:34,701 --> 01:02:35,902 THAT IS INTERFERON STIMULATED 1673 01:02:35,902 --> 01:02:36,103 GENES. 1674 01:02:36,103 --> 01:02:41,141 IN BLUE YOU CAN SEE WHAT'S 1675 01:02:41,141 --> 01:02:45,746 CALLED VCAN HIGH MONOCYTES, IN 1676 01:02:45,746 --> 01:02:47,614 GREEN, TRANSCRIPTIONAL PROFILE 1677 01:02:47,614 --> 01:02:49,583 IS VERY DIFFERENT. 1678 01:02:49,583 --> 01:02:51,318 SO, WE ASK WHAT HAPPENS WITH 1679 01:02:51,318 --> 01:02:52,519 EACH OF THESE ADJUVANTS? 1680 01:02:52,519 --> 01:02:57,657 LET'S TAKE A LOOK AT, FOR 1681 01:02:57,657 --> 01:02:59,092 EXAMPLE, THE 3M 052, HOW DO THEY 1682 01:02:59,092 --> 01:03:00,193 CHANGE IN IMMUNE RESPONSE? 1683 01:03:00,193 --> 01:03:04,664 ON THE LEFT YOU CAN SEE THIS 1684 01:03:04,664 --> 01:03:09,936 DIAGRAM WHERE IF YOU TRAVERSE 1685 01:03:09,936 --> 01:03:11,905 PERIPHERY, BOTTOM IS BASELINE, 1686 01:03:11,905 --> 01:03:17,944 DAY 1, DAY 7, DAY 18, DAY 22 ONE 1687 01:03:17,944 --> 01:03:21,314 DAY AFTER, AND SO ON. 1688 01:03:21,314 --> 01:03:24,384 CLUSTERS ARE CHANGING. 1689 01:03:24,384 --> 01:03:26,453 TO SIMPLIFY, SEROTIME TRAJECTORY 1690 01:03:26,453 --> 01:03:29,623 ANALYSIS, A FANCY WORD, IT MEANS 1691 01:03:29,623 --> 01:03:30,724 COMPUTATIONALLY YOU CAN INFER 1692 01:03:30,724 --> 01:03:32,359 THE SEQUENCE OF EVENTS THAT 1693 01:03:32,359 --> 01:03:33,460 HAPPENED DURING IMMUNE RESPONSE. 1694 01:03:33,460 --> 01:03:36,530 SO YOU CAN SEE WITH THIS 1695 01:03:36,530 --> 01:03:39,800 PARTICULAR ADJUVANT THE MONOCYTE 1696 01:03:39,800 --> 01:03:42,202 RESPONSE GOES FROM HIGH 1697 01:03:42,202 --> 01:03:49,409 POPULATION IN BLUE TO S100A9, 1698 01:03:49,409 --> 01:03:50,043 CUTS ACROSS INTERFERON 1699 01:03:50,043 --> 01:03:53,146 STIMULATED GENES AND GETS INTO 1700 01:03:53,146 --> 01:03:59,920 THE INTERMEDIATE AND 1701 01:03:59,920 --> 01:04:01,788 NON-CLASSICAL PATROLLING 1702 01:04:01,788 --> 01:04:02,055 MONOCYTES. 1703 01:04:02,055 --> 01:04:03,857 BUT DIFFERENT ADJUVANT, 1704 01:04:03,857 --> 01:04:04,958 TRAJECTORY FOLLOWS TO ORANGE 1705 01:04:04,958 --> 01:04:05,792 INTERFERON STIMULATED GENES BUT 1706 01:04:05,792 --> 01:04:08,128 DON'T PROGRESS TO THE 1707 01:04:08,128 --> 01:04:09,029 INTERMEDIATE OR NON-CLASSICAL. 1708 01:04:09,029 --> 01:04:10,430 LOOPS BACK TO THE MIDDLE WHICH 1709 01:04:10,430 --> 01:04:13,500 IS A SUBSET OF MONOCYTES WHICH 1710 01:04:13,500 --> 01:04:14,668 IS ENRICHED IN NF-kappaB AND 1711 01:04:14,668 --> 01:04:15,702 TARGET GENES. 1712 01:04:15,702 --> 01:04:17,671 IF YOU DO THIS ANALYSIS BROADLY 1713 01:04:17,671 --> 01:04:19,172 ACROSS DIFFERENT ADJUVANTS WHAT 1714 01:04:19,172 --> 01:04:21,274 YOU CAN SEE IS THAT THERE ARE 1715 01:04:21,274 --> 01:04:26,413 TWO BROADLY DIFFERENT 1716 01:04:26,413 --> 01:04:27,380 TRAJECTORIES, THIS SEEMS TO 1717 01:04:27,380 --> 01:04:31,785 DRIVE CELLS THROUGH TO THE 1718 01:04:31,785 --> 01:04:34,421 INTERMEDIATE, BUT ALUM SO 3, S 1719 01:04:34,421 --> 01:04:36,923 37 AND CpG COME HALFWAY THERE 1720 01:04:36,923 --> 01:04:38,325 BUT LOOP BACK TO NF-kappaB 1721 01:04:38,325 --> 01:04:38,892 HIGH POPULATION. 1722 01:04:38,892 --> 01:04:40,193 WHY IS THIS IMPORTANT? 1723 01:04:40,193 --> 01:04:41,561 WHAT IS THE FUNCTIONAL RELEVANCE 1724 01:04:41,561 --> 01:04:43,730 OF THIS IN TERMS OF INNATE 1725 01:04:43,730 --> 01:04:45,131 IMMUNITY, CYTOKINES AND THE 1726 01:04:45,131 --> 01:04:46,233 NATURE OF THE ADAPTIVE RESPONSE? 1727 01:04:46,233 --> 01:04:48,969 THIS IS SOMETHING THAT WE'RE 1728 01:04:48,969 --> 01:04:50,403 LOOKING AT NOW. 1729 01:04:50,403 --> 01:04:54,207 LET ME CONCLUDE BY SAYING I'VE 1730 01:04:54,207 --> 01:04:56,510 SHOWN MONOCYTES ACTIVATE -- 1731 01:04:56,510 --> 01:04:57,477 SORRY, ADJUVANTS ACTIVATE 1732 01:04:57,477 --> 01:04:58,912 MONOCYTES, THAT'S THE INNATE 1733 01:04:58,912 --> 01:04:59,145 SYSTEM. 1734 01:04:59,145 --> 01:05:02,649 THE CARTOON AT THE FRONT. 1735 01:05:02,649 --> 01:05:05,252 SURPRISE FOR US WAS THAT WHEN 1736 01:05:05,252 --> 01:05:08,788 YOU LOOK AT THE DATA IT'S NOT 1737 01:05:08,788 --> 01:05:10,724 JUST THE INNATE CELLS ACTIVATED. 1738 01:05:10,724 --> 01:05:16,530 YOU CAN SEE, FOCUS ON 1739 01:05:16,530 --> 01:05:19,432 PENULTIMATE ROW, 3M-052, THERE'S 1740 01:05:19,432 --> 01:05:21,701 A CLUSTER OF T CELLS ON THE LEFT 1741 01:05:21,701 --> 01:05:24,538 PANEL, YOU CAN SEE THE 1742 01:05:24,538 --> 01:05:28,942 JUXTAPOSED TO YELLOW IS RED 1743 01:05:28,942 --> 01:05:30,911 CELLS THAT EXPRESS INTERFERON 1744 01:05:30,911 --> 01:05:32,979 STIMULATED GENES AT DAY 1, NOT 1745 01:05:32,979 --> 01:05:34,514 ANTIGEN SPECIFIC T CELLS THAT 1746 01:05:34,514 --> 01:05:35,282 HAVE BECOME ACTIVATED. 1747 01:05:35,282 --> 01:05:37,784 THEY TAKE A LONGER TIME. 1748 01:05:37,784 --> 01:05:40,020 THESE ARE SOME SUBSET OF T CELLS 1749 01:05:40,020 --> 01:05:44,691 QUICKLY RESPONSING BUT NOT 1750 01:05:44,691 --> 01:05:46,126 INTERFERON STIMULATED GENES. 1751 01:05:46,126 --> 01:05:48,762 SAME DAY AT DAY 22, ONE DAY 1752 01:05:48,762 --> 01:05:50,530 AFTER SECOND IMMIZATION, WHAT IS 1753 01:05:50,530 --> 01:05:51,598 THE FUNCTIONAL BASIS? 1754 01:05:51,598 --> 01:05:54,100 THEY ARE GUIDING SUBSEQUENT 1755 01:05:54,100 --> 01:05:56,202 MONOCYTE RESPONSE, WHAT'S THE 1756 01:05:56,202 --> 01:05:56,736 LINK? 1757 01:05:56,736 --> 01:05:58,605 WE DON'T KNOW, WE'RE EXPLORING. 1758 01:05:58,605 --> 01:06:00,106 YOU CAN SEE KINETICS HERE. 1759 01:06:00,106 --> 01:06:01,341 IN THE LAST TWO OR THREE SLIDES 1760 01:06:01,341 --> 01:06:04,711 WHAT I WANT TO TELL YOU IS THAT 1761 01:06:04,711 --> 01:06:07,247 WE'RE NOW DOING 1762 01:06:07,247 --> 01:06:08,148 CROSS-COMPARATIVE ANALYSIS 1763 01:06:08,148 --> 01:06:10,750 BETWEEN MONKEYS AND MICE, SAME 1764 01:06:10,750 --> 01:06:12,285 ADJUVANTS NOW USED IN MICE. 1765 01:06:12,285 --> 01:06:14,220 ALREADY YOU CAN SEE VERY MAJOR 1766 01:06:14,220 --> 01:06:14,554 DIFFERENCES. 1767 01:06:14,554 --> 01:06:16,890 FIRST OF ALL LOOK AT THE RATIO 1768 01:06:16,890 --> 01:06:20,493 OF B CELLS TO T CELLS IN A 1769 01:06:20,493 --> 01:06:21,227 MONKEY, .33. 1770 01:06:21,227 --> 01:06:28,935 LOOK WHAT HAPPENS IN A MOUSE, 1771 01:06:28,935 --> 01:06:29,469 1.39. 1772 01:06:29,469 --> 01:06:30,403 THIS INTERFERON STIMULATED 1773 01:06:30,403 --> 01:06:32,005 SIGNATURE IN T CELLS THAT I 1774 01:06:32,005 --> 01:06:33,773 MENTIONED WHICH ARE SO PROMINENT 1775 01:06:33,773 --> 01:06:35,809 IN MONKEYS, WE DON'T SEE THAT IN 1776 01:06:35,809 --> 01:06:36,109 MICE. 1777 01:06:36,109 --> 01:06:39,179 IF YOU TAKE MOUSE BLOOD, ISOLATE 1778 01:06:39,179 --> 01:06:41,081 MOUSE PBMCs LIKE WHAT YOU DO 1779 01:06:41,081 --> 01:06:42,716 IN MONKEYS, YOU SIMPLY DON'T SEE 1780 01:06:42,716 --> 01:06:42,916 THAT. 1781 01:06:42,916 --> 01:06:45,318 BUT YOU DO SEE IT IN THE 1782 01:06:45,318 --> 01:06:46,653 DRAINING LYMPH NODES, YOU CAN 1783 01:06:46,653 --> 01:06:48,722 SEE THE CLUSTER THERE. 1784 01:06:48,722 --> 01:06:50,490 AND SO FINALLY, ALL THESE 1785 01:06:50,490 --> 01:06:54,327 CHANGES THAT ARE HAPPENING WITH 1786 01:06:54,327 --> 01:06:55,061 ADJUVANTS IS DIFFERENT 1787 01:06:55,061 --> 01:06:56,296 TRAJECTORIES, HOW LONG DO THEY 1788 01:06:56,296 --> 01:06:56,496 LAST? 1789 01:06:56,496 --> 01:06:58,798 IS THERE A CHANGE IN THE 1790 01:06:58,798 --> 01:06:59,666 EPIGENOME OF THESE? 1791 01:06:59,666 --> 01:07:01,001 WE'VE BEEN LOOKING AT THIS. 1792 01:07:01,001 --> 01:07:03,303 THIS IS AN EXAMPLE IN HUMANS. 1793 01:07:03,303 --> 01:07:04,938 WHERE WE WERE GIVING THESE 1794 01:07:04,938 --> 01:07:06,906 HUMANS THE PANDEMIC FLU VACCINE 1795 01:07:06,906 --> 01:07:11,945 WITH ASO 3, IN THAT STUDY 1796 01:07:11,945 --> 01:07:12,579 MONOCYTES UNDERGOING INCREDIBLE 1797 01:07:12,579 --> 01:07:13,346 EPIGENETIC PROGRAMMING THAT 1798 01:07:13,346 --> 01:07:14,681 LASTED FOR ABOUT TWO MONTHS. 1799 01:07:14,681 --> 01:07:18,918 SO IN OTHER WORDS, AFTER TWO 1800 01:07:18,918 --> 01:07:22,656 MONTHS, THE CHROMATIN LOCI 1801 01:07:22,656 --> 01:07:24,391 TARGETED BY INTERFERON FACTORS 1802 01:07:24,391 --> 01:07:27,961 STAT1 AND STAT2 WERE MORE 1803 01:07:27,961 --> 01:07:31,865 ACCESSIBLE THAN BEFORE VACCINE. 1804 01:07:31,865 --> 01:07:34,868 IN CONTRAST TARGETED BY API 1805 01:07:34,868 --> 01:07:36,069 TRANSCRIPTION FACTORS WERE LESS 1806 01:07:36,069 --> 01:07:37,704 ACCESSIBLE THAN BEFORE YOU GAVE 1807 01:07:37,704 --> 01:07:38,672 THE ADJUVANT. 1808 01:07:38,672 --> 01:07:39,873 SO THAT WAS PUBLISHED BUT NOW 1809 01:07:39,873 --> 01:07:44,377 WHAT WE'RE DOING IS DOING A 1810 01:07:44,377 --> 01:07:45,712 CROSS-COMPARATIVE ANALYSIS OF 1811 01:07:45,712 --> 01:07:49,282 SIX VACCINES INCLUDING THE 1812 01:07:49,282 --> 01:07:49,849 SHINGRIX ASO-1, ALSO PFIZER 1813 01:07:49,849 --> 01:07:50,750 mRNA, AND SO ON. 1814 01:07:50,750 --> 01:07:52,686 WHAT I CAN TELL YOU IS WE'RE 1815 01:07:52,686 --> 01:07:57,190 BEGINNING TO DEFINE WHAT WE CALL 1816 01:07:57,190 --> 01:07:59,492 MOTIF SUPER CLUSTERS, SINGLE 1817 01:07:59,492 --> 01:08:01,995 CELL LEVEL THAT SEEM TO BE 1818 01:08:01,995 --> 01:08:03,329 DIFFERENTIALLY INDUCED BY 1819 01:08:03,329 --> 01:08:05,165 DIFFERENCE VACCINES. 1820 01:08:05,165 --> 01:08:08,001 SOME ARE CO-REGULATED. 1821 01:08:08,001 --> 01:08:10,103 IF YOU LOOK WITH IRF CHROMATIN 1822 01:08:10,103 --> 01:08:12,672 ACCESSIBILITY ON X-AXIS IN 1823 01:08:12,672 --> 01:08:14,374 MACHINEOCYTES VERSUS AP 1 1824 01:08:14,374 --> 01:08:15,675 ACCESSIBILITY THERE'S MOST 1825 01:08:15,675 --> 01:08:17,644 DEFINITE INVERSE CORRELATION 1826 01:08:17,644 --> 01:08:21,581 ACROSS ALL THESE VACCINES H1N1, 1827 01:08:21,581 --> 01:08:23,883 WITHOUT ADJUVANT, SEASONAL FLU 1828 01:08:23,883 --> 01:08:25,719 VACCINE, PFIZER mRNA, YELLOW 1829 01:08:25,719 --> 01:08:34,260 FEVER, SHINGRIX. 1830 01:08:34,260 --> 01:08:36,563 THESE ARE DISTANT REGIONS IN THE 1831 01:08:36,563 --> 01:08:37,997 CHROMATIN, HOW IS THIS 1832 01:08:37,997 --> 01:08:38,631 EPIGENETIC COORDINATION 1833 01:08:38,631 --> 01:08:39,733 HAPPENING, WHAT DOES THIS MEAN 1834 01:08:39,733 --> 01:08:40,734 FOR ADJUVANT BIOLOGY? 1835 01:08:40,734 --> 01:08:41,501 WE DON'T KNOW. 1836 01:08:41,501 --> 01:08:42,469 THERE'S LOTS OF QUESTIONS. 1837 01:08:42,469 --> 01:08:45,638 LET ME END WITH THIS SLIDE. 1838 01:08:45,638 --> 01:08:47,741 LET ME REITERATE MICE ARE 1839 01:08:47,741 --> 01:08:48,842 WONDERFUL TOOLS AND YET THEY 1840 01:08:48,842 --> 01:08:50,143 SEEM TO BE SO DIFFERENT FROM 1841 01:08:50,143 --> 01:08:50,376 HUMANS. 1842 01:08:50,376 --> 01:08:52,545 THIS IS A VERY SIMPLE ASSAY. 1843 01:08:52,545 --> 01:08:56,950 THIS IS THE SAME VACCINE, ASO 3 1844 01:08:56,950 --> 01:08:58,051 ADJUVANTED GIVEN IN HUMANS, 1845 01:08:58,051 --> 01:08:59,786 MONKEYS, MICE. 1846 01:08:59,786 --> 01:09:02,055 WE'RE MEASURING IN SERUM 1847 01:09:02,055 --> 01:09:02,956 INTERFERON GAMMA AND IL-5. 1848 01:09:02,956 --> 01:09:04,591 LOOK WHAT HAPPENS IN HUMANS. 1849 01:09:04,591 --> 01:09:06,659 A VERY NICE INTERFERON GAMMA 1850 01:09:06,659 --> 01:09:08,428 Th1 RESPONSE. 1851 01:09:08,428 --> 01:09:11,064 LOOK AT RHESUS MACAQUES, THE 1852 01:09:11,064 --> 01:09:12,732 OPPOSITE, A Th2 RESPONSE. 1853 01:09:12,732 --> 01:09:15,468 LOOK AT MICE, MORE LIKE A Th2 1854 01:09:15,468 --> 01:09:16,002 RESPONSE. 1855 01:09:16,002 --> 01:09:18,505 AGAIN, WE'RE SEEING MANY, MANY 1856 01:09:18,505 --> 01:09:20,039 SPECIES DIFFERENCES THAT, AGAIN, 1857 01:09:20,039 --> 01:09:22,575 HIGHLIGHT IMPORTANCE OF ACTUALLY 1858 01:09:22,575 --> 01:09:24,444 LOOKING AT THESE ACROSS SPECIES 1859 01:09:24,444 --> 01:09:25,211 PARTICULARLY IN HUMANS. 1860 01:09:25,211 --> 01:09:26,379 THAT'S THE PURPOSE OF THE 1861 01:09:26,379 --> 01:09:27,981 PROGRAM THAT WE'RE EXCITED TO BE 1862 01:09:27,981 --> 01:09:29,749 PART OF. 1863 01:09:29,749 --> 01:09:31,417 THIS IS REALLY THE CONCLUSION, 1864 01:09:31,417 --> 01:09:33,820 BASICALLY THE IDEA THAT YOU 1865 01:09:33,820 --> 01:09:34,821 COULD DEVELOP ADJUVANTED 1866 01:09:34,821 --> 01:09:37,557 VACCINES OR ANY VACCINES BY 1867 01:09:37,557 --> 01:09:42,695 GOING THROUGH THE STANDARD PHASE 1868 01:09:42,695 --> 01:09:46,332 1, PHASE 2, PHASE 3. 1869 01:09:46,332 --> 01:09:48,268 IF YOU'RE SUCCESSFUL LICENSE, OR 1870 01:09:48,268 --> 01:09:49,936 YOU'RE SCRATCHING YOUR HEAD WHAT 1871 01:09:49,936 --> 01:09:53,072 SHOULD WE DO. 1872 01:09:53,072 --> 01:09:57,177 TOOLS SHOULD GO INTEGRATED INTO 1873 01:09:57,177 --> 01:10:00,113 THE VACCINE TESTING PIPELINE TO 1874 01:10:00,113 --> 01:10:01,748 DO IN VITRO ANIMAL MODELS, IT'S 1875 01:10:01,748 --> 01:10:03,716 A VIRTUAL CYCLE OF UNDERSTANDING 1876 01:10:03,716 --> 01:10:04,984 THE BASIS OF IMMUNOGENICITY. 1877 01:10:04,984 --> 01:10:06,719 WITH THAT I'D LIKE TO CONCLUDE 1878 01:10:06,719 --> 01:10:10,523 THESE ARE THE AMAZING PEOPLE WHO 1879 01:10:10,523 --> 01:10:13,893 DID THE WORK. 1880 01:10:13,893 --> 01:10:15,895 AND OF COURSE HUGE THANKS TO 1881 01:10:15,895 --> 01:10:17,630 NIAID AND NIH FOR ALL THEIR 1882 01:10:17,630 --> 01:10:23,570 SUPPORT THROUGHOUT THE LAST FEW 1883 01:10:23,570 --> 01:10:23,770 YEARS. 1884 01:10:23,770 --> 01:10:27,173 THANK YOU. 1885 01:10:27,173 --> 01:10:37,217 1886 01:10:38,117 --> 01:10:45,491 >> I WAS INTRIGUED BY THE PAPER, 1887 01:10:45,491 --> 01:10:48,194 IN YOUR TALK WHEN YOU SHOWED THE 1888 01:10:48,194 --> 01:10:52,165 DATA, YOU SUGGESTED THERE WAS 1889 01:10:52,165 --> 01:10:53,132 INCREASED -- OF COURSE 1890 01:10:53,132 --> 01:10:54,000 DURABILITY, WHICH YOU WOULD 1891 01:10:54,000 --> 01:10:56,302 EXPECT FROM VACCINE BUT ALSO 1892 01:10:56,302 --> 01:10:58,605 THERE WAS A CHANGE IN THE 1893 01:10:58,605 --> 01:11:02,041 ANTIBODY REPERTOIRE THAT THERE 1894 01:11:02,041 --> 01:11:02,976 WAS EXPANDED 1895 01:11:02,976 --> 01:11:04,377 DO YOU THINK ADJUVANT THAT YOU 1896 01:11:04,377 --> 01:11:07,680 WERE USING IN THAT, DOES THAT 1897 01:11:07,680 --> 01:11:08,781 HAVE EFFECT ON SOMATIC 1898 01:11:08,781 --> 01:11:10,850 RECOMBINATION IN SOME RESPECT OR 1899 01:11:10,850 --> 01:11:14,020 AFFINITY MATURATION OR BOTH? 1900 01:11:14,020 --> 01:11:14,821 IF IT'S SOMATIC RECOMBINATION 1901 01:11:14,821 --> 01:11:16,756 THAT WOULD BE A HUGE PARADIGM 1902 01:11:16,756 --> 01:11:17,657 SHIFT I WOULD THINK. 1903 01:11:17,657 --> 01:11:19,058 >> THANK YOU FOR THAT. 1904 01:11:19,058 --> 01:11:22,028 THAT WAS REALLY THE CRUX OF THE 1905 01:11:22,028 --> 01:11:22,228 PAPER. 1906 01:11:22,228 --> 01:11:24,864 ON THE ONE HAND, EVERYONE AGREED 1907 01:11:24,864 --> 01:11:26,399 THAT ADJUVANTS INCREASE 1908 01:11:26,399 --> 01:11:27,834 MAGNITUDE AND SO THROUGH THAT 1909 01:11:27,834 --> 01:11:29,602 RISING TIDE RAISES ALL BOATS 1910 01:11:29,602 --> 01:11:31,237 MODEL, IF THE MAGNITUDE IS 1911 01:11:31,237 --> 01:11:33,506 HIGHER, OF COURSE YOU WOULD 1912 01:11:33,506 --> 01:11:34,407 PREDICT SEROLOGICALLY BREADTH 1913 01:11:34,407 --> 01:11:38,544 WOULD BE HIGHER BECAUSE THERE 1914 01:11:38,544 --> 01:11:40,313 ARE MANY CLONES EMERGING. 1915 01:11:40,313 --> 01:11:43,816 WE SHOWED THESE ARE INDUCING 1916 01:11:43,816 --> 01:11:45,351 GERMINAL RESPONSES WHICH LEADS 1917 01:11:45,351 --> 01:11:48,288 TO PERSISTENT ACQUISITION OF 1918 01:11:48,288 --> 01:11:50,590 SOMATIC MUTATIONS OVER SIX-MONTH 1919 01:11:50,590 --> 01:11:52,659 PERIOD, COULD YOU ISOLATE CLONES 1920 01:11:52,659 --> 01:11:53,426 BEFORE, SHORTLY AFTER 1921 01:11:53,426 --> 01:11:54,994 VACCINATION, A MONTH AFTER 1922 01:11:54,994 --> 01:11:58,264 VACCINATION, OR SIX MONTHS AFTER 1923 01:11:58,264 --> 01:11:59,198 VACCINATION, IN ESTABLISHED 1924 01:11:59,198 --> 01:12:00,533 CLONAL LINEAGES TRAJECTORY AND 1925 01:12:00,533 --> 01:12:03,069 SHOW THE SAME CLONE HAD ACQUIRED 1926 01:12:03,069 --> 01:12:05,271 A THOUSAND-FOLD MORE AFFINITY 1927 01:12:05,271 --> 01:12:07,874 AND ALSO ACQUIRED BREADTH. 1928 01:12:07,874 --> 01:12:10,109 WE THINK ONE PATHWAY BY WHICH 1929 01:12:10,109 --> 01:12:10,944 ADJUVANT IS PROMOTING BREADTH AT 1930 01:12:10,944 --> 01:12:13,813 CLONAL LEVEL IS AS YOU SAY 1931 01:12:13,813 --> 01:12:15,982 THROUGH THE ACQUISITION, 1932 01:12:15,982 --> 01:12:16,549 CONTINUOUS ACCUMULATION OF 1933 01:12:16,549 --> 01:12:17,750 SOMATIC MUTATION THAT GIVES THE 1934 01:12:17,750 --> 01:12:20,153 OPPORTUNITY TO BIND NOT JUST THE 1935 01:12:20,153 --> 01:12:21,888 PARENT STRAIN BUT ALSO OTHER 1936 01:12:21,888 --> 01:12:22,155 VARIANTS. 1937 01:12:22,155 --> 01:12:24,424 THERE'S ANOTHER PATHWAY THAT'S 1938 01:12:24,424 --> 01:12:28,828 NOT THE ONLY PATHWAY, WHAT WE 1939 01:12:28,828 --> 01:12:32,966 CALL THE -- IT'S EPITOPE MASK, 1940 01:12:32,966 --> 01:12:33,499 INITIAL RESPONSE GENERATES 1941 01:12:33,499 --> 01:12:34,834 ANTIBODIES THAT ARE HIGHLY 1942 01:12:34,834 --> 01:12:38,438 SPECIFIC TO THE PARENT STRAIN, 1943 01:12:38,438 --> 01:12:40,840 WHICH THEN BLOCKS THE DOMINANT 1944 01:12:40,840 --> 01:12:44,477 EPITOPE ON THE RBD, LEAVING 1945 01:12:44,477 --> 01:12:46,112 EXPOSED THE OTHER SUBDOMINANT 1946 01:12:46,112 --> 01:12:48,414 EPITOPES WHICH THE CLONES THAT 1947 01:12:48,414 --> 01:12:49,382 RECOGNIZE THOSE EPITOPES NEVER 1948 01:12:49,382 --> 01:12:52,452 HAD A CHANCE TO COMPLETE IN THE 1949 01:12:52,452 --> 01:12:54,954 FIRST PLACE WITH DOMINANT CLONES 1950 01:12:54,954 --> 01:13:05,498 BUT NOW DOMINANT UP -- EPITOPE 1951 01:13:15,208 --> 01:13:15,908 IS BLOCKED. 1952 01:13:15,908 --> 01:13:17,877 >> DAY 1 ISG POPULATION THAT YOU 1953 01:13:17,877 --> 01:13:21,147 SEE IN HUMANS, NOT IN MICE, IS 1954 01:13:21,147 --> 01:13:25,952 THIS AN EXPANSION OF BASELINE IN 1955 01:13:25,952 --> 01:13:29,122 T CELL COMPARTMENT OR IS THIS 1956 01:13:29,122 --> 01:13:32,392 RESPONSIVE POPULATION TO THE 1957 01:13:32,392 --> 01:13:33,926 VACCINE AND ADJUVANT, AND DOES 1958 01:13:33,926 --> 01:13:35,795 IT CORRELATE WITH ANY OF THE 1959 01:13:35,795 --> 01:13:36,462 RESPONSES? 1960 01:13:36,462 --> 01:13:36,896 >> GREAT QUESTION. 1961 01:13:36,896 --> 01:13:39,399 WE DON'T KNOW IF IT IS AN 1962 01:13:39,399 --> 01:13:40,266 EXPANSION OF PREEXISTING ISG 1963 01:13:40,266 --> 01:13:41,601 CELLS IN MONKEYS BECAUSE OF 1964 01:13:41,601 --> 01:13:43,569 THEIR PRIOR EXPOSURE TO SO MANY 1965 01:13:43,569 --> 01:13:45,671 OTHER PATHOGENS, RIGHT? 1966 01:13:45,671 --> 01:13:50,043 BUT WHAT WE ARE PLANNING TO DO 1967 01:13:50,043 --> 01:13:54,747 IS LINEAGE TRACING USING MITO 1968 01:13:54,747 --> 01:13:55,848 Seq, MITOCHONDRIAL MUTATIONS, 1969 01:13:55,848 --> 01:13:57,483 YOU CAN SEE WHETHER THE SAME 1970 01:13:57,483 --> 01:13:58,684 CELL, SAME LINEAGE, IS CONVERTED 1971 01:13:58,684 --> 01:14:00,219 TO THE OTHER TYPE. 1972 01:14:00,219 --> 01:14:01,187 WE DON'T HAVE THAT DATA YET BUT 1973 01:14:01,187 --> 01:14:02,255 WE'RE DOING THAT. 1974 01:14:02,255 --> 01:14:03,389 YOUR QUESTION DOES IT MEAN 1975 01:14:03,389 --> 01:14:05,925 ANYTHING IN TERMS OF IMMUNE 1976 01:14:05,925 --> 01:14:06,793 RESPONSES, DURABILITY, LONGEVITY 1977 01:14:06,793 --> 01:14:08,294 AND SO ON, WE'RE WORKING ON 1978 01:14:08,294 --> 01:14:08,494 THAT. 1979 01:14:08,494 --> 01:14:12,465 WE DON'T HAVE ANY DATA ON THAT 1980 01:14:12,465 --> 01:14:14,867 YET. 1981 01:14:14,867 --> 01:14:16,736 >> HI, JIM BURN, JUST A TERRIFIC 1982 01:14:16,736 --> 01:14:16,936 TALK. 1983 01:14:16,936 --> 01:14:18,938 THANKS SO MUCH. 1984 01:14:18,938 --> 01:14:22,341 ONE QUESTION THOUGH WITH THE 1985 01:14:22,341 --> 01:14:23,709 ADJUVANTS THAT MARKEDLY INCREASE 1986 01:14:23,709 --> 01:14:24,811 BREADTH OF THE ANTIBODY RESPONSE 1987 01:14:24,811 --> 01:14:27,113 IS THERE ANY WORRY THERE THAT 1988 01:14:27,113 --> 01:14:28,014 YOU'LL START TO INCREASE TO THE 1989 01:14:28,014 --> 01:14:31,417 POINT WHERE YOU GET OFF TARGET 1990 01:14:31,417 --> 01:14:31,918 ANTIBODIES? 1991 01:14:31,918 --> 01:14:33,586 >> YEAH, THERE'S ALWAYS A WORRY 1992 01:14:33,586 --> 01:14:35,855 WITH OFF TARGET EFFECTS. 1993 01:14:35,855 --> 01:14:38,724 HOWEVER, I THINK THERE'S A LIMIT 1994 01:14:38,724 --> 01:14:41,127 TO HOW MUCH BREADTH AND ADJUVANT 1995 01:14:41,127 --> 01:14:42,228 CAN INCREASE. 1996 01:14:42,228 --> 01:14:43,329 WE'RE VERY LUCKY IN THE CONTEXT 1997 01:14:43,329 --> 01:14:46,499 OF WHAT WE'RE SEEING WITH COVID 1998 01:14:46,499 --> 01:14:47,567 ANTIGENS. 1999 01:14:47,567 --> 01:14:50,336 BUT IT IS FAR -- FALLS FAR SHORT 2000 01:14:50,336 --> 01:14:51,838 OF WHAT HIV VACCINE PEOPLE WOULD 2001 01:14:51,838 --> 01:14:52,105 LIKE. 2002 01:14:52,105 --> 01:14:54,707 I THINK ALTHOUGH IT'S AN 2003 01:14:54,707 --> 01:14:56,142 ENCOURAGING STEP TO INCREASING 2004 01:14:56,142 --> 01:14:57,643 BREADTH WE'RE FAR SHORT OF 2005 01:14:57,643 --> 01:15:01,247 INCREASING TO SUCH A DEGREE IT 2006 01:15:01,247 --> 01:15:03,149 GOES TO OFF-TARGET ANTIGENS. 2007 01:15:03,149 --> 01:15:13,426 >> THANK YOU. 2008 01:15:13,893 --> 01:15:15,061 2009 01:15:15,061 --> 01:15:17,997 >> NEXT SPEAKER WILL TALK ABOUT 2010 01:15:17,997 --> 01:15:22,535 THE EVALUATION OF NOVEL ADJUVANT 2011 01:15:22,535 --> 01:15:24,804 IN A CLINICAL TRIAL. 2012 01:15:24,804 --> 01:15:26,772 DR. EVANS, THE FLOOR IS YOURS. 2013 01:15:26,772 --> 01:15:28,441 >> CAN YOU HEAR ME OKAY? 2014 01:15:28,441 --> 01:15:28,708 >> YES. 2015 01:15:28,708 --> 01:15:30,510 >> AND THE SCREEN IS ON THE 2016 01:15:30,510 --> 01:15:31,711 RIGHT PRESENTER MODE? 2017 01:15:31,711 --> 01:15:33,446 >> YES, IT IS. 2018 01:15:33,446 --> 01:15:33,746 >> GREAT. 2019 01:15:33,746 --> 01:15:35,081 THANK YOU. 2020 01:15:35,081 --> 01:15:36,616 THANKS FOR THE OPPORTUNITY TO 2021 01:15:36,616 --> 01:15:36,949 TALK TODAY. 2022 01:15:36,949 --> 01:15:39,919 I'M SORRY I COULDN'T BE THERE IN 2023 01:15:39,919 --> 01:15:40,153 PERSON. 2024 01:15:40,153 --> 01:15:42,121 I'M ACTUALLY FLYING OUT THERE 2025 01:15:42,121 --> 01:15:44,290 FOR THE ADJUVANT COMPARISON 2026 01:15:44,290 --> 01:15:45,057 MEETING, I'LL BE THERE ON 2027 01:15:45,057 --> 01:15:47,126 WEDNESDAY AND THURSDAY OF THIS 2028 01:15:47,126 --> 01:15:48,995 WEEK, SO IF PEOPLE WANT TO MEET 2029 01:15:48,995 --> 01:15:58,804 IN PERSON AND ASK QUESTIONS. 2030 01:15:58,804 --> 01:16:00,606 SO I'M GOING TO TELL YOU A 2031 01:16:00,606 --> 01:16:03,042 LITTLE BIT ABOUT THE ADJUVANT 2032 01:16:03,042 --> 01:16:09,015 RESEARCH AT UNIVERSITY OF 2033 01:16:09,015 --> 01:16:09,248 MONTANA. 2034 01:16:09,248 --> 01:16:18,191 I'M JAY EVANS, DIRECTOR AT 2035 01:16:18,191 --> 01:16:25,331 UNIVERSITY OF MONTANA, AND A 2036 01:16:25,331 --> 01:16:33,539 UNIQUE PUBLIC/PRIVATE 2037 01:16:33,539 --> 01:16:35,074 PARTNERSHIP IN 2016. 2038 01:16:35,074 --> 01:16:38,244 SO OUR FOCUS IS THE DISCOVER AND 2039 01:16:38,244 --> 01:16:40,213 DEVELOPMENT OF NOVEL 2040 01:16:40,213 --> 01:16:40,813 DISEASE-MODIFYING THERAPIES, 2041 01:16:40,813 --> 01:16:43,716 ADJUVANTS ARE AT THE CORE. 2042 01:16:43,716 --> 01:16:46,319 WE DEVELOPED NOVEL ADJUVANTS FOR 2043 01:16:46,319 --> 01:16:47,553 VACCINE INDICATIONS, AND THEN 2044 01:16:47,553 --> 01:16:53,559 EXPAND INTO OTHER INDICATIONS 2045 01:16:53,559 --> 01:16:57,463 SUCH ONCOLOGY, AUTOIMMUNE 2046 01:16:57,463 --> 01:17:00,967 DISEASES, ALL ABOUT THE 2047 01:17:00,967 --> 01:17:03,269 MODIFICATION. 2048 01:17:03,269 --> 01:17:05,805 WE FORMED THIS UNIQUE 2049 01:17:05,805 --> 01:17:06,405 PUBLIC/PRIVATE PARTNERSHIP IN 2050 01:17:06,405 --> 01:17:08,541 JANUARY OF 2016. 2051 01:17:08,541 --> 01:17:14,914 WE WERE FORMERLY THE GSC 2052 01:17:14,914 --> 01:17:21,454 DISCOVERY TEAM, NONE OF US WERE 2053 01:17:21,454 --> 01:17:24,090 THERE IN 1980, BUT WE'VE BEEN 2054 01:17:24,090 --> 01:17:25,825 DOING THIS FOR WELL OVER 20 2055 01:17:25,825 --> 01:17:31,964 YEARS AND WE HAVE A STRONG TRACK 2056 01:17:31,964 --> 01:17:35,368 RECORD WITH NIAID, PROGRAMS WITH 2057 01:17:35,368 --> 01:17:36,102 PATENTS. 2058 01:17:36,102 --> 01:17:40,906 WE'RE FULLY INTEGRATED TEAM, 2059 01:17:40,906 --> 01:17:44,777 UNIVERSITY OF MONTANA AND DO 2060 01:17:44,777 --> 01:17:48,581 SYNTHETIC SMALL MOLECULE DESIGN, 2061 01:17:48,581 --> 01:17:50,549 FORMULATION, ANALYTICS FOR DRUG 2062 01:17:50,549 --> 01:17:54,820 DELIVER, IMMUNOLOGY. 2063 01:17:54,820 --> 01:18:00,760 WE HAVE 70 PEOPLE HERE IN 2064 01:18:00,760 --> 01:18:01,494 MISSOULA, COLLABORATORS. 2065 01:18:01,494 --> 01:18:06,532 WE HAVE HUNDREDS OF PEOPLE WE'RE 2066 01:18:06,532 --> 01:18:11,137 WORKING WITH NOW ADVANCING NOVEL 2067 01:18:11,137 --> 01:18:11,904 IMMUNE MODULATORS. 2068 01:18:11,904 --> 01:18:15,274 SO THIS IS THE PIPELINE 2069 01:18:15,274 --> 01:18:16,342 CURRENTLY. 2070 01:18:16,342 --> 01:18:18,978 AGAIN, ALL BASELINE ADJUVANTS 2071 01:18:18,978 --> 01:18:22,615 THAT CAME OUT OF THE NIAID DRUG 2072 01:18:22,615 --> 01:18:25,051 DISCOVERY DEVELOPMENT PROGRAM, 2073 01:18:25,051 --> 01:18:34,360 I'LL TALK MORE, PHASE 1 CLINICAL 2074 01:18:34,360 --> 01:18:38,397 TRIAL CANDIDATES, HANDLING PHASE 2075 01:18:38,397 --> 01:18:44,537 2, SYNTHETIC TRL 7/8 IN PHASE 1, 2076 01:18:44,537 --> 01:18:46,939 SOON ADVANCED INTO PHASE 1 FOR 2077 01:18:46,939 --> 01:18:51,110 VACCINE ACCESS, AND NEXT BOX 2078 01:18:51,110 --> 01:18:55,681 DOWN BELOW PRE-CLINICAL PROGRAM, 2079 01:18:55,681 --> 01:19:01,387 LATE STAGE IND, AND IN 2080 01:19:01,387 --> 01:19:10,996 2024-2025, OPIOID VACCINE. 2081 01:19:10,996 --> 01:19:17,870 [AUDIO DISTORTION] 2082 01:19:17,870 --> 01:19:19,739 NOW I'M GOING TO CHANGE GEARS A 2083 01:19:19,739 --> 01:19:22,041 LITTLE BIT ON THE ADJUVANT SIDE 2084 01:19:22,041 --> 01:19:23,776 AND TALK ABOUT LATE STAGE 2085 01:19:23,776 --> 01:19:26,612 ADJUVANT PROGRAMS, ALL OF THESE 2086 01:19:26,612 --> 01:19:29,048 PROGRAMS WERE ORIGINALLY FUNDED 2087 01:19:29,048 --> 01:19:30,816 FROM NIAID. 2088 01:19:30,816 --> 01:19:33,652 WE HAVE A LONGSTANDING HISTORY 2089 01:19:33,652 --> 01:19:39,225 IN TLR 4 AGONIST STARTING IN 2090 01:19:39,225 --> 01:19:39,892 EARLY 2091 01:19:39,892 --> 01:19:40,326 [AUDIO DISTORTION] 2092 01:19:40,326 --> 01:19:50,870 WE HAVE A NEW PATENTEDDED FAMILY 2093 01:19:55,174 --> 01:19:58,110 OF SYNTHETIC CONSTRUCT. 2094 01:19:58,110 --> 01:20:02,782 WE HAVE A LONGSTANDING WORK IN 2095 01:20:02,782 --> 01:20:08,087 TLR7, NOW HAVE A LEAD COMPOUND, 2096 01:20:08,087 --> 01:20:16,796 IN PHASE 1 CLINICAL TRIALS RIGHT 2097 01:20:16,796 --> 01:20:19,865 NOW, THEY WERE DESIGNED FOR 2098 01:20:19,865 --> 01:20:27,106 FORMULATION IN MICE, THEY CAN BE 2099 01:20:27,106 --> 01:20:35,080 FORMULATED WITH AQUEOUS WITH 2100 01:20:35,080 --> 01:20:36,949 ALUM, REPLACEMENT FOR 2101 01:20:36,949 --> 01:20:37,950 [AUDIO DISTORTION] 2102 01:20:37,950 --> 01:20:48,427 ALONG THE SAME LINES WE HAVE 2103 01:20:49,495 --> 01:20:50,963 MANUFACTURING cGMP MOVING TO 2104 01:20:50,963 --> 01:20:54,266 PHASE 1 CLINICAL TRIALS. 2105 01:20:54,266 --> 01:20:55,901 MOUNT SINAI. 2106 01:20:55,901 --> 01:21:06,445 AS I MENTIONED EARLIER WE HAVE A 2107 01:21:10,182 --> 01:21:11,016 SYNTHETIC VERSION. 2108 01:21:11,016 --> 01:21:18,090 WE ALSO HAVE A NUMBER OF MID-AND 2109 01:21:18,090 --> 01:21:21,927 EARLY STAGE PROGRAMS, PARTNER 2110 01:21:21,927 --> 01:21:23,529 WITH BOSTON CHILDREN'S, OHSU, 2111 01:21:23,529 --> 01:21:26,432 EXPANDED THIS PUBLIC/PRIVATE 2112 01:21:26,432 --> 01:21:27,199 PARTNERSHIP ORIGINALLY 2113 01:21:27,199 --> 01:21:30,503 ESTABLISHED WITH UNIVERSITY OF 2114 01:21:30,503 --> 01:21:35,541 MONTANA, WE WORK ON THE SCALE 2115 01:21:35,541 --> 01:21:40,679 HELPING THEM GET ADJUVANTS, THEY 2116 01:21:40,679 --> 01:21:44,149 SPAN FROM LIGAND TARGETING 2117 01:21:44,149 --> 01:21:46,151 Th17 RESPONSE, ADJUVANT 2118 01:21:46,151 --> 01:21:49,555 DEVELOPMENT PROGRAM, STING 2119 01:21:49,555 --> 01:21:52,057 LIGAND PARTNERED WITH OHSU, 2120 01:21:52,057 --> 01:21:58,631 PARTNERING WITH AARON NOW, 2121 01:21:58,631 --> 01:21:59,198 MODIFIERS. 2122 01:21:59,198 --> 01:22:03,435 AND SO THIS HELPS GENERATE 2123 01:22:03,435 --> 01:22:08,474 ADJUVANT, BASED ON NEEDS OF 2124 01:22:08,474 --> 01:22:10,109 ANTIGEN OR TARGETING, IN 2125 01:22:10,109 --> 01:22:12,978 FORMULATION NOW READY TO WORK 2126 01:22:12,978 --> 01:22:19,685 THAT DRIVE A BROAD Th1 2127 01:22:19,685 --> 01:22:20,553 RESPONSE. 2128 01:22:20,553 --> 01:22:31,063 TLR 4 AGONIST, ASO 1 OR ASO 4, 2129 01:22:40,906 --> 01:22:43,742 SYNTHETIC SAPHONIN. 2130 01:22:43,742 --> 01:22:46,245 [AUDIO DISTORTION] 2131 01:22:46,245 --> 01:22:50,516 ONE OTHER ASPECT THAT HAS COME 2132 01:22:50,516 --> 01:22:54,219 TO OUR ATTENTION, SOMETIMES IT'S 2133 01:22:54,219 --> 01:22:58,123 EASIER TO TAKE ADJUVANTS TO 2134 01:22:58,123 --> 01:23:04,830 PHASE 1 TO STAND ALONE, 2135 01:23:04,830 --> 01:23:05,598 ESTABLISH A SAFETY PROFILE. 2136 01:23:05,598 --> 01:23:10,302 THE PROGRAM WE HAVE NOW, PHASE 1 2137 01:23:10,302 --> 01:23:13,238 CLINICAL TRIALS WITH, SEASONAL 2138 01:23:13,238 --> 01:23:14,807 ALLERGIC RHINITIS, EVERYONE IN 2139 01:23:14,807 --> 01:23:17,676 THE AUDIENCE WILL RECOGNIZE 2140 01:23:17,676 --> 01:23:23,582 NEARLY 1 IN 3 ADULTS, 1 IN 4 2141 01:23:23,582 --> 01:23:31,557 CHILDREN HAVE SEASONAL ALLERGY, 2142 01:23:31,557 --> 01:23:32,558 GROWING INCIDENCE. 2143 01:23:32,558 --> 01:23:42,267 WE'VE KNOWN THIS FOR MANY YEARS, 2144 01:23:42,267 --> 01:23:42,868 INTRANATIONALLY DELIVERED TRL 2145 01:23:42,868 --> 01:23:51,176 AGONIST CAN DRIVE RESPONSE. 2146 01:23:51,176 --> 01:23:59,918 WE'RE USING INI-2004, IF YOU USE 2147 01:23:59,918 --> 01:24:03,422 GOA INTRANASALLY, YOU FIND YOU 2148 01:24:03,422 --> 01:24:04,923 NEED A MORE ACTIVE -- 2149 01:24:04,923 --> 01:24:06,158 [AUDIO DISTORTION] 2150 01:24:06,158 --> 01:24:08,394 THIS IS BEING DELIVERED IN 2151 01:24:08,394 --> 01:24:18,937 UNIQUE LIPO SO MANY FORMULATION, 2152 01:24:21,340 --> 01:24:21,907 INTRANASAL, DISEASE MODIFYING, 2153 01:24:21,907 --> 01:24:24,343 CHANGE UNDERLYING T-CELL 2154 01:24:24,343 --> 01:24:24,610 RESPONSE. 2155 01:24:24,610 --> 01:24:26,845 POTENTIAL CURATIVE, NOT JUST 2156 01:24:26,845 --> 01:24:29,615 TREATING SYMPTOMS. 2157 01:24:29,615 --> 01:24:39,258 THIS IS AN ADJUVANT-ONLY 2158 01:24:39,258 --> 01:24:40,025 DELIVERED INTRANASALLY, THE 2159 01:24:40,025 --> 01:24:41,994 ANTIGEN DOESN'T COME ON BOARD, 2160 01:24:41,994 --> 01:24:44,930 YOU DON'T GET THE DISEASE 2161 01:24:44,930 --> 01:24:46,131 MODIFYING RESPONSE. 2162 01:24:46,131 --> 01:24:54,907 YOU DON'T HAVE TO NECESSARILY 2163 01:24:54,907 --> 01:24:55,374 IDENTIFY -- 2164 01:24:55,374 --> 01:24:56,909 [AUDIO DISTORTION] 2165 01:24:56,909 --> 01:25:00,412 GIVEN IN ALLERGY SEASON OR PRIOR 2166 01:25:00,412 --> 01:25:06,285 TO EXPOSURE, AND THEN YOU'LL 2167 01:25:06,285 --> 01:25:06,952 NATURALLY -- 2168 01:25:06,952 --> 01:25:09,354 [AUDIO DISTORTION] 2169 01:25:09,354 --> 01:25:12,424 MOST PEOPLE ARE WELL AWARE, 2170 01:25:12,424 --> 01:25:20,866 TYPICALLY SYNTHESIZED TO 2171 01:25:20,866 --> 01:25:30,375 ALLERGEN. 2172 01:25:30,375 --> 01:25:32,111 HERE WHEN YOU'RE REEXPOSED 2173 01:25:32,111 --> 01:25:35,614 [AUDIO DISTORTION] 2174 01:25:35,614 --> 01:25:45,390 PATIENTS SEE ALLERGEN, MORE OF A 2175 01:25:45,390 --> 01:25:46,692 Th1 PROFILE, ALLERGEN IgG, 2176 01:25:46,692 --> 01:25:53,165 UPON REEXPOSURE YOU ARE GET NO 2177 01:25:53,165 --> 01:25:58,103 RESPONSE, REPROGRAMMING IMMUNE 2178 01:25:58,103 --> 01:26:01,607 SYSTEM, Th2, Th1 RESPONSE, 2179 01:26:01,607 --> 01:26:03,976 DESENSITIZING. 2180 01:26:03,976 --> 01:26:06,311 SO THIS IS SOME DATA IN MICE. 2181 01:26:06,311 --> 01:26:10,783 THESE ARE MICE THAT WERE 2182 01:26:10,783 --> 01:26:14,520 PRE-SENSITIZED WITH ALUM AND 2183 01:26:14,520 --> 01:26:17,256 ALLERGEN, A THERAPEUTIC MODEL. 2184 01:26:17,256 --> 01:26:19,625 WE TREAT WITH 2004 2185 01:26:19,625 --> 01:26:23,695 INTRANATIONALLY, AND 48 HOURS 2186 01:26:23,695 --> 01:26:25,664 LATER WITH ALLERGEN. 2187 01:26:25,664 --> 01:26:27,833 WINDOW OF INFECTION HERE, WEEK 2188 01:26:27,833 --> 01:26:31,570 TO 14 DAYS, THEN YOU WOULD NEED 2189 01:26:31,570 --> 01:26:32,671 ANOTHER DOSE. 2190 01:26:32,671 --> 01:26:38,143 SO HERE ON THE LEFT-HAND 2191 01:26:38,143 --> 01:26:40,245 TIMELINE YOU SEE RESPONSE, 2192 01:26:40,245 --> 01:26:46,552 NORMAL CHALLENGE IN MOUSE, 2193 01:26:46,552 --> 01:26:47,553 INTERFERON GAMMA. 2194 01:26:47,553 --> 01:26:51,256 IF YOU HAVE THIS SENSITIZED 2195 01:26:51,256 --> 01:27:00,399 MOUSE, TREAT WITH 2004 2196 01:27:00,399 --> 01:27:01,300 INTRANASALLY, THEN TREAT WITH 2197 01:27:01,300 --> 01:27:02,835 ALLERGEN YOU SEE THIS RESPONSE. 2198 01:27:02,835 --> 01:27:07,172 IF YOU HAVE A NORMAL MOUSE 2199 01:27:07,172 --> 01:27:09,908 CHALLENGED WITH ALLERGEN, YOU 2200 01:27:09,908 --> 01:27:10,108 IL-5. 2201 01:27:10,108 --> 01:27:12,644 A MOUSE THAT'S ALLERGIC AND 2202 01:27:12,644 --> 01:27:13,278 SENSITIZED, CHALLENGED, HIGHER 2203 01:27:13,278 --> 01:27:14,346 IL-5 RESPONSE. 2204 01:27:14,346 --> 01:27:18,951 IN FACT, IT'S THE SAME MOUSE, 2205 01:27:18,951 --> 01:27:20,752 TREATED WITH 2004, THEN 2206 01:27:20,752 --> 01:27:22,120 CHALLENGED YOU COMPLETELY 2207 01:27:22,120 --> 01:27:24,356 EXPRESS IL-5 RESPONSE. 2208 01:27:24,356 --> 01:27:30,262 YOU CAN SEE THIS SHIFT IN THESE 2209 01:27:30,262 --> 01:27:30,762 MICE. 2210 01:27:30,762 --> 01:27:37,803 SO ANOTHER HALLMARK OF BIOLOGY 2211 01:27:37,803 --> 01:27:42,074 IN THESE MICE, SENSITIZED TO 2212 01:27:42,074 --> 01:27:47,446 ALLERGEN AND THEN CHALLENGE 2213 01:27:47,446 --> 01:27:49,114 NORMAL MOUSE, IF YOU SENSITIZE 2214 01:27:49,114 --> 01:27:51,383 THE MOUSE TO ALLERGEN, YOU COME 2215 01:27:51,383 --> 01:27:57,189 BACK AND CHALLENGE THEM YOU GET 2216 01:27:57,189 --> 01:28:00,158 A REALLY STRONG ROBUST. 2217 01:28:00,158 --> 01:28:02,995 SAME MOUSE THEN TREATED WITH 2218 01:28:02,995 --> 01:28:06,398 2004, CHALLENGED 48 HOURS LATER, 2219 01:28:06,398 --> 01:28:09,501 YOU CAN SEE THIS. 2220 01:28:09,501 --> 01:28:17,743 SO WE'VE SWITCHED FROM Th2, 2221 01:28:17,743 --> 01:28:18,076 Th1 PHENOTYPE. 2222 01:28:18,076 --> 01:28:24,950 THE PANEL ON THE RIGHT HERE IS 2223 01:28:24,950 --> 01:28:26,685 AIRWAY RESISTANCE INDUCED BY 2224 01:28:26,685 --> 01:28:27,119 ALLERGEN CHALLENGE. 2225 01:28:27,119 --> 01:28:29,454 RED BARS ON TOP WOULD BE THOSE 2226 01:28:29,454 --> 01:28:31,623 MICE THAT WERE ALLERGIC AND THEN 2227 01:28:31,623 --> 01:28:32,925 CHALLENGED WITH ALLERGEN, YOU 2228 01:28:32,925 --> 01:28:36,528 CAN SEE HIGH LEVELS OF AIRWAY 2229 01:28:36,528 --> 01:28:36,828 RESISTANCE. 2230 01:28:36,828 --> 01:28:39,631 COMPARED TO IN GOLD A NORMAL 2231 01:28:39,631 --> 01:28:40,933 MOUSE, CHALLENGED WITH ALLERGEN, 2232 01:28:40,933 --> 01:28:43,802 DOESN'T SEE THAT AIRWAY 2233 01:28:43,802 --> 01:28:44,369 RESISTANCE. 2234 01:28:44,369 --> 01:28:49,474 IN BLUE BAR A MOUSE TREATED WITH 2235 01:28:49,474 --> 01:28:50,943 2004, THEN CHALLENGED WITH THE 2236 01:28:50,943 --> 01:28:52,644 ALLERGEN TWO DAYS LATER, AND YOU 2237 01:28:52,644 --> 01:28:54,279 CAN SEE EVEN BETTER THAN THE 2238 01:28:54,279 --> 01:28:58,984 NORMAL MICE THAT WERE 2239 01:28:58,984 --> 01:29:03,055 CHALLENGED. 2240 01:29:03,055 --> 01:29:03,956 AGAIN SHOWING IMPROVEMENT. 2241 01:29:03,956 --> 01:29:06,925 AND SO THIS PAST YEAR WE 2242 01:29:06,925 --> 01:29:08,961 COMPLETED TWO PHASE 1 CLINICAL 2243 01:29:08,961 --> 01:29:11,096 TRIALS. 2244 01:29:11,096 --> 01:29:14,666 FIRST WAS A PHASE 1A ASCENDING 2245 01:29:14,666 --> 01:29:19,805 DOSE STUDY, FOUR COHORTS, 2246 01:29:19,805 --> 01:29:24,810 HEALTHY VOLUNTEERS, UP TO 500 2247 01:29:24,810 --> 01:29:26,345 MICROGRAMS INTRANASALLY, WELL 2248 01:29:26,345 --> 01:29:27,546 TOLERATED, NO SAD. 2249 01:29:27,546 --> 01:29:32,384 MOVED TO PHASE 1B, MULTI-DOSE 2250 01:29:32,384 --> 01:29:37,422 STUDY, PATIENTS WERE GIVEN THREE 2251 01:29:37,422 --> 01:29:38,957 DOSES OVER WEEKS, END TONIGHTS 2252 01:29:38,957 --> 01:29:47,265 OF SAFETY AND PK, ADHERENCE. 2253 01:29:47,265 --> 01:29:49,368 WE DID A CHALLENGE. 2254 01:29:49,368 --> 01:29:54,039 WE START BY PRE-SCREENING VISIT, 2255 01:29:54,039 --> 01:29:55,340 CHALLENGED, MAKE SURE PATIENTS 2256 01:29:55,340 --> 01:30:03,782 WERE SENSITIVE TO RAGWEED, TWO 2257 01:30:03,782 --> 01:30:06,418 WEEK WAITING PERIOD. 2258 01:30:06,418 --> 01:30:09,721 WE THEN TREATED WITH 2004, HERE 2259 01:30:09,721 --> 01:30:12,991 ON DAY 14 AND 21, A WEEK APART, 2260 01:30:12,991 --> 01:30:14,826 THEN CHALLENGED WITH RAGWEED TWO 2261 01:30:14,826 --> 01:30:16,395 DAYS LATER. 2262 01:30:16,395 --> 01:30:18,897 FOLLOWED BY TWO MORE TREATMENTS 2263 01:30:18,897 --> 01:30:25,137 WITH 2004 A WEEK APART PART, 2264 01:30:25,137 --> 01:30:26,571 CHALLENGED AGAIN. 2265 01:30:26,571 --> 01:30:29,174 REST FOR TWO WEEKS. 2266 01:30:29,174 --> 01:30:32,244 CHALLENGED AGAIN AT DAY 51 TO 2267 01:30:32,244 --> 01:30:34,780 SEE IF RESPONSE HAD DESENSITIZED 2268 01:30:34,780 --> 01:30:39,384 PATIENTS FOR RAGWEED OR GAINED 2269 01:30:39,384 --> 01:30:40,085 SENSITIVITY. 2270 01:30:40,085 --> 01:30:44,890 YOU'LL SEE WITH THIS STUDY ONLY 2271 01:30:44,890 --> 01:30:53,565 DONE IN COHORTS OF NINE ACTIVE, 2272 01:30:53,565 --> 01:30:54,566 THREE PLACEBO. 2273 01:30:54,566 --> 01:30:58,036 AND SO HERE YOU'LL SEE THE 2274 01:30:58,036 --> 01:31:02,207 RESULTS FOR THE GRADE 1, FOR 2275 01:31:02,207 --> 01:31:02,974 SAFETY. 2276 01:31:02,974 --> 01:31:05,877 WE DID 125, 250, AND 2277 01:31:05,877 --> 01:31:10,882 500-MICROGRAM DOSES IN PHASE 1B 2278 01:31:10,882 --> 01:31:14,352 STUDY AS WELL AS EACH OF THE 2279 01:31:14,352 --> 01:31:16,121 COHORTS, YOU CAN LOOK AT 2280 01:31:16,121 --> 01:31:20,926 PLACEBO, JUST AS MANY MINOR 2281 01:31:20,926 --> 01:31:22,461 ADVERSE EVENTS AS ACTIVE 2282 01:31:22,461 --> 01:31:23,728 COMPONENTS, MOST RELATED TO 2283 01:31:23,728 --> 01:31:30,335 NASAL CONGESTION . 2284 01:31:30,335 --> 01:31:34,239 TO PUT IN PERSPECTIVE THIS 2285 01:31:34,239 --> 01:31:36,908 COMPOUND T 2004 A THOUSAND MIMES 2286 01:31:36,908 --> 01:31:40,178 MORE ACTIVE THAN MPL, EQUIVALENT 2287 01:31:40,178 --> 01:31:50,155 OF 50 MILLIGRAMS OF MPL, 2004, 2288 01:31:50,155 --> 01:31:52,424 INTRANASAL 2004 WAS WELL 2289 01:31:52,424 --> 01:31:53,492 TOLERATED. 2290 01:31:53,492 --> 01:31:55,594 THIS IS ANOTHER SUMMARY OF THE 2291 01:31:55,594 --> 01:32:00,565 CHARACTERISTICS OF THE PEOPLE IN 2292 01:32:00,565 --> 01:32:04,269 THE TRIAL, MEAN AGE 36. 2293 01:32:04,269 --> 01:32:12,344 AND WITH MOST HAD 10-YEAR 2294 01:32:12,344 --> 01:32:12,577 HISTORY. 2295 01:32:12,577 --> 01:32:16,081 50% OF PATIENTS AT LEAST ONE 2296 01:32:16,081 --> 01:32:18,283 MILD ADVERSE EVENT, MOST WERE 2297 01:32:18,283 --> 01:32:22,187 RELATED TO NASAL SYMPTOMS, 2298 01:32:22,187 --> 01:32:24,189 CONGESTION, THINGS YOU MIGHT 2299 01:32:24,189 --> 01:32:33,365 EXPECT FROM NASAL SPRAY, ALL 2300 01:32:33,365 --> 01:32:35,800 GRADE 1/MILD. 2301 01:32:35,800 --> 01:32:44,209 AND WE ALSO DID SYNTHETIC PK, 2302 01:32:44,209 --> 01:32:47,946 YOU DON'T WANT PERCENT OF 2303 01:32:47,946 --> 01:32:50,549 INFLAMMATION, IN THESE SUBJECTS, 2304 01:32:50,549 --> 01:32:53,185 GIVEN THIS, ALL PK VALUES OF ALL 2305 01:32:53,185 --> 01:32:55,954 DOSES IN SAD AND MAD BELOW LEVEL 2306 01:32:55,954 --> 01:33:01,726 OF QUANTIFICATION, NO SYSTEMIC 2307 01:33:01,726 --> 01:33:04,129 ABSORPTION OF 2004 WHEN GIVEN 2308 01:33:04,129 --> 01:33:04,462 INTRANASALLY. 2309 01:33:04,462 --> 01:33:08,300 HERE IS THE SECONDARY ENDPOINT, 2310 01:33:08,300 --> 01:33:10,268 DOSE DEPENDENT IMPROVEMENT 2311 01:33:10,268 --> 01:33:13,071 CONGESTION COMPARED TO PLACEBO, 2312 01:33:13,071 --> 01:33:23,615 WE WERE SURPRISED TO SEE 250 AND 2313 01:33:25,784 --> 01:33:27,352 500-MICROGRAM DOSE LEVELS, 34% 2314 01:33:27,352 --> 01:33:30,855 AND 53% IMPROVEMENT. 2315 01:33:30,855 --> 01:33:34,159 ALSO GOOD TO SEE AT LATER TIME 2316 01:33:34,159 --> 01:33:35,427 POINT TWO WEEKS FOLLOWING 2317 01:33:35,427 --> 01:33:42,767 TREATMENT, THEY WERE REDOSED 2318 01:33:42,767 --> 01:33:44,970 WITH RAGWEED. 2319 01:33:44,970 --> 01:33:47,939 AND WE WERE EXCITED TO SEE 2320 01:33:47,939 --> 01:33:49,708 INITIAL EFFICACY SIGNAL FROM 2321 01:33:49,708 --> 01:33:57,849 THIS TRIAL, SOME OTHER CLINICAL 2322 01:33:57,849 --> 01:34:01,653 MEASURES RESULTED -- 2323 01:34:01,653 --> 01:34:05,257 [AUDIO DISTORTION] 2324 01:34:05,257 --> 01:34:08,026 SO CONTINUING EVALUATION OF 2325 01:34:08,026 --> 01:34:12,831 COURSE, THESE ARE STATISTICALLY 2326 01:34:12,831 --> 01:34:14,466 DIFFERENT THAN PLACEBO. 2327 01:34:14,466 --> 01:34:17,736 WE'RE EXCITED NOW TO MOVE THIS 2328 01:34:17,736 --> 01:34:24,542 PROGRAM TO A PHASE 2 ALLERGEN 2329 01:34:24,542 --> 01:34:28,480 CHAMBER STUDY, REALLY TO CONFIRM 2330 01:34:28,480 --> 01:34:30,782 2004 SAFETY, TO DEMONSTRATE 2331 01:34:30,782 --> 01:34:33,852 EFFICACY WITH RESPECT TO 2332 01:34:33,852 --> 01:34:37,155 ALLERGEN CHALLENGE IN CONTROLLED 2333 01:34:37,155 --> 01:34:39,224 SETTING WITH AIRWAY ALLERGY 2334 01:34:39,224 --> 01:34:41,760 EXPOSURE IN DEFINED DOSE, NUMBER 2335 01:34:41,760 --> 01:34:44,029 OF GRAINS OF RAGWEED AND 2336 01:34:44,029 --> 01:34:45,697 INCREASE COHORT SIZE A LITTLE 2337 01:34:45,697 --> 01:34:48,566 BIT TO UNDERSTAND MORE OF THE 2338 01:34:48,566 --> 01:34:50,635 KINETICS HOW THE RESPONSE WORDS 2339 01:34:50,635 --> 01:34:56,041 AND IF WE CAN SEE RESPONSE WITH 2340 01:34:56,041 --> 01:34:59,778 THE DRUG AND HOW WE SCORE THEM. 2341 01:34:59,778 --> 01:35:04,149 SO, EVEN MORE EXCITING THESE 2342 01:35:04,149 --> 01:35:08,253 PHASE 1 ARE THE INDICATION AND 2343 01:35:08,253 --> 01:35:10,922 FOLLOW-ON WITH THE 2004 2344 01:35:10,922 --> 01:35:14,192 INTRANASAL VACCINE TRIAL, NOW WE 2345 01:35:14,192 --> 01:35:18,129 HAVE MUCOSAL ADJUVANT THAT 2346 01:35:18,129 --> 01:35:21,433 DE-RISKS, NOT ONLY WE'LL USE IN 2347 01:35:21,433 --> 01:35:24,803 ALLERGEN POTENTIALLY EXPAND TO 2348 01:35:24,803 --> 01:35:25,904 INDICATION WITH FOOD ALLERGIES 2349 01:35:25,904 --> 01:35:31,710 BUT WE NOW HAVE EFFECT OF 2350 01:35:31,710 --> 01:35:40,685 MUCOSAL ADJUVANT, 2004, MUCOSAL 2351 01:35:40,685 --> 01:35:41,152 ADJUVANT. 2352 01:35:41,152 --> 01:35:44,756 [AUDIO DISTORTION] 2353 01:35:44,756 --> 01:35:46,991 FOR FLU, COVID, RSV, NOW WE CAN 2354 01:35:46,991 --> 01:35:50,095 POTENTIALLY MOVE INTO OTHER 2355 01:35:50,095 --> 01:35:54,599 INDICATIONS, NOW THAT WE'VE BEEN 2356 01:35:54,599 --> 01:35:54,866 DE-RISKED. 2357 01:35:54,866 --> 01:35:56,034 [AUDIO DISTORTION] 2358 01:35:56,034 --> 01:36:03,375 AS WELL AS POTENTIAL MUTATIONS, 2359 01:36:03,375 --> 01:36:07,746 NASOPHARYNGEAL CANCERS, WE NOW 2360 01:36:07,746 --> 01:36:09,481 2004 HAS IMPACTS AS FAR AS 2361 01:36:09,481 --> 01:36:14,619 CHECKPOINT, THERE MIGHT BE 2362 01:36:14,619 --> 01:36:16,187 CAUSALLY DELIVERED -- 2363 01:36:16,187 --> 01:36:17,122 [AUDIO DISTORTION] 2364 01:36:17,122 --> 01:36:21,426 WITH THAT I'D BE HAPPY TO TAKE 2365 01:36:21,426 --> 01:36:22,060 ANY QUESTIONS. 2366 01:36:22,060 --> 01:36:25,163 AND AGAIN I WILL THERE BE AT NIH 2367 01:36:25,163 --> 01:36:27,565 HERE ON WEDNESDAY AND THURSDAY 2368 01:36:27,565 --> 01:36:30,068 THIS WEEK. 2369 01:36:30,068 --> 01:36:36,074 2370 01:36:36,074 --> 01:36:38,209 2371 01:36:38,209 --> 01:36:40,378 >> ANY QUESTIONS FOR DR. EVANS? 2372 01:36:40,378 --> 01:36:42,547 I HAVE A COUPLE QUESTIONS. 2373 01:36:42,547 --> 01:36:44,949 JAY, REALLY GOOD TALK. 2374 01:36:44,949 --> 01:36:47,485 THE QUESTIONS ARE IN YOUR MOUTH, 2375 01:36:47,485 --> 01:36:51,956 YOU'RE DOSING RAGWEED TWO DAYS, 2376 01:36:51,956 --> 01:36:54,025 48 HOURS AFTER THE LAST -- YOUR 2377 01:36:54,025 --> 01:36:54,626 ADJUVANT, RIGHT? 2378 01:36:54,626 --> 01:36:57,762 SO, YOU'RE GOING TO HAVE 2379 01:36:57,762 --> 01:36:59,597 INFLAMMATION WITH ADJUVANT. 2380 01:36:59,597 --> 01:37:01,599 THEN YOU'RE EXPOSING RAGWEED 2381 01:37:01,599 --> 01:37:02,233 DURING THAT INFLAMMATION RELATED 2382 01:37:02,233 --> 01:37:03,902 TO THE ADJUVANT. 2383 01:37:03,902 --> 01:37:06,538 WHAT IF YOU GO, YOU KNOW, TWO OR 2384 01:37:06,538 --> 01:37:08,740 THREE OR FOUR WEEKS AFTER THE 2385 01:37:08,740 --> 01:37:10,475 ADJUVANT BEFORE YOU GIVE THE 2386 01:37:10,475 --> 01:37:13,311 RAGWEED, DO YOU SEE SAME AFFECT? 2387 01:37:13,311 --> 01:37:15,513 MY FEAR, YOU'RE HAVING ANTIGEN 2388 01:37:15,513 --> 01:37:18,817 SPECIFIC EFFECT BECAUSE YOU'RE 2389 01:37:18,817 --> 01:37:20,452 EXPOSING TO RAGWEED, ALMOST 2390 01:37:20,452 --> 01:37:21,553 IMMEDIATELY THEREAFTER, WITHIN 2391 01:37:21,553 --> 01:37:23,588 TWO DAYS, SO THEREFORE YOU'RE 2392 01:37:23,588 --> 01:37:24,489 GOING TO HAVE RESIDUAL 2393 01:37:24,489 --> 01:37:25,256 INFLAMMATION FROM THAT. 2394 01:37:25,256 --> 01:37:26,458 I WONDER IF THAT'S ALSO WHAT 2395 01:37:26,458 --> 01:37:28,326 YOU'RE SEEING IN YOUR HUMAN 2396 01:37:28,326 --> 01:37:31,062 STUDIES TOO WITH RAGWEED 2397 01:37:31,062 --> 01:37:34,098 CHALLENGES BECAUSE YOU'RE DOSING 2398 01:37:34,098 --> 01:37:38,503 WITH ADJUVANT, YET THE RAGWEED 2399 01:37:38,503 --> 01:37:41,439 COMING CLOSE THEREAFTER, AND 2400 01:37:41,439 --> 01:37:42,073 INDUCING ANTIGEN-SPECIFIC 2401 01:37:42,073 --> 01:37:44,843 RESPONSE IN HUMANS, INTERESTED 2402 01:37:44,843 --> 01:37:46,044 IN YOUR THOUGHTS, WHETHER YOU 2403 01:37:46,044 --> 01:37:47,679 DELAYED PERIOD OF TIME FROM 2404 01:37:47,679 --> 01:37:48,446 RAGWEED EXPOSURE IN MICE, YOU 2405 01:37:48,446 --> 01:37:51,316 KNOW, THREE OR FOUR WEEKS AFTER 2406 01:37:51,316 --> 01:37:52,717 THE ADJUVANT. 2407 01:37:52,717 --> 01:37:55,787 >> THAT'S A GREAT QUESTION. 2408 01:37:55,787 --> 01:37:57,989 UNFORTUNATELY, THE MOUSE ALLERGY 2409 01:37:57,989 --> 01:37:59,090 MODEL IS ACUTE MODEL. 2410 01:37:59,090 --> 01:38:03,761 IF YOU LEAVE OVER TIME WITHOUT 2411 01:38:03,761 --> 01:38:04,863 REEXPOSING THEY DESENSITIZE. 2412 01:38:04,863 --> 01:38:06,965 WE HAVE A WEEK WINDOW WHERE WE 2413 01:38:06,965 --> 01:38:07,932 CAN CHALLENGE WITH ALLERGEN 2414 01:38:07,932 --> 01:38:11,469 BEFORE THE MICE START LOSING 2415 01:38:11,469 --> 01:38:13,304 THEIR SENSITIVITY. 2416 01:38:13,304 --> 01:38:15,907 THEY LOSE SENSITIVITY, THAT 2417 01:38:15,907 --> 01:38:17,742 COMPLICATED EFFECT, THOSE ARE 2418 01:38:17,742 --> 01:38:20,745 SOME QUESTIONS WE WANT TO ANSWER 2419 01:38:20,745 --> 01:38:23,248 IN HUMANS. 2420 01:38:23,248 --> 01:38:26,985 WE DO KNOW IN MICE, GIVE 2421 01:38:26,985 --> 01:38:28,520 INTRANASALLY, COME BACK WITH 2422 01:38:28,520 --> 01:38:29,821 LIKE INFLUENZA CHALLENGE, YOU 2423 01:38:29,821 --> 01:38:34,192 GET A WINDOW OF NON-SPECIFIC 2424 01:38:34,192 --> 01:38:36,494 PROTECTION WHERE MICE HAVE SOME 2425 01:38:36,494 --> 01:38:40,532 PROTECTION, INDUCED BY SIMILAR 2426 01:38:40,532 --> 01:38:41,966 MECHANISM, STIMULATING NATURE 2427 01:38:41,966 --> 01:38:45,637 IMMUNE RESPONSE, IN THAT MODEL 2428 01:38:45,637 --> 01:38:52,243 WE'VE SEEN UP TO 14 DAYS 2429 01:38:52,243 --> 01:38:54,546 [AUDIO DISTORTION] 2430 01:38:54,546 --> 01:38:56,948 WE THINK THAT WINDOW WILL BE 2431 01:38:56,948 --> 01:38:57,181 SIMILAR. 2432 01:38:57,181 --> 01:38:58,750 OF COURSE WE WON'T KNOW UNTIL WE 2433 01:38:58,750 --> 01:39:05,924 GET INTO PEOPLE, IF YOU GIVE A 2434 01:39:05,924 --> 01:39:07,091 DOSE OF 2004, INTRANASALLY, 2435 01:39:07,091 --> 01:39:10,595 DIFFERENT TIME SLOT TO 7 DAYS IN 2436 01:39:10,595 --> 01:39:13,932 MOUSE MODEL, IN VIVO CHALLENGE 2437 01:39:13,932 --> 01:39:16,434 AS WELL, TWO OR THREE DAYS, YOU 2438 01:39:16,434 --> 01:39:18,036 SEE THAT PROTECTION. 2439 01:39:18,036 --> 01:39:21,673 BUT UNFORTUNATELY THE MOUSE 2440 01:39:21,673 --> 01:39:27,478 MODEL HAS LIMITATIONS. 2441 01:39:27,478 --> 01:39:29,113 >> JAY, WONDERFUL TALK. 2442 01:39:29,113 --> 01:39:34,218 AND ALONG THOSE SAME LINES IN 2443 01:39:34,218 --> 01:39:38,523 YOUR HUMAN STUDY WITH INI 2004 2444 01:39:38,523 --> 01:39:40,592 ARE YOU COLLECTING NASAL WASH 2445 01:39:40,592 --> 01:39:41,559 SAMPLES TO MONITOR IMMUNE 2446 01:39:41,559 --> 01:39:44,228 RESPONSE, HOW LONG THEY LAST 2447 01:39:44,228 --> 01:39:44,562 FOR? 2448 01:39:44,562 --> 01:39:48,399 >> WE DID DO SOME ON NASAL SWAB, 2449 01:39:48,399 --> 01:39:52,437 TO LOOK AT CYTOKINES. 2450 01:39:52,437 --> 01:39:54,973 THOSE ANALYSES, IT LOOKS LIKE WE 2451 01:39:54,973 --> 01:39:57,475 MIGHT HAVE INCREASE IN TNF, 2452 01:39:57,475 --> 01:39:59,677 IL-10, PLACEBO MODEL, ONLY NINE 2453 01:39:59,677 --> 01:40:00,979 SUBJECTS, IT'S HARD. 2454 01:40:00,979 --> 01:40:03,014 IT'S TOUGH BECAUSE ANYTHING TO 2455 01:40:03,014 --> 01:40:05,249 DO WITH A PATIENT, NASAL MUCOSA, 2456 01:40:05,249 --> 01:40:10,989 CAN IMPACT ANYTHING YOU DO THAT 2457 01:40:10,989 --> 01:40:14,258 CAUSES INFLAMMATION. 2458 01:40:14,258 --> 01:40:18,963 WE SAW IN PLACEBO GROUP SOME 2459 01:40:18,963 --> 01:40:20,832 PROTECTION WITH RAGWEED, DOING 2460 01:40:20,832 --> 01:40:22,467 SALINE RINSE CAN HELP ALLEVIATE 2461 01:40:22,467 --> 01:40:22,734 SYMPTOMS. 2462 01:40:22,734 --> 01:40:27,505 WE TALKED ABOUT DOING OTHER 2463 01:40:27,505 --> 01:40:28,706 TYPES OF COLLECTION INTRANASALLY 2464 01:40:28,706 --> 01:40:31,876 TO GET MORE INTRACELLULAR 2465 01:40:31,876 --> 01:40:34,979 RESPONSES BUT HAD TO BOUNCE BACK 2466 01:40:34,979 --> 01:40:35,813 WITH SAFETY AND EFFICACY. 2467 01:40:35,813 --> 01:40:40,652 WE'D LOVE TO HEAR THOUGHTS ON 2468 01:40:40,652 --> 01:40:44,455 OTHER WAYS TO USE MULTI- OMICS 2469 01:40:44,455 --> 01:40:45,123 TO ASSESS. 2470 01:40:45,123 --> 01:40:49,761 >> I HAVE THE SAME SORTS OF 2471 01:40:49,761 --> 01:40:50,662 THOUGHTS. 2472 01:40:50,662 --> 01:40:54,098 THIS IS JIM GURN FROM WISCONSIN. 2473 01:40:54,098 --> 01:40:56,300 THE NASAL SWABS THESE DAYS, IT'S 2474 01:40:56,300 --> 01:40:58,269 THE SAME TECHNIQUE AS THE COVID 2475 01:40:58,269 --> 01:41:01,005 TESTS, CAN GIVE A REALLY NICE 2476 01:41:01,005 --> 01:41:04,509 CELLULAR SAMPLE YOU CAN ANALYZE 2477 01:41:04,509 --> 01:41:08,112 FOR RNA AND DNA, AND AS WE MOVE 2478 01:41:08,112 --> 01:41:08,946 FORWARD, HOPEFULLY YOU'LL 2479 01:41:08,946 --> 01:41:09,981 CONTINUE TO SEE POSITIVE RESULTS 2480 01:41:09,981 --> 01:41:11,849 BUT IT WOULD BE REALLY HELPFUL 2481 01:41:11,849 --> 01:41:14,252 TO KNOW WHAT'S GOING ON AT THE 2482 01:41:14,252 --> 01:41:16,220 MUCOSA, AT THE GENE LEVEL. 2483 01:41:16,220 --> 01:41:17,789 AND, YOU KNOW, THAT I THINK THE 2484 01:41:17,789 --> 01:41:23,995 POINT'S BEEN MADE IN THE LAST 2485 01:41:23,995 --> 01:41:24,962 TWO LECTURES KNOWING MECHANISMS 2486 01:41:24,962 --> 01:41:26,631 WILL HELP IN TERMS OF APPLYING 2487 01:41:26,631 --> 01:41:28,633 ADJUVANTS IN THE BEST POSSIBLE 2488 01:41:28,633 --> 01:41:30,902 WAY, BUT THAT JUST SOMETHING TO 2489 01:41:30,902 --> 01:41:33,638 CONSIDER BECAUSE IT'S PRETTY 2490 01:41:33,638 --> 01:41:35,273 NON-TRAUMATIC, WE KNOW IF KIDS, 2491 01:41:35,273 --> 01:41:37,575 EVERY KID HAS HAD 20 OF THESE 2492 01:41:37,575 --> 01:41:38,943 THINGS, GOING TO SCHOOL, MAY NOT 2493 01:41:38,943 --> 01:41:42,613 LIKE THEM THAT MUCH BUT IT'S NOT 2494 01:41:42,613 --> 01:41:44,048 VERY TRAUMATIC AND THINGS 2495 01:41:44,048 --> 01:41:47,418 RESOLVE QUICKLY AFTER A LITTLE 2496 01:41:47,418 --> 01:41:47,685 BRUSHING. 2497 01:41:47,685 --> 01:41:50,054 >> I NEED TO CUT THE DISCUSSION 2498 01:41:50,054 --> 01:41:50,388 SHORT. 2499 01:41:50,388 --> 01:41:52,023 WE'RE RUNNING SIGNIFICANTLY 2500 01:41:52,023 --> 01:41:53,858 BEHIND SCHEDULE ALREADY. 2501 01:41:53,858 --> 01:41:55,126 THANK YOU SO MUCH. 2502 01:41:55,126 --> 01:42:00,765 >> THANK YOU. 2503 01:42:00,765 --> 01:42:01,632 2504 01:42:01,632 --> 01:42:05,703 >> NEXT SPEAKER, DR. CHEVRIE. 2505 01:42:05,703 --> 01:42:13,044 WE HEARD ABOUT ADVANCED STAGE 2506 01:42:13,044 --> 01:42:15,012 ADJUVANTS FROM DR. PULENDRAN, 2507 01:42:15,012 --> 01:42:18,816 NOW WE'LL HEAR ABOUT EVEN MORE 2508 01:42:18,816 --> 01:42:21,452 COMPLEX ADJUVANTS. 2509 01:42:21,452 --> 01:42:27,458 2510 01:42:27,458 --> 01:42:30,027 2511 01:42:30,027 --> 01:42:32,630 >> CAN YOU HEAR ME? 2512 01:42:32,630 --> 01:42:38,736 >> YES, WE CAN. 2513 01:42:38,736 --> 01:42:39,103 PLEASE PROCEED. 2514 01:42:39,103 --> 01:42:40,071 >> I'LL TRY TO KEEP IT IN THE 2515 01:42:40,071 --> 01:42:42,573 FIVE MINUTES I HAVE. 2516 01:42:42,573 --> 01:42:42,907 JUST KIDDING. 2517 01:42:42,907 --> 01:42:45,309 I'LL TRY TO BE AS SHORT AS 2518 01:42:45,309 --> 01:42:46,244 POSSIBLE. 2519 01:42:46,244 --> 01:42:49,781 I'LL TELL YOU BRIEFLY IN THE LAB 2520 01:42:49,781 --> 01:42:51,215 WE'RE INTERESTED IN ASKING AND 2521 01:42:51,215 --> 01:42:51,849 HOPEFULLY ANSWERING FUNDAMENTAL 2522 01:42:51,849 --> 01:42:53,317 QUESTIONS ABOUT THE IMMUNE 2523 01:42:53,317 --> 01:42:55,052 SYSTEM ACROSS MULTIPLE SCALES 2524 01:42:55,052 --> 01:42:57,188 RANGING FROM CELLS AND PATHWAYS 2525 01:42:57,188 --> 01:43:00,625 TO ORGANS AND HOW CELLS 2526 01:43:00,625 --> 01:43:02,593 COMMUNICATE WITH TISSUES. 2527 01:43:02,593 --> 01:43:03,561 AND TODAY THE PROJECT I'D LIKE 2528 01:43:03,561 --> 01:43:06,197 TO DISCUSS STARTED FROM A VERY 2529 01:43:06,197 --> 01:43:10,468 BASIC QUESTION, HOW DO IMMUNE 2530 01:43:10,468 --> 01:43:11,702 CELLS SENSE COMBINATIONS. 2531 01:43:11,702 --> 01:43:14,939 WHEN WE ASKED THROUGH THE LENS 2532 01:43:14,939 --> 01:43:17,608 OF INNATE IMMUNE PATHWAYS, AS 2533 01:43:17,608 --> 01:43:21,612 WE'VE HEARD, CHARLIE JANEWAY AND 2534 01:43:21,612 --> 01:43:25,683 BEFORE HIM FOLKS FOUND TOLL 2535 01:43:25,683 --> 01:43:28,186 PATHWAYS, FAST FORWARD THREE 2536 01:43:28,186 --> 01:43:30,721 DECADES THERE'S DOZENS OF SUCH 2537 01:43:30,721 --> 01:43:37,061 PATHWAYS THAT CAN SENSE 2538 01:43:37,061 --> 01:43:37,929 MOLECULES, CONSERVED IN 2539 01:43:37,929 --> 01:43:38,496 MICROBES. 2540 01:43:38,496 --> 01:43:41,899 THE POINT I'M TRYING TO MAKE 2541 01:43:41,899 --> 01:43:44,202 THERE'S DOZENS OF PATHWAYS 2542 01:43:44,202 --> 01:43:44,936 INCLUDING TOLL LIKE RECEPTORS, 2543 01:43:44,936 --> 01:43:48,806 AND A BUNCH OF OTHERS THAT ALL 2544 01:43:48,806 --> 01:43:50,975 CONVERGE WITHIN CELLS, SHARED 2545 01:43:50,975 --> 01:43:53,177 AMONG FAMILIES OF SUCH PATHWAYS. 2546 01:43:53,177 --> 01:43:55,780 AND TARGET PROTEINS AND IMPACT 2547 01:43:55,780 --> 01:43:56,881 ADAPTATION RESPONSE. 2548 01:43:56,881 --> 01:43:59,617 ANOTHER STUDY ABOUT THE PATHWAYS 2549 01:43:59,617 --> 01:44:01,052 IN ISOLATION, WHEN WE STARTED 2550 01:44:01,052 --> 01:44:04,222 STUDIES THE QUESTION WAS DRIVING 2551 01:44:04,222 --> 01:44:07,058 US HOW DO CELLS SENSE MULTIPLE, 2552 01:44:07,058 --> 01:44:08,492 BECAUSE THERE'S PAUCITY OF 2553 01:44:08,492 --> 01:44:10,695 KNOWLEDGE ABOUT HOW THESE 2554 01:44:10,695 --> 01:44:12,330 PATHWAYS WORK TOGETHER, RIGHT? 2555 01:44:12,330 --> 01:44:16,133 WE HAD TO DISCOVER WHAT ARE THE 2556 01:44:16,133 --> 01:44:17,001 RECEPTORS, MOLECULES DOWNSTREAM, 2557 01:44:17,001 --> 01:44:21,072 NOW HOW DO THEY WORK TOGETHER, 2558 01:44:21,072 --> 01:44:21,272 RIGHT? 2559 01:44:21,272 --> 01:44:23,374 AS BALI SHOWED, IN THE YELLOW 2560 01:44:23,374 --> 01:44:24,575 FEVER VACCINE MULTIPLE MOLECULES 2561 01:44:24,575 --> 01:44:26,110 THAT ACT TOGETHER, VERY 2562 01:44:26,110 --> 01:44:28,312 DIFFICULT TO STUDY THESE. 2563 01:44:28,312 --> 01:44:32,483 AND SO ONE OF THE PROBLEMS, I'LL 2564 01:44:32,483 --> 01:44:35,553 SKIP THROUGH THIS, ONE POINT IS 2565 01:44:35,553 --> 01:44:37,622 THAT TWO SIGNALS AT A TIME 2566 01:44:37,622 --> 01:44:42,326 STUDIES AND MANY EXAMPLES OF 2567 01:44:42,326 --> 01:44:46,497 SYNERGY, INDEPENDENCE AND 2568 01:44:46,497 --> 01:44:46,964 ANTAGONISM. 2569 01:44:46,964 --> 01:44:50,568 IT'S DIFFICULT TO PREDICT FROM 2570 01:44:50,568 --> 01:44:52,737 EFFECTING OF SINGLES. 2571 01:44:52,737 --> 01:44:54,805 IF YOU GO HIGHER, THERE'S MUCH 2572 01:44:54,805 --> 01:44:55,573 LESS STUDIES. 2573 01:44:55,573 --> 01:44:58,643 SO HERE WHAT WE SET OUT TO DO IS 2574 01:44:58,643 --> 01:45:00,711 TRY TO STUDY HOW CELLS RESPONSE 2575 01:45:00,711 --> 01:45:02,813 TO HIGHER EFFECTS OF 2576 01:45:02,813 --> 01:45:04,048 COMBINATION. 2577 01:45:04,048 --> 01:45:07,118 ONE OF THE PROBLEMS IS THAT 2578 01:45:07,118 --> 01:45:08,219 BECOMES QUICKLY INTRACTABLE 2579 01:45:08,219 --> 01:45:10,988 EXPERIMENTALLY, NUMBER OF 2580 01:45:10,988 --> 01:45:12,790 EXPERIMENTS WITH COMBINATIONS 2581 01:45:12,790 --> 01:45:13,591 EXPLODES EXPONENTIALLY, RIGHT? 2582 01:45:13,591 --> 01:45:15,993 A WAY OF EXAMPLE I LIKE TO USE 2583 01:45:15,993 --> 01:45:17,962 IMAGINE YOU HAVE A THOUSAND 2584 01:45:17,962 --> 01:45:19,630 MOLECULES IN THE LIBRARY, 2585 01:45:19,630 --> 01:45:21,799 INTERESTED IN MINING ALL 2586 01:45:21,799 --> 01:45:23,734 POSSIBLE COMBINATIONS OF 2587 01:45:23,734 --> 01:45:24,535 RECOMMENDATIONS, THAT'S ABOUT 40 2588 01:45:24,535 --> 01:45:26,837 BILLION ASSAYS, THAT WOULD TAKE 2589 01:45:26,837 --> 01:45:28,239 A VERY LONG TIME, A LOT OF GRAD 2590 01:45:28,239 --> 01:45:29,573 STUDENTS AND POSTDOCS, EVEN ME 2591 01:45:29,573 --> 01:45:31,275 JOINING IN WOULD NOT DO 2592 01:45:31,275 --> 01:45:31,876 ANYTHING, RIGHT? 2593 01:45:31,876 --> 01:45:37,114 THE QUESTION WE'RE INTERESTED 2594 01:45:37,114 --> 01:45:39,650 IN, COULD WE DO AWAY, AND JUST 2595 01:45:39,650 --> 01:45:41,385 PREDICT WITHOUT TESTING 2596 01:45:41,385 --> 01:45:41,819 EVERYTHING? 2597 01:45:41,819 --> 01:45:43,587 TO TEST THIS, THAT WOULD 2598 01:45:43,587 --> 01:45:44,555 HOPEFULLY UNCOVER SOME RULES 2599 01:45:44,555 --> 01:45:47,858 ABOUT THE RELATIONSHIP BETWEEN 2600 01:45:47,858 --> 01:45:49,293 THE SIGNAL IN THE SYSTEM. 2601 01:45:49,293 --> 01:45:54,432 TO TEST THIS ON A SMALL SCALE 2602 01:45:54,432 --> 01:45:56,067 INITIALLY BASICALLY HYPOTHESIS 2603 01:45:56,067 --> 01:45:58,903 SELECTED HALF A DOZEN LIGANDS 2604 01:45:58,903 --> 01:46:03,774 THAT TARGET DIFFERENT PATHWAYS, 2605 01:46:03,774 --> 01:46:06,711 TRLs, C TYPE LECTIN RECEPTORS, 2606 01:46:06,711 --> 01:46:11,549 DNA SENSORS, USING SETS OF SEVEN 2607 01:46:11,549 --> 01:46:12,516 SIGNALS PERFORMED THE SCREEN, 2608 01:46:12,516 --> 01:46:14,618 WHAT IS IT SHOWING? 2609 01:46:14,618 --> 01:46:17,321 ESSENTIALLY EFFECTS OF SEVEN 2610 01:46:17,321 --> 01:46:20,624 SIGNALS, EITHER USED ALONE OR 2611 01:46:20,624 --> 01:46:21,292 PAIRWISE COMBINATIONS IN GREEN, 2612 01:46:21,292 --> 01:46:23,694 21 PAIRS. 2613 01:46:23,694 --> 01:46:26,731 IF YOU COMBINE, UP TO 35 2614 01:46:26,731 --> 01:46:28,265 TRIPLETS IN ORANGE. 2615 01:46:28,265 --> 01:46:30,568 COLORS SHOW YOU ESSENTIALLY 2616 01:46:30,568 --> 01:46:31,836 NUMBER OF T CELLS DIFFERENTIATED 2617 01:46:31,836 --> 01:46:35,840 IN THE PRESENCE OF DENDRITIC 2618 01:46:35,840 --> 01:46:37,575 CELLS STIMULATED WITH DIFFERENT 2619 01:46:37,575 --> 01:46:38,542 ADJUVANTS. 2620 01:46:38,542 --> 01:46:39,343 I'LL SKIP THROUGH THE DETAILS 2621 01:46:39,343 --> 01:46:41,645 BUT THE KEY THING WE'RE ABLE TO 2622 01:46:41,645 --> 01:46:44,782 EXTRACT FROM THE DATASET WAS 2623 01:46:44,782 --> 01:46:46,984 THAT ESSENTIALLY THE EFFECTS OF 2624 01:46:46,984 --> 01:46:47,985 THE TRIPLET, HIGHER ORDER 2625 01:46:47,985 --> 01:46:49,420 EFFECT, CAN BE PREDICTED WITH 2626 01:46:49,420 --> 01:46:52,790 KNOWLEDGE FROM ONLY THE BLUE AND 2627 01:46:52,790 --> 01:46:54,125 GREEN, SIGNALS AND PAIRS, IN 2628 01:46:54,125 --> 01:46:58,829 OTHER WORDS MEASURING SINGLES 2629 01:46:58,829 --> 01:47:00,464 AND PAIRS. 2630 01:47:00,464 --> 01:47:02,767 ON THIS PLOT THE X-AXIS SHOWS 2631 01:47:02,767 --> 01:47:10,875 YOU -- EACH DO T -- EACH DOT ISA 2632 01:47:10,875 --> 01:47:11,108 TRIPLET 2633 01:47:11,108 --> 01:47:12,743 WHAT IS THE T-CELL RESPONSE WHEN 2634 01:47:12,743 --> 01:47:14,178 EXPOSED TO CELLS TREATED WITH 2635 01:47:14,178 --> 01:47:17,148 ANY OF THE 35 TRIPLETS? 2636 01:47:17,148 --> 01:47:20,117 AND Y-AXIS SHOWS THE CALCULATED 2637 01:47:20,117 --> 01:47:22,286 PROLIFERATION INDEX. 2638 01:47:22,286 --> 01:47:24,155 IN OTHER WORDS THE VALUE 2639 01:47:24,155 --> 01:47:25,456 PREDICTED BY USING ONLY DATA 2640 01:47:25,456 --> 01:47:27,224 FROM SINGLES AND PAIRS. 2641 01:47:27,224 --> 01:47:30,828 YOU SEE TRACKING CORRELATION 2642 01:47:30,828 --> 01:47:32,463 THAT SUGGESTS INDEED PAIRWISE 2643 01:47:32,463 --> 01:47:35,099 AND SINGLING ARE SUFFICIENT TO 2644 01:47:35,099 --> 01:47:39,703 MEASURE THIS SUGGESTING 2645 01:47:39,703 --> 01:47:41,238 EXPERIMENTS ARE PERHAPS 2646 01:47:41,238 --> 01:47:42,973 TRACTABLE BY UNCOVERING RULES IN 2647 01:47:42,973 --> 01:47:44,075 THE SYSTEM. 2648 01:47:44,075 --> 01:47:45,276 DOES THIS PROPERTY APPLY IN VIVO 2649 01:47:45,276 --> 01:47:47,478 OR ANOTHER WAY TO FRAME THIS 2650 01:47:47,478 --> 01:47:50,181 DOES IT I HAVE APPLICATION, IS 2651 01:47:50,181 --> 01:47:51,282 IT USEFUL TO BUILD SOME 2652 01:47:51,282 --> 01:47:52,283 VACCINES, FOR EXAMPLE? 2653 01:47:52,283 --> 01:47:54,919 SO TO GET TO THAT QUESTION AND 2654 01:47:54,919 --> 01:47:55,920 TEST OUR HYPOTHESIS REGARDING 2655 01:47:55,920 --> 01:47:58,322 THE RULE IN VIVO WHAT WE DID 2656 01:47:58,322 --> 01:48:01,926 FIRST IS TO USE A CELL BASED 2657 01:48:01,926 --> 01:48:04,028 VACCINE, WHEREBY THE CELLS ARE 2658 01:48:04,028 --> 01:48:07,431 STIMULATED IN A DISH WITH THIS 2659 01:48:07,431 --> 01:48:09,066 COMBINATION OF ADJUVANTS, WHAT 2660 01:48:09,066 --> 01:48:14,805 NOT, INJECT IN A MOUSE, FOCUSED 2661 01:48:14,805 --> 01:48:15,973 ON SIMPLIFIED MAMMALIAN MODEL 2662 01:48:15,973 --> 01:48:17,408 THAT CARRIES MODEL ANTIGEN AND 2663 01:48:17,408 --> 01:48:18,943 MEASURED TUMOR VOLUME OVER TIME. 2664 01:48:18,943 --> 01:48:20,478 THE REASON WE TURN TO DISEASE 2665 01:48:20,478 --> 01:48:23,080 JUST SO I RELATE TO PREVIOUS 2666 01:48:23,080 --> 01:48:27,118 COMMENTS MADE IS THAT OF COURSE 2667 01:48:27,118 --> 01:48:28,552 SOME MOLECULES CAN ACTIVATE 2668 01:48:28,552 --> 01:48:29,987 CELLS, HERE BY DOING THIS TYPE 2669 01:48:29,987 --> 01:48:32,490 OF IN VITRO SYSTEMS YOU CAN 2670 01:48:32,490 --> 01:48:34,125 ISOLATE WHICH CELLS ARE 2671 01:48:34,125 --> 01:48:37,428 STIMULATED AND NOT OTHERS. 2672 01:48:37,428 --> 01:48:38,629 AND RESULTS WERE STRIKING, HERE, 2673 01:48:38,629 --> 01:48:40,431 FOR EXAMPLE, I'M SHOWING EFFECTS 2674 01:48:40,431 --> 01:48:43,134 OF 12 OUT OF THE 35 TRIPLETS. 2675 01:48:43,134 --> 01:48:46,403 AND YOU CAN SEE TOP ROW AGAIN 2676 01:48:46,403 --> 01:48:47,471 THIS IS TUMOR VOLUME, AS A 2677 01:48:47,471 --> 01:48:48,806 FUNCTION OF TIME. 2678 01:48:48,806 --> 01:48:50,975 TOP ROW YOU SEE FOUR TRIPLETS 2679 01:48:50,975 --> 01:48:54,512 THAT HAVE QUITE A STRONG EFFECT 2680 01:48:54,512 --> 01:48:55,713 ON DECREASING TUMOR GROWTH. 2681 01:48:55,713 --> 01:48:57,982 HERE YOU SEE ORANGE LINE IS MICE 2682 01:48:57,982 --> 01:49:02,253 THAT WERE IMMUNIZED WITH THE 2683 01:49:02,253 --> 01:49:03,187 CELL-BASED VACCINES. 2684 01:49:03,187 --> 01:49:05,456 WHILE CONTROLS WERE GROWING 2685 01:49:05,456 --> 01:49:06,824 RAPIDLY, THAT WAS STRONGLY 2686 01:49:06,824 --> 01:49:08,726 DECREASED BY THE FOUR TRIPLETS. 2687 01:49:08,726 --> 01:49:10,494 THE EIGHT OTHER TRIPLETS WE 2688 01:49:10,494 --> 01:49:12,997 TESTED AT TIME WERE NOT ABLE TO 2689 01:49:12,997 --> 01:49:14,865 DO THIS. 2690 01:49:14,865 --> 01:49:17,168 AND IMPORTANTLY THE KEY THING TO 2691 01:49:17,168 --> 01:49:19,136 HIGHLIGHT IS THAT IF WE GO BACK 2692 01:49:19,136 --> 01:49:21,539 AND MEASURE ONLY SINGLES AND 2693 01:49:21,539 --> 01:49:23,741 PAIRS AND TEST OUR HYPOTHESIS 2694 01:49:23,741 --> 01:49:25,776 SHOW INDEED WE HAVE HAVE 2695 01:49:25,776 --> 01:49:26,443 PREDICTED WHICH TRIPLETS WOULD 2696 01:49:26,443 --> 01:49:29,513 HAVE BEEN USEFUL TO TEST. 2697 01:49:29,513 --> 01:49:31,482 SO THIS TO ME LED TO A 2698 01:49:31,482 --> 01:49:35,886 CONCLUSION THAT I LIKE TO THINK 2699 01:49:35,886 --> 01:49:37,087 OF THE PATHOGEN SENSING NETWORK 2700 01:49:37,087 --> 01:49:39,156 MORE THAN THE SUM OF PARTS, NOT 2701 01:49:39,156 --> 01:49:41,792 MORE THAN THE SUM OF PAIRS. 2702 01:49:41,792 --> 01:49:45,596 AGAIN, HIGHER ORDER EFFECTS, AND 2703 01:49:45,596 --> 01:49:47,898 THIS SUGGESTS A SIMPLIFYING RULE 2704 01:49:47,898 --> 01:49:49,433 NOW INNATE SENSING OPERATES. 2705 01:49:49,433 --> 01:49:51,202 THIS HAS IMPLICATION THAT I 2706 01:49:51,202 --> 01:49:52,203 WON'T DISCUSS TODAY. 2707 01:49:52,203 --> 01:49:55,372 THE MAIN THING TO FOCUS IS THAT 2708 01:49:55,372 --> 01:49:56,574 THIS STUDY WAS FOUNDATIONAL IN 2709 01:49:56,574 --> 01:49:58,742 TERMS OF BUILDING OUR ADJUVANT 2710 01:49:58,742 --> 01:49:58,976 EFFORTS. 2711 01:49:58,976 --> 01:50:05,216 AND THANKS TO SUPPORT FROM THE 2712 01:50:05,216 --> 01:50:06,317 MMCA PROGRAM, MOLECULAR 2713 01:50:06,317 --> 01:50:08,519 MECHANISM, WERE ABLE TO LAUNCH 2714 01:50:08,519 --> 01:50:10,154 MECHANISTIC STUDIES THAT AIM TO 2715 01:50:10,154 --> 01:50:12,022 TRY TO UNDERSTAND WHY SOME OF 2716 01:50:12,022 --> 01:50:15,960 THE TRIPLETS WORKED, WHAT IS THE 2717 01:50:15,960 --> 01:50:16,560 SECRET MECHANISTIC EFFECTS. 2718 01:50:16,560 --> 01:50:19,363 AND THIS IS A BIT OF BUSY SLIDE. 2719 01:50:19,363 --> 01:50:23,701 I'LL GIVE A BRIEF OVERVIEW, 2720 01:50:23,701 --> 01:50:25,035 SYSTEMATICALLY WITH THE IDEA 2721 01:50:25,035 --> 01:50:27,438 ACROSS SCALE, TRYING TO TEASE 2722 01:50:27,438 --> 01:50:30,975 APART WHAT HAPPENS IN 2723 01:50:30,975 --> 01:50:36,747 INTRACELLULAR CROSS-TALK, AS 2724 01:50:36,747 --> 01:50:37,748 WELL AS ORGANISM WIDE. 2725 01:50:37,748 --> 01:50:43,554 I'LL TELL YOU ABOUT A COUPLE 2726 01:50:43,554 --> 01:50:44,855 SNAPSHOT RESULTS. 2727 01:50:44,855 --> 01:50:46,724 FIRST THE PROTEIN LIFE CYCLE, 2728 01:50:46,724 --> 01:50:49,326 WHAT HAPPENS IN THE 2729 01:50:49,326 --> 01:50:50,427 TRANSLATIONAL MACHINERY WHEN 2730 01:50:50,427 --> 01:50:51,962 CELLS ARE EXPOSED TO TRIPLETS 2731 01:50:51,962 --> 01:50:54,965 THAT SEEM TO HAVE VERY STRONG 2732 01:50:54,965 --> 01:50:57,001 ANTITUMOR EFFECT. 2733 01:50:57,001 --> 01:51:02,039 WHEN WE LOOK AT ONE OF THE 2734 01:51:02,039 --> 01:51:05,943 TRIPLETS, LPS THAT TARGET THREE 2735 01:51:05,943 --> 01:51:07,778 FAMILIES OF PATHOGEN SENSORS, WE 2736 01:51:07,778 --> 01:51:09,546 MEASURED PROTEOME EXCHANGES, 2737 01:51:09,546 --> 01:51:11,415 WHAT IS THE EXCHANGES OF ALL 2738 01:51:11,415 --> 01:51:12,950 PROTEINS IN THE CELL, ASKED WHAT 2739 01:51:12,950 --> 01:51:15,352 ARE THE CODONS THAT MIGHT BE 2740 01:51:15,352 --> 01:51:16,453 PREFERENTIALLY USED, WE FOUND 2741 01:51:16,453 --> 01:51:18,656 THERE'S A VERY STRONG BIAS IN 2742 01:51:18,656 --> 01:51:21,158 BOTH UP AND DOWNREGULATED GENES, 2743 01:51:21,158 --> 01:51:24,762 OR PROTEINS, RATHER, IN THE 2744 01:51:24,762 --> 01:51:26,330 GLUTAMINE CODONS. 2745 01:51:26,330 --> 01:51:28,799 WHEN WE COLLABORATED WITH LOCAL 2746 01:51:28,799 --> 01:51:32,736 EXPERT IN TRANSLATION, TAU PAN, 2747 01:51:32,736 --> 01:51:36,006 WE MEASURED ALL TRANSFERASE RNA 2748 01:51:36,006 --> 01:51:39,410 IN THE CELL TO SHOW THIS WAS 2749 01:51:39,410 --> 01:51:42,780 CORRELATED WITH THIS SHIFT IN 2750 01:51:42,780 --> 01:51:44,982 TRANSFER RNA, SO tRNAs THAT 2751 01:51:44,982 --> 01:51:47,284 ENCODE FOR THIS GLUTAMINE, SO 2752 01:51:47,284 --> 01:51:52,289 YOU HAVE CTC AND TTC BASICALLY 2753 01:51:52,289 --> 01:51:52,990 DECODER SITES. 2754 01:51:52,990 --> 01:51:56,026 ONE OF THE OTHER THINGS WE 2755 01:51:56,026 --> 01:51:58,962 OBSERVED WAS INTERESTING AS 2756 01:51:58,962 --> 01:52:00,631 WELL, THESE tRNAs SHOWN ON 2757 01:52:00,631 --> 01:52:03,033 THE RIGHT SIDE, THIS IS THE 2758 01:52:03,033 --> 01:52:04,902 TERTIARY STRUCTURE OF A TRANSFER 2759 01:52:04,902 --> 01:52:07,971 RNA, YOU CAN SEE WHEN YOU LOOK 2760 01:52:07,971 --> 01:52:12,209 AT THE TRIPLET, LSG, THERE'S 2761 01:52:12,209 --> 01:52:13,210 DECREASES IN EPITRANSCRIPTOMIC 2762 01:52:13,210 --> 01:52:14,745 MODIFICATION, THOSE ARE CHEMICAL 2763 01:52:14,745 --> 01:52:16,580 MODIFICATIONS INSTALLED ON SOME 2764 01:52:16,580 --> 01:52:20,884 OF THE BASES THAT COMPOSE THIS 2765 01:52:20,884 --> 01:52:21,418 RNA. 2766 01:52:21,418 --> 01:52:25,222 AND SPECIFICALLY AT THIS U34 2767 01:52:25,222 --> 01:52:28,892 SITE, GOING DOWN BUT BEING 2768 01:52:28,892 --> 01:52:34,965 HYPO-MODIFIED AT THIS 2769 01:52:34,965 --> 01:52:37,434 TRANSCRIPTOMIC SITE. 2770 01:52:37,434 --> 01:52:39,203 THERE MIGHT BE SOMETHING IN 2771 01:52:39,203 --> 01:52:42,373 TERMS OF HOW IMMUNE CELLS CAN 2772 01:52:42,373 --> 01:52:43,140 REGULATE TRANSITIONAL EFFECT. 2773 01:52:43,140 --> 01:52:44,041 I'LL SKIP THIS. 2774 01:52:44,041 --> 01:52:46,310 I WAS GOING TO TELL YOU THE 2775 01:52:46,310 --> 01:52:48,178 ENZYME THAT MODIFIED IS ALSO 2776 01:52:48,178 --> 01:52:49,713 REGULATED ONLY BY TRIPLET AND 2777 01:52:49,713 --> 01:52:51,548 NOT SINGLES AND PAIRS, BACK TO 2778 01:52:51,548 --> 01:52:52,883 THE FACT PERHAPS THERE'S 2779 01:52:52,883 --> 01:52:54,184 SOMETHING SPECIAL THAT HAPPENS. 2780 01:52:54,184 --> 01:52:56,820 NOW ONE OF THE THINGS ASKED 2781 01:52:56,820 --> 01:52:58,789 GOING FROM THIS TENSION BETWEEN 2782 01:52:58,789 --> 01:53:00,991 THEORY OR FUNDAMENTAL QUESTIONS 2783 01:53:00,991 --> 01:53:02,326 IN APPLICATIONS, COULD THIS BE 2784 01:53:02,326 --> 01:53:04,828 HELPFUL IN TERMS OF MANIPULATING 2785 01:53:04,828 --> 01:53:08,232 IMMUNE SYSTEM, IN OTHER WORDS IF 2786 01:53:08,232 --> 01:53:10,401 WE TWEAK RESPONSES COULD WE 2787 01:53:10,401 --> 01:53:15,105 IMPACT THINGS? 2788 01:53:15,105 --> 01:53:16,206 HERE KATE OVEREXPRESSED 2789 01:53:16,206 --> 01:53:17,508 tRNAs, FROM GLUTAMINE. 2790 01:53:17,508 --> 01:53:23,647 IF YOU FOCUS ON LEFT PLOT AT 2791 01:53:23,647 --> 01:53:26,617 IL-12, CTC AND NOT TTC, YOU SEE 2792 01:53:26,617 --> 01:53:28,585 HOW BOOST IN SOME OF THESE 2793 01:53:28,585 --> 01:53:29,353 CYTOKINES, RIGHT? 2794 01:53:29,353 --> 01:53:31,622 SUGGESTING AGAIN THIS IS SORT OF 2795 01:53:31,622 --> 01:53:34,258 A PROOF OF PRINCIPLE MODIFYING 2796 01:53:34,258 --> 01:53:35,692 tRNAs MIGHT HELP MODULATE 2797 01:53:35,692 --> 01:53:37,861 ADJUVANT RESPONSES WHICH IS AN 2798 01:53:37,861 --> 01:53:39,863 AREA THAT HASN'T BEEN MUCH 2799 01:53:39,863 --> 01:53:40,764 EXPLORED TO MY KNOWLEDGE. 2800 01:53:40,764 --> 01:53:43,801 THIS IS JUST TO GIVE SNAPSHOTS 2801 01:53:43,801 --> 01:53:45,335 ABOUT HOW THESE DETAILED 2802 01:53:45,335 --> 01:53:46,236 MOLECULAR STUDIES CAN YIELD 2803 01:53:46,236 --> 01:53:48,071 VALUABLE INFORMATION ON HOW YOU 2804 01:53:48,071 --> 01:53:50,808 MIGHT WANT TO MODULATE ADJUVANT 2805 01:53:50,808 --> 01:53:51,074 RESPONSES. 2806 01:53:51,074 --> 01:53:55,279 AND A COUPLE MINUTES TO TELL YOU 2807 01:53:55,279 --> 01:53:57,047 HOW THESE THINGS -- WHAT DID WE 2808 01:53:57,047 --> 01:53:59,650 DISCOVER IN TERMS OF MECHANISM 2809 01:53:59,650 --> 01:54:00,417 IN IN VIVO. 2810 01:54:00,417 --> 01:54:06,256 WE TURNED TO A MODEL, A POX 2811 01:54:06,256 --> 01:54:07,758 VIRUS, WE'VE HEARD ABOUT 2812 01:54:07,758 --> 01:54:09,960 MONKEYPOX IN THE PAST YEARS. 2813 01:54:09,960 --> 01:54:12,162 WE TURNED TO POX VIRUSES BECAUSE 2814 01:54:12,162 --> 01:54:13,931 OF LIKE INSPIRED BY SOME OF THE 2815 01:54:13,931 --> 01:54:15,566 WORK WITH THE YELLOW FEVER 2816 01:54:15,566 --> 01:54:17,968 VACCINE, PERHAPS THE OLDEST 2817 01:54:17,968 --> 01:54:20,904 VACCINE EVER, POX VIRUS VACCINE 2818 01:54:20,904 --> 01:54:22,005 AGAINST SMALLPOX, RIGHT? 2819 01:54:22,005 --> 01:54:24,942 THAT LED TO ERADICATION OF THE 2820 01:54:24,942 --> 01:54:28,445 DISEASE IN THE LATE '70s, SAME 2821 01:54:28,445 --> 01:54:29,947 WITH ADJUVANTS, VACCINES CHANGE, 2822 01:54:29,947 --> 01:54:32,716 WE DON'T KNOW HOW IT WORKS TO 2823 01:54:32,716 --> 01:54:33,951 DATE, WE HAVE CLUES BUT DON'T 2824 01:54:33,951 --> 01:54:36,253 KNOW SPECIFIC DETAILS. 2825 01:54:36,253 --> 01:54:39,790 WE CAN USE THIS VACCINE THAT CAN 2826 01:54:39,790 --> 01:54:41,191 AGAIN IMMUNIZE AGAINST SMALLPOX 2827 01:54:41,191 --> 01:54:47,431 IN HUMAN, IN MICE WHAT WE DO, WE 2828 01:54:47,431 --> 01:54:48,298 USE THIS WESTERN RESERVE STRAIN 2829 01:54:48,298 --> 01:54:50,501 OF VIRUS THAT IS LETHAL, AND IT 2830 01:54:50,501 --> 01:54:52,336 IS LETHAL BECAUSE IT CARRIES -- 2831 01:54:52,336 --> 01:54:54,371 YOU SEE WHITE PARTS, THE TWO 2832 01:54:54,371 --> 01:54:56,106 CIRCLES, TWO SIDES OF THE 2833 01:54:56,106 --> 01:54:58,141 CIRCLES ARE THE GENOMIC DNA OF 2834 01:54:58,141 --> 01:55:00,244 EACH VIRUS STRAIN. 2835 01:55:00,244 --> 01:55:02,112 YOU CAN SEE THAT THE VACCINE 2836 01:55:02,112 --> 01:55:08,685 STRAIN WHICH WAS OBTAINED 2837 01:55:08,685 --> 01:55:09,720 THROUGH EMPIRICAL, LOST THE 2838 01:55:09,720 --> 01:55:19,196 WHITE PARTS IN THE PATHOGENIC 2839 01:55:19,196 --> 01:55:21,598 GENOME, THE RED STRAIN WESTERN 2840 01:55:21,598 --> 01:55:24,134 RESEARCH IS LETHAL, THE BLUE 2841 01:55:24,134 --> 01:55:27,838 STRAIN CAN INNOCUOUS. 2842 01:55:27,838 --> 01:55:30,841 WE TESTED A PROTECTIVE TRIPLET, 2843 01:55:30,841 --> 01:55:33,544 BENCHMARKED IT, I'M SHOWING MICE 2844 01:55:33,544 --> 01:55:34,645 THAT WERE VACCINATED AND THREE 2845 01:55:34,645 --> 01:55:37,581 TO FOUR WEEKS LATER CHALLENGED 2846 01:55:37,581 --> 01:55:38,949 THROUGH RESPIRATORY ROUTE WITH 2847 01:55:38,949 --> 01:55:43,053 LETHAL DOSE OF THE WESTERN 2848 01:55:43,053 --> 01:55:43,854 RESERVE STRAIN. 2849 01:55:43,854 --> 01:55:46,023 EACH LINE IS INDIVIDUAL MOUSE, 2850 01:55:46,023 --> 01:55:47,991 WEIGHT OVER TIME, MICE NOT 2851 01:55:47,991 --> 01:55:49,092 VACCINATED IN LIGHT GRAY DO NOT 2852 01:55:49,092 --> 01:55:50,961 DO VERY WELL. 2853 01:55:50,961 --> 01:55:54,031 THE ONES VACCINATED WITH MVA ARE 2854 01:55:54,031 --> 01:55:54,898 FULLY PROTECTED AS EXPECTED. 2855 01:55:54,898 --> 01:55:59,970 WHEN YOU DO VERY SIMPLE VACCINE 2856 01:55:59,970 --> 01:56:02,940 WITH POLY ICs, THE 2857 01:56:02,940 --> 01:56:04,274 COMBINATION, YOU HAVE VERY 2858 01:56:04,274 --> 01:56:07,644 STRONG PROTECTION, NOT AS GOOD 2859 01:56:07,644 --> 01:56:09,846 AS MVA, YOU'RE JUST USING A 2860 01:56:09,846 --> 01:56:13,317 SINGLE PEPTIDE AS ANTIGEN SO 2861 01:56:13,317 --> 01:56:14,952 QUITE REMARKABLE YOU CAN EVEN DO 2862 01:56:14,952 --> 01:56:15,152 THIS. 2863 01:56:15,152 --> 01:56:17,387 TO GO FURTHER WE CHECKED WHETHER 2864 01:56:17,387 --> 01:56:19,690 THERE WAS TRUE SYNERGY IN THE 2865 01:56:19,690 --> 01:56:22,225 TRIPLETS, HERE I'M SHOWING THE 2866 01:56:22,225 --> 01:56:24,728 WEIGHT CHANGES IN MICE 2867 01:56:24,728 --> 01:56:25,929 IMMUNIZED, CHANNELED WITH 2868 01:56:25,929 --> 01:56:34,404 SINGLES IN BLUE, PAIRS IN GREEN. 2869 01:56:34,404 --> 01:56:41,912 THERE'S SUPPOSED TO BE DATA 2870 01:56:41,912 --> 01:56:42,946 THERE. 2871 01:56:42,946 --> 01:56:47,751 THE ORANGE ONE IS PROTECTED. 2872 01:56:47,751 --> 01:56:50,921 WHEN WE COMPARED AND ASKED WHAT 2873 01:56:50,921 --> 01:56:56,259 IF WE JUST TOOK OFF THE SHELF 2874 01:56:56,259 --> 01:56:58,795 ADJUVANTS, WOULD THEY DO THEIR 2875 01:56:58,795 --> 01:56:59,129 JOB? 2876 01:56:59,129 --> 01:57:02,299 YOU HAVE TO BELIEVE ME ALL THE 2877 01:57:02,299 --> 01:57:06,470 GUYS IN BLACK BASICALLY DO WORSE 2878 01:57:06,470 --> 01:57:14,211 OR SIMILAR TO ASO1, NOT 2879 01:57:14,211 --> 01:57:17,147 PROTECTING MUCH, HZG, YOU'RE 2880 01:57:17,147 --> 01:57:18,448 SUPPOSED TO SEE THIS, THIS 2881 01:57:18,448 --> 01:57:19,883 TRIPLET IS POTENT IN PROTECTION, 2882 01:57:19,883 --> 01:57:21,952 MORE SO THAN EXISTING ADJUVANTS. 2883 01:57:21,952 --> 01:57:24,921 IF WE LOOK AT SOME JUST VERY 2884 01:57:24,921 --> 01:57:29,626 BRIEF MECHANISTIC INSIGHTS, ABLE 2885 01:57:29,626 --> 01:57:39,936 TO GATHER, SEEMS TO DEPENDENT ON 2886 01:57:39,936 --> 01:57:41,004 IL-18. 2887 01:57:41,004 --> 01:57:42,439 NOT IL--1B OR TNF. 2888 01:57:42,439 --> 01:57:44,741 WE ASKED WHETHER THIS MIGHT BE 2889 01:57:44,741 --> 01:57:45,475 CORRELATED WITH T-CELL RESPONSES 2890 01:57:45,475 --> 01:57:47,611 BECAUSE AS MOST OF YOU PROBABLY 2891 01:57:47,611 --> 01:57:49,913 KNOW IT'S DIFFICULT TO MAKE 2892 01:57:49,913 --> 01:57:51,214 VACCINES GOOD AT INDUCING T-CELL 2893 01:57:51,214 --> 01:57:51,648 RESPONSES. 2894 01:57:51,648 --> 01:57:54,818 HERE WHAT I DIDN'T TELL YOU IS 2895 01:57:54,818 --> 01:57:57,320 THAT THIS ADJUVANT TRIPLET WAS 2896 01:57:57,320 --> 01:57:58,655 DOING ITS JOB THROUGH INDUCING 2897 01:57:58,655 --> 01:57:59,956 T-CELL RESPONSES. 2898 01:57:59,956 --> 01:58:00,957 AND WHEN YOU COMPARE INDUCTION 2899 01:58:00,957 --> 01:58:03,460 OF T CELLS IN DRAINING LYMPH 2900 01:58:03,460 --> 01:58:04,895 NODE IN TRIPLET IN ORANGE 2901 01:58:04,895 --> 01:58:06,530 COMPARED TO SINGLES IN BLUE OR 2902 01:58:06,530 --> 01:58:10,600 PAIRS IN GREEN YOU SEE YOU HAVE 2903 01:58:10,600 --> 01:58:14,104 THIS CORRELATION IN TERMS OF 2904 01:58:14,104 --> 01:58:14,671 PROTECTION EFFECT, SO THE 2905 01:58:14,671 --> 01:58:16,640 TRIPLET WITH THE HIGH NUMBER OF 2906 01:58:16,640 --> 01:58:20,877 T CELLS IS BETTER AT PROTECTING. 2907 01:58:20,877 --> 01:58:23,513 AND PERHAPS ALSO TO RESONATE 2908 01:58:23,513 --> 01:58:24,581 WITH COMMENTS MADE EARLIER ABOUT 2909 01:58:24,581 --> 01:58:29,186 THE FACT THAT IT IS DIFFICULT TO 2910 01:58:29,186 --> 01:58:31,955 INDUCE MEMORY T CELLS IN MUCOSAL 2911 01:58:31,955 --> 01:58:33,824 SITES, DIFFICULT TO DELIVER 2912 01:58:33,824 --> 01:58:35,592 ADJUVANTS THROUGH THIS ROUTE, 2913 01:58:35,592 --> 01:58:37,594 HERE WHAT WE DISCOVERED BOTH IN 2914 01:58:37,594 --> 01:58:40,197 MVA CASE BACK IN THE DAY, ALSO 2915 01:58:40,197 --> 01:58:41,598 IN ADJUVANT TRIPLET, IF YOU 2916 01:58:41,598 --> 01:58:43,467 ADMINISTER TRIPLET AT SKIN 2917 01:58:43,467 --> 01:58:53,110 YOU'RE ABLE TO REMOTELY OR 2918 01:58:53,110 --> 01:58:54,544 DISTANTLY SEE RESIDENT MEMORY T 2919 01:58:54,544 --> 01:58:56,079 CELLS IN THE LUNG, BROAD 2920 01:58:56,079 --> 01:58:56,847 IMPLICATIONS, IMPORTANT TO SEE 2921 01:58:56,847 --> 01:58:58,381 THE T CELLS. 2922 01:58:58,381 --> 01:58:59,382 I'LL SKIP THE DATA. 2923 01:58:59,382 --> 01:59:03,286 IF YOU LOOK AT MVA THIS PLOT 2924 01:59:03,286 --> 01:59:06,089 SHOWS NUMBER OF CELLS PER TOTAL 2925 01:59:06,089 --> 01:59:08,125 LIVE CELLS IN THE LUNGS AT 3 TO 2926 01:59:08,125 --> 01:59:11,394 4 WEEKS, YOU CAN SEE THEY INDUCE 2927 01:59:11,394 --> 01:59:13,797 SIMILAR NUMBER OF MEMORY T CELLS 2928 01:59:13,797 --> 01:59:17,734 SPECIFIC FOR THAT ANTIGEN. 2929 01:59:17,734 --> 01:59:19,503 LOOKING FORWARD I'LL JUST -- 2930 01:59:19,503 --> 01:59:20,370 LAST TID-BIT OF INFORMATION, 2931 01:59:20,370 --> 01:59:22,773 INTERESTED IN TRYING TO MAP OUT 2932 01:59:22,773 --> 01:59:24,875 WHAT HAPPENS BEYOND INNATE AND 2933 01:59:24,875 --> 01:59:26,610 ADAPTIVE CELLS, WHAT HAPPENS 2934 01:59:26,610 --> 01:59:27,844 ACROSS TISSUES, YOU MENTIONED 2935 01:59:27,844 --> 01:59:30,147 IT'S IMPORTANT TO FIGURE OUT 2936 01:59:30,147 --> 01:59:32,215 WHAT DO THESE VACCINES AND 2937 01:59:32,215 --> 01:59:35,819 ADJUVANTS DO ACROSS THE BODY. 2938 01:59:35,819 --> 01:59:37,921 FOR THAT IN OTHER EFFORTS 2939 01:59:37,921 --> 01:59:39,089 DEVELOPED TOOLS TO ESSENTIALLY 2940 01:59:39,089 --> 01:59:40,690 MAP OUT EFFECTS OF ANYTHING YOU 2941 01:59:40,690 --> 01:59:42,959 INJECT INTO A MOUSE ON ALL CELLS 2942 01:59:42,959 --> 01:59:45,395 OF THE BODY AT ONCE. 2943 01:59:45,395 --> 01:59:48,131 WHAT WE DO, WHOLE MOUSE 2944 01:59:48,131 --> 01:59:49,766 SECTIONS, FOLLOWED BY SPATIAL 2945 01:59:49,766 --> 01:59:50,534 TRANSCRIPTOMICS, FOR EXAMPLE 2946 01:59:50,534 --> 01:59:52,169 TYPE OF DATA YOU CAN LOOK AT 2947 01:59:52,169 --> 01:59:52,936 LOOKS LIKE THIS. 2948 01:59:52,936 --> 01:59:55,105 WE HAVE A SECTION OF A MOUSE, 2949 01:59:55,105 --> 01:59:57,641 SAGITTAL SECTION OF A MOUSE, THE 2950 01:59:57,641 --> 01:59:59,042 BRAIN HERE, THYMUS, HEART, THE 2951 01:59:59,042 --> 02:00:01,678 LUNGS, THE LIVER, THE STOMACH, 2952 02:00:01,678 --> 02:00:04,314 THE SPLEEN, KIDNEY AND SO ON. 2953 02:00:04,314 --> 02:00:06,917 THIS IS ESSENTIALLY mRNA 2954 02:00:06,917 --> 02:00:11,855 LEVELS ACROSS THE TRANSCRIPTOME, 2955 02:00:11,855 --> 02:00:16,226 EVERY 30-MICRON SPOT, YOU CAN 2956 02:00:16,226 --> 02:00:17,761 RECAPITULATE ALL THE TISSUES YOU 2957 02:00:17,761 --> 02:00:19,963 EXPECT IN A MOUSE. 2958 02:00:19,963 --> 02:00:23,033 INJECT WITH LPS YOU CAN SEE THE 2959 02:00:23,033 --> 02:00:25,001 CONTROL SETTING LOOKING AT 2960 02:00:25,001 --> 02:00:27,504 INFLAMMATORY MEDIATORS WHICH IS 2961 02:00:27,504 --> 02:00:31,208 SAA FAMILY SERUM, AMYLOID 2962 02:00:31,208 --> 02:00:31,675 FACTORS. 2963 02:00:31,675 --> 02:00:34,477 SAA 1, 2, 3 SHOWN HERE. 2964 02:00:34,477 --> 02:00:36,479 1 IS INDUCED IN LIVER AND COLON, 2965 02:00:36,479 --> 02:00:43,887 2 IN LIVER AND KIDNEY, SAA 3 2966 02:00:43,887 --> 02:00:45,522 INDUCED IN EVERY CELL TYPE. 2967 02:00:45,522 --> 02:00:47,190 A SIMPLE EXAMPLE YOU CAN MAP OUT 2968 02:00:47,190 --> 02:00:49,259 WHAT HAPPENS ACROSS THE BODY, WE 2969 02:00:49,259 --> 02:00:52,128 HOPE TO APPLY TO TRY TO BETTER 2970 02:00:52,128 --> 02:00:59,469 UNDERSTAND WHAT HAPPENS WHEN YOU 2971 02:00:59,469 --> 02:01:00,337 INJECT INTO ANIMAL. 2972 02:01:00,337 --> 02:01:01,805 WE COULDN'T DO THIS IN ANY OTHER 2973 02:01:01,805 --> 02:01:03,840 SYSTEM AT THE MOMENT. 2974 02:01:03,840 --> 02:01:04,407 WITH THAT I'LL CONCLUDE AND 2975 02:01:04,407 --> 02:01:08,445 THANK YOU VERY MUCH FOR YOUR 2976 02:01:08,445 --> 02:01:16,419 ATTENTION. 2977 02:01:16,419 --> 02:01:18,955 2978 02:01:18,955 --> 02:01:19,389 >> ANY QUESTIONS? 2979 02:01:19,389 --> 02:01:20,390 >> JUST A COMMENT. 2980 02:01:20,390 --> 02:01:23,727 WHAT YOU'RE SAYING IS WE ALREADY 2981 02:01:23,727 --> 02:01:25,395 HAVE THE TOOLS TO RESCUE 2982 02:01:25,395 --> 02:01:26,830 VACCINES THAT HAVE FAILED BEFORE 2983 02:01:26,830 --> 02:01:35,672 BECAUSE WE HAVEN'T LOOKED AT THE 2984 02:01:35,672 --> 02:01:37,741 COMBINATIONS. 2985 02:01:37,741 --> 02:01:38,942 2986 02:01:38,942 --> 02:01:47,851 THANK YOU. 2987 02:01:47,851 --> 02:01:49,352 >> THANK YOU FOR HELPING CATCH 2988 02:01:49,352 --> 02:01:51,121 US UP ON TIME A BIT. 2989 02:01:51,121 --> 02:01:52,856 WE'RE ABOUT HALF AN HOUR BEHIND 2990 02:01:52,856 --> 02:01:57,360 WHERE WE EXPECTED TO BE. 2991 02:01:57,360 --> 02:01:59,529 SO, I'M GOING ASK STAFF TO BE 2992 02:01:59,529 --> 02:02:03,366 VERY BRIEF IN THE CONCEPT 2993 02:02:03,366 --> 02:02:04,467 CLEARANCE PRESENTATIONS, I THINK 2994 02:02:04,467 --> 02:02:07,170 EACH HAVE BETWEEN FOUR AND SEVEN 2995 02:02:07,170 --> 02:02:11,241 SLIDES, SO I'M SURE WE'LL CATCH 2996 02:02:11,241 --> 02:02:11,741 UP. 2997 02:02:11,741 --> 02:02:15,478 I DON'T WANT TO GO BEYOND 3:45 2998 02:02:15,478 --> 02:02:18,815 OR SO BECAUSE I WANT TO BE 2999 02:02:18,815 --> 02:02:19,516 RESPECTFUL OF COUNCIL MEMBERS, 3000 02:02:19,516 --> 02:02:22,852 MAY HAVE TRAINS OR PLANES TO 3001 02:02:22,852 --> 02:02:25,388 WATCH, AND OTHER MEET, ON THEIR 3002 02:02:25,388 --> 02:02:26,489 AGENDA THIS AFTERNOON. 3003 02:02:26,489 --> 02:02:29,292 CARMEN, YOU'RE UP FIRST. 3004 02:02:29,292 --> 02:02:33,563 FOR THE NEW COUNCIL MEMBERS, 3005 02:02:33,563 --> 02:02:35,098 BRIEF PRESENTATIONS BY OUR STAFF 3006 02:02:35,098 --> 02:02:38,268 ON INITIATIVES THAT ARE EITHER 3007 02:02:38,268 --> 02:02:41,171 NEW OR UP FOR RENEWAL 3008 02:02:41,171 --> 02:02:44,607 RECOMPETITION AND PROGRAMS THAT 3009 02:02:44,607 --> 02:02:46,710 WILL BE DEVELOPED INTO RESEARCH 3010 02:02:46,710 --> 02:02:48,378 SOLICITATIONS, AND WE LOOK 3011 02:02:48,378 --> 02:02:51,982 FORWARD TO YOUR INPUT ON THESE 3012 02:02:51,982 --> 02:02:55,251 AND IN THE INTEREST OF TIME 3013 02:02:55,251 --> 02:02:58,088 WE'LL ASK FOR AN EN BLOC 3014 02:02:58,088 --> 02:03:00,390 APPROVAL FOR THESE AFTER THE 3015 02:03:00,390 --> 02:03:01,624 THREE ARE PRESENTED. 3016 02:03:01,624 --> 02:03:04,995 IF IT TURNS OUT DISCUSSION ABOUT 3017 02:03:04,995 --> 02:03:06,196 ANY ONE GETS PROBLEMATIC, WE MAY 3018 02:03:06,196 --> 02:03:07,297 GO ONE BY ONE. 3019 02:03:07,297 --> 02:03:16,339 BUT THAT'S A RARE OCCURRENCE. 3020 02:03:16,339 --> 02:03:18,174 CARMEN, THANK YOU 3021 02:03:18,174 --> 02:03:21,745 >> THANK YOU, DAN. 3022 02:03:21,745 --> 02:03:24,114 I'M TALKING ABOUT A NEW 3023 02:03:24,114 --> 02:03:27,317 INITIATIVE TO STUDY RADIATION 3024 02:03:27,317 --> 02:03:27,550 INJURY. 3025 02:03:27,550 --> 02:03:30,053 FOR THE NEW COLLEAGUES IN THE 3026 02:03:30,053 --> 02:03:33,656 ROOM, HIGHLIGHTS ABOUT A 3027 02:03:33,656 --> 02:03:34,224 PROGRAM, RADIATION NUCLEAR 3028 02:03:34,224 --> 02:03:36,526 COUNTERMEASURES PROGRAM, THE 3029 02:03:36,526 --> 02:03:38,962 GOAL TO DEVELOP PRODUCTS FOR 3030 02:03:38,962 --> 02:03:40,530 TREATMENT AND DIAGNOSIS OF 3031 02:03:40,530 --> 02:03:41,331 RADIATION INJURY. 3032 02:03:41,331 --> 02:03:44,834 WE DEVELOP ANIMAL MODELS, 3033 02:03:44,834 --> 02:03:45,502 ESTABLISH RADIATION FACILITIES, 3034 02:03:45,502 --> 02:03:46,970 FUND RESEARCH ACROSS THE 3035 02:03:46,970 --> 02:03:49,239 SPECTRUM FROM BASIC TO ADVANCED, 3036 02:03:49,239 --> 02:03:51,307 WORKING WITH OUR GOVERNMENT 3037 02:03:51,307 --> 02:03:53,676 PARTNERS, WE WORK WITH PRIVATE 3038 02:03:53,676 --> 02:03:54,944 INDUSTRY, ACADEMIA, THIS 3039 02:03:54,944 --> 02:03:56,346 PARTICULAR INITIATIVE WILL BE 3040 02:03:56,346 --> 02:03:58,715 FOCUSED ON THE BASIC RESEARCH 3041 02:03:58,715 --> 02:04:00,483 END OF THE SPECTRUM, 3042 02:04:00,483 --> 02:04:01,251 ANTICIPATING THAT APPLICANTS 3043 02:04:01,251 --> 02:04:04,320 WILL COME IN WITH MODELS THAT 3044 02:04:04,320 --> 02:04:06,423 ARE EARLY IN DEVELOPMENT, 3045 02:04:06,423 --> 02:04:07,924 EXPLORING MECHANISMS, TARGETS OF 3046 02:04:07,924 --> 02:04:12,829 INJURY, AND DOING VERY EARLY 3047 02:04:12,829 --> 02:04:13,930 EFFICACY STUDIES FOR MEDICAL 3048 02:04:13,930 --> 02:04:14,831 COUNTERMEASURES. 3049 02:04:14,831 --> 02:04:16,699 SO WE WORK CLOSELY WITH THE FDA, 3050 02:04:16,699 --> 02:04:19,502 WE'LL CONTINUE TO DO THAT. 3051 02:04:19,502 --> 02:04:22,238 THEY ACTUALLY HAVE A LOT OF 3052 02:04:22,238 --> 02:04:23,807 INTEREST IN ALTERNATIVE MODELS, 3053 02:04:23,807 --> 02:04:26,209 IN DECEMBER 2022 THE FDA 3054 02:04:26,209 --> 02:04:28,311 MODERNIZATION ACT WAS PASSED, 3055 02:04:28,311 --> 02:04:31,147 AUTHORIZING USE OF THESE 3056 02:04:31,147 --> 02:04:32,882 ALTERNATIVE PLATFORMS IN LIEU OF 3057 02:04:32,882 --> 02:04:34,751 ANIMAL STUDIES FOR CERTAIN DRUGS 3058 02:04:34,751 --> 02:04:35,618 BEFORE ENTERING A SAFETY TRIAL. 3059 02:04:35,618 --> 02:04:37,487 THAT'S OF INTEREST TO US TOO 3060 02:04:37,487 --> 02:04:39,255 BECAUSE WE HAVE ALREADY BEEN 3061 02:04:39,255 --> 02:04:41,157 FUNDING SOME PROGRAMS IN OUR 3062 02:04:41,157 --> 02:04:42,959 PORTFOLIO, TO GIVE A FEW 3063 02:04:42,959 --> 02:04:44,727 HIGHLIGHTS OF EXAMPLES OF 3064 02:04:44,727 --> 02:04:47,030 STUDIES, THIS PARTICULAR STUDY 3065 02:04:47,030 --> 02:04:57,540 OUT OF STANFORD UNIVERSITY, DR. 3066 02:04:57,540 --> 02:04:59,976 WU'S WORK, PLURIPOTENT STEM 3067 02:04:59,976 --> 02:05:02,812 CELLS, CREATING HEART AND 3068 02:05:02,812 --> 02:05:04,781 VASCULAR TISSUES, CELL-TO-CELL 3069 02:05:04,781 --> 02:05:08,051 INTERACTIONS CAN BE STUDIED IN 3070 02:05:08,051 --> 02:05:09,052 MATURE TISSUES. 3071 02:05:09,052 --> 02:05:15,258 A VISUAL OF THE CARDIAC ORGANIE 3072 02:05:15,258 --> 02:05:16,359 UNDER EXPOSURE. 3073 02:05:16,359 --> 02:05:20,630 TOP ROW, FOCUS ON ROW 1, OVERLAY 3074 02:05:20,630 --> 02:05:24,200 OF GFP, RED STAIN FOR VASCULAR, 3075 02:05:24,200 --> 02:05:26,769 GREEN IS CARDIAC TISSUE. 3076 02:05:26,769 --> 02:05:30,039 YOU MAY APPRECIATE COMPARING TO 3077 02:05:30,039 --> 02:05:32,809 ROW 3, DIMINISHING ARE 3078 02:05:32,809 --> 02:05:33,276 CARDIOMYOCYTES, GREEN 3079 02:05:33,276 --> 02:05:35,345 DIMINISHING, THIS IS A VISUAL 3080 02:05:35,345 --> 02:05:37,547 REPRESENTATION OF DATA HE HAS 3081 02:05:37,547 --> 02:05:37,881 QUANTIFIED. 3082 02:05:37,881 --> 02:05:40,950 SO THIS IS OF INTEREST TO US, 3083 02:05:40,950 --> 02:05:43,453 IMPACT OF RADIATION ON CARDIAC 3084 02:05:43,453 --> 02:05:44,220 TISSUE. 3085 02:05:44,220 --> 02:05:45,989 AND FOR OUR AGENCY PARTNERS FROM 3086 02:05:45,989 --> 02:05:49,459 NASA, WHO ARE PART OF THIS 3087 02:05:49,459 --> 02:05:51,895 INITIATIVE WITH US, THEY ARE 3088 02:05:51,895 --> 02:05:55,832 INTERESTED IN PROLONGED EFFECTS 3089 02:05:55,832 --> 02:05:57,467 OF SPACE FLIGHT RADIATION. 3090 02:05:57,467 --> 02:05:58,968 ANOTHER PROJECT WITHIN OUR 3091 02:05:58,968 --> 02:06:04,807 PORTFOLIO IS FROM CORNELL 3092 02:06:04,807 --> 02:06:05,909 UNIVERSITY, DR. RAPHI CREATED 3093 02:06:05,909 --> 02:06:08,077 ENDOTHELIAL CELLS THAT ARE ABLE 3094 02:06:08,077 --> 02:06:12,382 TO BE MATURED TO REGENERATE WITH 3095 02:06:12,382 --> 02:06:14,651 ETV-2, MASTER REGULATOR IN FETAL 3096 02:06:14,651 --> 02:06:22,992 JESS RATION -- GESTATION, ABLE 3097 02:06:22,992 --> 02:06:26,162 TO SHOW STABLE STRUCTURE IS 3098 02:06:26,162 --> 02:06:28,331 CREATED WITH POSSIBILITY OF -- 3099 02:06:28,331 --> 02:06:30,967 HE'S SHOWN IT'S ABLE TO SHUTTLE 3100 02:06:30,967 --> 02:06:33,036 HUMAN BLOOD ADEQUATELY SO THE 3101 02:06:33,036 --> 02:06:35,338 IDEA HERE IS THAT THESE RESET 3102 02:06:35,338 --> 02:06:40,476 ENDOTHELIAL CELLS COULD BE USED 3103 02:06:40,476 --> 02:06:45,848 AS A MEDICAL COUNTERMEASURE FOR 3104 02:06:45,848 --> 02:06:47,483 INJURY TO VASCULAR TISSUE, TO 3105 02:06:47,483 --> 02:06:49,018 FREEZE CELLS, BANK, TRANSPORT TO 3106 02:06:49,018 --> 02:06:53,389 TREATMENT SITES AFTER PUBLIC 3107 02:06:53,389 --> 02:06:55,792 HEALTH ENERGY INVOLVING 3108 02:06:55,792 --> 02:06:56,059 RADIATION. 3109 02:06:56,059 --> 02:07:01,364 ONE MORE EXAMPLE, OUT OF 3110 02:07:01,364 --> 02:07:03,399 UNIVERSITY OF PITTSBURGH, HE HAS 3111 02:07:03,399 --> 02:07:05,301 PERFUSABLE BIOREACTOR, HAS BEEN 3112 02:07:05,301 --> 02:07:08,238 ABLE TO TAKE A FULL THICKNESS 3113 02:07:08,238 --> 02:07:12,008 HUMAN SKIN FLAP FROM PLASTIC 3114 02:07:12,008 --> 02:07:13,676 SURGERY DISCARD, RESOURCE -- 3115 02:07:13,676 --> 02:07:14,877 REPURPOSED MATERIAL, HE'S ABLE 3116 02:07:14,877 --> 02:07:16,412 TO KEEP THE SKIN FLAP VIABLE FOR 3117 02:07:16,412 --> 02:07:18,147 UP TO A MONTH. 3118 02:07:18,147 --> 02:07:20,149 THIS IS REALLY INTERESTING 3119 02:07:20,149 --> 02:07:21,284 BECAUSE BIOREACTOR IS PORTABLE, 3120 02:07:21,284 --> 02:07:23,987 SMALL ENOUGH TO FIT INTO AN 3121 02:07:23,987 --> 02:07:25,488 IRRADIATOR, ABLE TO SEE IN REAL 3122 02:07:25,488 --> 02:07:27,490 TIME THE EFFECTS OF RADIATION ON 3123 02:07:27,490 --> 02:07:28,124 THE SKIN. 3124 02:07:28,124 --> 02:07:29,259 THAT'S REALLY IMPORTANT BECAUSE 3125 02:07:29,259 --> 02:07:31,227 THE SKIN IS THE FIRST ORGAN TO 3126 02:07:31,227 --> 02:07:34,030 FEEL THE IMPACT OF IONIZING 3127 02:07:34,030 --> 02:07:36,132 RADIATION, AND THERE ARE LIMITED 3128 02:07:36,132 --> 02:07:37,667 COUNTER-MEASURES AVAILABLE TO 3129 02:07:37,667 --> 02:07:38,868 TREAT SKIN RADIATION INJURY. 3130 02:07:38,868 --> 02:07:42,372 AFTER THAT HE'S ABLE TO EXTRACT 3131 02:07:42,372 --> 02:07:43,039 VARIOUS CELLS, CONDUCT 3132 02:07:43,039 --> 02:07:46,943 ASSESSMENTS TO GET AT THE 3133 02:07:46,943 --> 02:07:47,210 MECHANISM. 3134 02:07:47,210 --> 02:07:49,479 AND SO WE'RE VERY INTERESTED IN 3135 02:07:49,479 --> 02:07:52,348 THE U01 MECHANISM, WE HAVE 3136 02:07:52,348 --> 02:07:55,518 EXPERIENCE WITH U01 GRANTS. 3137 02:07:55,518 --> 02:07:57,854 THIS GRAPH SHOWS SINCE 2012 THE 3138 02:07:57,854 --> 02:08:00,556 MANY SPECIFIC TOPIC AREAS WE'VE 3139 02:08:00,556 --> 02:08:04,527 COVERED, FROM VASCULAR INJURY TO 3140 02:08:04,527 --> 02:08:06,829 CELLULAR THERAPIES, CAME IN WITH 3141 02:08:06,829 --> 02:08:08,464 THIS COHORT WITH CELLULAR 3142 02:08:08,464 --> 02:08:09,332 THERAPIES. 3143 02:08:09,332 --> 02:08:10,867 WE HAVE A MICROBIOME COHORT 3144 02:08:10,867 --> 02:08:13,803 FINISHING THE FIRST YEAR, MAKING 3145 02:08:13,803 --> 02:08:15,138 GREAT STRIDES IN UNDERSTANDING 3146 02:08:15,138 --> 02:08:16,906 EFFECTS OF RADIATION ON THE 3147 02:08:16,906 --> 02:08:18,308 MICROBIOME AND HOW THE 3148 02:08:18,308 --> 02:08:27,483 MICROBIOME COULD BE HARNESSED TO 3149 02:08:27,483 --> 02:08:29,352 REJUVENATE INJURED TISSUE. 3150 02:08:29,352 --> 02:08:32,021 WE HAVE ANNUAL MEETINGS, INVITE 3151 02:08:32,021 --> 02:08:33,423 GOVERNMENT PARTNERS, ENCOURAGE 3152 02:08:33,423 --> 02:08:34,057 COLLABORATION ACROSS THE 3153 02:08:34,057 --> 02:08:36,693 CONSORTIUM TO LEVERAGE THE 3154 02:08:36,693 --> 02:08:37,460 PROJECT. 3155 02:08:37,460 --> 02:08:39,662 AND THEN FINALLY MY LAST SLIDE, 3156 02:08:39,662 --> 02:08:42,932 THIS INITIATIVE HAS THE GOALS OF 3157 02:08:42,932 --> 02:08:43,599 DEVELOPING THESE ALTERNATIVE 3158 02:08:43,599 --> 02:08:46,235 HUMAN MODELS TO SIMULATE 3159 02:08:46,235 --> 02:08:48,304 RADIATION INJURIES, TO DEVELOP 3160 02:08:48,304 --> 02:08:49,305 MEDICAL COUNTERMEASURES, TEST 3161 02:08:49,305 --> 02:08:50,807 EFFICACY, WE'RE HOPING THESE 3162 02:08:50,807 --> 02:08:56,646 WILL ADDRESS THE GAPS THAT ARE 3163 02:08:56,646 --> 02:08:57,513 INNATELY SEEN BETWEEN 3164 02:08:57,513 --> 02:09:00,249 PRE-CLINICAL AND HUMAN STUDIES 3165 02:09:00,249 --> 02:09:01,284 AND UNDERSTAND ORGAN-SPECIFIC 3166 02:09:01,284 --> 02:09:02,752 INJURIES AND FINALLY REDUCE 3167 02:09:02,752 --> 02:09:04,387 ANIMAL USE, THESE ARE FIVE-YEAR 3168 02:09:04,387 --> 02:09:05,922 AWARDS, PLENTY OF TIME TO MAKE A 3169 02:09:05,922 --> 02:09:07,690 LOT OF PROGRESS. 3170 02:09:07,690 --> 02:09:10,960 AND WE'RE HOPING TO AWARD ABOUT 3171 02:09:10,960 --> 02:09:11,961 SEVEN TO EIGHT APPLICATIONS. 3172 02:09:11,961 --> 02:09:12,929 AND THAT'S IT. 3173 02:09:12,929 --> 02:09:23,106 I'M HAPPY TO TAKE QUESTIONS. 3174 02:09:23,106 --> 02:09:25,074 >> ANY QUESTIONS OR DISCUSSION? 3175 02:09:25,074 --> 02:09:26,943 FOR NEW COUNCIL MEMBERS, OVER 3176 02:09:26,943 --> 02:09:28,344 THE NEXT FEW YEARS YOU'LL HEAR 3177 02:09:28,344 --> 02:09:32,215 QUITE A FEW OF THESE RADIATION 3178 02:09:32,215 --> 02:09:33,015 COUNTERMEASURE PROPOSALS BECAUSE 3179 02:09:33,015 --> 02:09:36,219 WE HAVE A LOT OF FLEXIBILITY 3180 02:09:36,219 --> 02:09:40,356 WITH THE FUNDING THAT GOES INTO 3181 02:09:40,356 --> 02:09:43,459 THIS PROGRAM. 3182 02:09:43,459 --> 02:09:44,427 AND WE HAVE HISTORICALLY 3183 02:09:44,427 --> 02:09:47,263 DEVELOPED QUITE A FEW LONGER AND 3184 02:09:47,263 --> 02:09:49,232 SHORT-TERM INITIATIVES TO TAKE 3185 02:09:49,232 --> 02:09:51,234 ADVANTAGE OF THAT FLEXIBILITY. 3186 02:09:51,234 --> 02:09:57,673 THIS IS A PROGRAM THAT HHS ASKED 3187 02:09:57,673 --> 02:10:00,109 NIAID TO BE RESPONSIBLE FOR, IN 3188 02:10:00,109 --> 02:10:03,679 CASE YOU'RE WONDERING WHY IS 3189 02:10:03,679 --> 02:10:06,015 THIS RADIATION COUNTERMEASURES 3190 02:10:06,015 --> 02:10:08,217 PROGRAM HOUSED IN DAIDS. 3191 02:10:08,217 --> 02:10:13,556 IT'S BECAUSE AT THE TIME IN 2005 3192 02:10:13,556 --> 02:10:15,324 WHEN THEY STARTED, NCI WAS NOT 3193 02:10:15,324 --> 02:10:18,828 PARTICULARLY INTERESTED IN THIS 3194 02:10:18,828 --> 02:10:22,331 AND WE HAD EXPERIENCE WITH 3195 02:10:22,331 --> 02:10:25,501 CONGRESS AND HHS HAVING A LOT OF 3196 02:10:25,501 --> 02:10:26,302 CONFIDENCE IN OUR INSTITUTE'S 3197 02:10:26,302 --> 02:10:29,639 ABILITY TO TAKE ON THINGS LIKE 3198 02:10:29,639 --> 02:10:35,211 THIS BASED ON -- AT THAT POINT 3199 02:10:35,211 --> 02:10:36,679 IT WAS ANTHRAX PRECEDED 3200 02:10:36,679 --> 02:10:37,647 BIODEFENSE FUNDING. 3201 02:10:37,647 --> 02:10:39,048 IT LANDED HERE AND OUR STAFF 3202 02:10:39,048 --> 02:10:40,483 HAVE DONE A GREAT JOB 3203 02:10:40,483 --> 02:10:41,684 SUCCESSFULLY MANAGING THIS 3204 02:10:41,684 --> 02:10:42,018 PROGRAM. 3205 02:10:42,018 --> 02:10:44,320 YOU'LL HEAR MORE ABOUT THESE 3206 02:10:44,320 --> 02:10:45,521 INITIATIVES. 3207 02:10:45,521 --> 02:10:48,257 AND THE NEXT ONE IS GOING TO BE 3208 02:10:48,257 --> 02:10:50,526 PRESENTED BY TOM WINTERS, WHO IS 3209 02:10:50,526 --> 02:10:52,728 ON THE SCREEN RIGHT THERE. 3210 02:10:52,728 --> 02:10:53,763 GO AHEAD, TOM. 3211 02:10:53,763 --> 02:10:54,464 >> THANK YOU. 3212 02:10:54,464 --> 02:10:59,502 LET ME SHARE MY SCREEN. 3213 02:10:59,502 --> 02:11:04,540 AND HOPEFULLY I'M GOING TO THE 3214 02:11:04,540 --> 02:11:13,883 CORRECT ONE. 3215 02:11:13,883 --> 02:11:17,487 CAN YOU SEE MY SCREEN OKAY? 3216 02:11:17,487 --> 02:11:19,355 >> WE CAN SEE YOUR SCREEN BUT 3217 02:11:19,355 --> 02:11:22,425 WE'RE SEEING ME, NOT YOU. 3218 02:11:22,425 --> 02:11:23,626 >> OKAY. 3219 02:11:23,626 --> 02:11:26,462 >> I'D RATHER SEE YOU. 3220 02:11:26,462 --> 02:11:27,997 >> I WOULD MUCH RATHER HAVE ME 3221 02:11:27,997 --> 02:11:28,598 UP THERE. 3222 02:11:28,598 --> 02:11:30,833 NOT SURE WHY IT'S SHOWING YOU, 3223 02:11:30,833 --> 02:11:31,000 DAN. 3224 02:11:31,000 --> 02:11:32,368 I'M SORRY. 3225 02:11:32,368 --> 02:11:34,036 LET ME TRY RESTARTING THIS. 3226 02:11:34,036 --> 02:11:36,539 MY APOLOGIES. 3227 02:11:36,539 --> 02:11:40,142 3228 02:11:40,142 --> 02:11:42,879 >> MAY NOT BE ANYTHING YOU CAN 3229 02:11:42,879 --> 02:11:45,381 CONTROL, SO I'LL LIP SYNC WHILE 3230 02:11:45,381 --> 02:11:46,382 YOU TALK. 3231 02:11:46,382 --> 02:11:48,150 [LAUGHTER] 3232 02:11:48,150 --> 02:11:49,085 >> OKAY. 3233 02:11:49,085 --> 02:11:51,420 WELL, LET ME GET THE SHARE UP SO 3234 02:11:51,420 --> 02:11:54,924 YOU CAN AT LEAST SEE MY SLIDES. 3235 02:11:54,924 --> 02:11:57,326 I'M HOPEFUL THAT THIS WILL WORK 3236 02:11:57,326 --> 02:11:57,960 FOR YOU. 3237 02:11:57,960 --> 02:11:58,394 OKAY. 3238 02:11:58,394 --> 02:12:02,465 CAN YOU SEE MY SLIDES OKAY? 3239 02:12:02,465 --> 02:12:04,967 3240 02:12:04,967 --> 02:12:06,969 >> YEAH, WE SEE YOUR SLIDES. 3241 02:12:06,969 --> 02:12:07,503 >> OKAY, GREAT. 3242 02:12:07,503 --> 02:12:08,137 ALL RIGHT. 3243 02:12:08,137 --> 02:12:13,209 SO I'M GOING TO BE PRESENTING A 3244 02:12:13,209 --> 02:12:14,944 2026 INITIATIVE CONCEPT FOR A 3245 02:12:14,944 --> 02:12:17,680 CONTRACT MECHANISM, FOR THE 3246 02:12:17,680 --> 02:12:24,253 DEVELOPMENT OF RADIATION/NUCLEAR 3247 02:12:24,253 --> 02:12:26,556 COUNTERMEASURES OR FOR 3248 02:12:26,556 --> 02:12:27,557 BIODOSEMETRY DEVICES. 3249 02:12:27,557 --> 02:12:30,159 CARMEN SHOWED YOU THIS 3250 02:12:30,159 --> 02:12:32,795 DEVELOPMENT PROCESS, RADIATION 3251 02:12:32,795 --> 02:12:33,763 NUCLEAR COUNTERMEASURES PROGRAM 3252 02:12:33,763 --> 02:12:34,096 USES. 3253 02:12:34,096 --> 02:12:35,865 FOR BASIC RESEARCH END OF THE 3254 02:12:35,865 --> 02:12:37,400 SCALE, WHICH SHE WAS TALKING 3255 02:12:37,400 --> 02:12:39,368 ABOUT, WE TYPICALLY USE GRANTS 3256 02:12:39,368 --> 02:12:43,940 AND COOPERATIVE AGREEMENTS, WHAT 3257 02:12:43,940 --> 02:12:44,607 THE U01 MECHANISMS AND 3258 02:12:44,607 --> 02:12:45,374 INTERAGENCY AGREEMENTS WITH 3259 02:12:45,374 --> 02:12:47,343 OTHER GOVERNMENT PARTNERS. 3260 02:12:47,343 --> 02:12:49,111 WE ALSO HAVE ADVANCED 3261 02:12:49,111 --> 02:12:52,148 DEVELOPMENT THAT WE DO PIVOTAL 3262 02:12:52,148 --> 02:12:54,884 STUDIES AND HELP PEOPLE MOVE 3263 02:12:54,884 --> 02:12:57,620 TOWARDS IND SUBMISSIONS TO THE 3264 02:12:57,620 --> 02:12:59,021 FDA, PHASE 1 SAFETY STUDIES, BUT 3265 02:12:59,021 --> 02:13:01,791 WHAT I'M GOING TO TALK ABOUT 3266 02:13:01,791 --> 02:13:02,992 TODAY IS EARLY PRE-CLINICAL 3267 02:13:02,992 --> 02:13:04,393 DEVELOPMENT WORK, TALKING ABOUT 3268 02:13:04,393 --> 02:13:07,463 DOING THINGS LIKE LEAD 3269 02:13:07,463 --> 02:13:09,131 OPTIMIZATION, LARGE ANIMAL 3270 02:13:09,131 --> 02:13:11,534 EFFICACY STUDIES, SAFETY AND 3271 02:13:11,534 --> 02:13:11,901 TOXICOLOGY. 3272 02:13:11,901 --> 02:13:14,704 THIS IN OUR PROGRAM USES THE 3273 02:13:14,704 --> 02:13:17,340 BROAD AGENCY ANNOUNCEMENT 3274 02:13:17,340 --> 02:13:19,875 CONTRACT MECHANISM, WE ISSUE 3275 02:13:19,875 --> 02:13:21,811 SOLICITATIONS ABOUT ONE TO TWO 3276 02:13:21,811 --> 02:13:22,812 YEARS, THREE-YEAR AWARDS, AND 3277 02:13:22,812 --> 02:13:25,214 ONE OF THE THINGS THAT'S 3278 02:13:25,214 --> 02:13:29,919 INSTRUMENTAL ABOUT THIS, ALLOWS 3279 02:13:29,919 --> 02:13:33,089 AUTHORS TO PROPOSED STATEMENT OF 3280 02:13:33,089 --> 02:13:35,524 WORK, TAILORED TO THE PRODUCT 3281 02:13:35,524 --> 02:13:39,462 THEY INTEND TO SUBMIT PROPOSALS 3282 02:13:39,462 --> 02:13:40,563 FOR AND ALLOWS CONTRACT OFFICERS 3283 02:13:40,563 --> 02:13:41,764 REPRESENTATIVE TO WORK WITH THEM 3284 02:13:41,764 --> 02:13:43,499 AND HELP THEM STAY ON THE 3285 02:13:43,499 --> 02:13:47,536 CRITICAL PATH TO LICENSURE WITH 3286 02:13:47,536 --> 02:13:49,939 THE FDA. 3287 02:13:49,939 --> 02:13:52,241 CURRENTLY FDA APPROVED SIX 3288 02:13:52,241 --> 02:13:53,442 HEMATOPOIETIC ACUTE RADIATION 3289 02:13:53,442 --> 02:13:54,844 SYNDROME COUNTER MEASURES, FIRST 3290 02:13:54,844 --> 02:13:57,413 TWO APPROVED IN 2015 WITH GREAT 3291 02:13:57,413 --> 02:14:04,854 DEAL OF SUPPORT FROM RNCP AND 3292 02:14:04,854 --> 02:14:08,824 NIAID, IN 2018 WITH OTHER 3293 02:14:08,824 --> 02:14:12,094 SUPPORT, LUKIN WAS APPROVED BY 3294 02:14:12,094 --> 02:14:13,295 FDA. 3295 02:14:13,295 --> 02:14:17,900 IN 2021 WITH RNCP AND NIAID 3296 02:14:17,900 --> 02:14:25,675 SUPPORT END PLATE WAS APPROVED, 3297 02:14:25,675 --> 02:14:29,712 IN 2022 AND 2023 THESE 3298 02:14:29,712 --> 02:14:31,881 APPROVALS, THESE DRUGS LIKE LAST 3299 02:14:31,881 --> 02:14:33,983 STIMULATE BONE MARROW TO 3300 02:14:33,983 --> 02:14:35,284 INCREASE NEUTROPHILS. 3301 02:14:35,284 --> 02:14:39,655 THESE ARE DRUGS THAT HELP WITH 3302 02:14:39,655 --> 02:14:41,023 REGENERATION OF THE 3303 02:14:41,023 --> 02:14:42,491 HEMATOPOIETIC SYSTEM, BUT THERE 3304 02:14:42,491 --> 02:14:45,995 IS A NEED FOR DRUGS TO TREAT 3305 02:14:45,995 --> 02:14:48,931 OTHER ORGAN INJURIES, FOLLOWING 3306 02:14:48,931 --> 02:14:50,032 RADIATION EXPOSURE, NO SUCH 3307 02:14:50,032 --> 02:14:51,033 DRUGS CURRENTLY EXIST. 3308 02:14:51,033 --> 02:14:53,202 WE NEED TO SUPPORT APPROVAL OF 3309 02:14:53,202 --> 02:14:57,473 PRODUCTS TO TREAT OTHER 3310 02:14:57,473 --> 02:14:58,240 RADIATION-INDUCED ORGAN 3311 02:14:58,240 --> 02:14:58,674 INJURIES. 3312 02:14:58,674 --> 02:15:00,009 THE HISTORY OF THIS PROGRAM 3313 02:15:00,009 --> 02:15:04,413 BETWEEN 2020 AND THE PRESENT IS 3314 02:15:04,413 --> 02:15:07,550 30 CONTRACTS HAVE BEEN AWARDED, 3315 02:15:07,550 --> 02:15:10,419 THROUGH 11 SOLICITATIONS, THESE 3316 02:15:10,419 --> 02:15:12,021 CONTRACTS HAVE STUDIED AGENTS TO 3317 02:15:12,021 --> 02:15:14,090 TREAT INJURY IN THE GI TRACT AND 3318 02:15:14,090 --> 02:15:24,600 VARIOUS ORGANS AS WELL AS LOOK 3319 02:15:35,878 --> 02:15:37,046 AT RADIONUCLIDE DECORPORATION. 3320 02:15:37,046 --> 02:15:39,648 WITH FOUR PRODUCT TRANSITIONS TO 3321 02:15:39,648 --> 02:15:40,983 BARDA. 3322 02:15:40,983 --> 02:15:42,952 WE'VE AWARDED TWO ADDITIONAL 3323 02:15:42,952 --> 02:15:43,152 BAAs. 3324 02:15:43,152 --> 02:15:45,121 JUST AS AN EXAMPLE OF SOME OF 3325 02:15:45,121 --> 02:15:46,856 THESE PRODUCTS THAT HAVE BEEN 3326 02:15:46,856 --> 02:15:50,926 LOOKED AT THROUGH THESE TYPES OF 3327 02:15:50,926 --> 02:15:57,933 CONTRACTS, THIS IS A 3328 02:15:57,933 --> 02:15:59,935 BIODOSEMETRY PRODUCT DEVELOPED 3329 02:15:59,935 --> 02:16:02,738 BY PERMALOGIC LOOKING FOR RISK 3330 02:16:02,738 --> 02:16:04,406 OF NEUTROPENIA IN HUMANS 3331 02:16:04,406 --> 02:16:07,109 FOLLOWING EXPOSURE THAT COULD 3332 02:16:07,109 --> 02:16:08,177 INDICATE NEED FOR INTERVENTION. 3333 02:16:08,177 --> 02:16:14,950 THIS IS A PRODUCT BEING 3334 02:16:14,950 --> 02:16:18,521 DEVELOPED WHICH IMPROVES WOUND 3335 02:16:18,521 --> 02:16:20,589 HEALING FOLLOWING RADIATION -- 3336 02:16:20,589 --> 02:16:22,792 CUTANEOUS RADIATION INJURY, THIS 3337 02:16:22,792 --> 02:16:26,495 IS A MODEL, WOUNDS FORMED ON THE 3338 02:16:26,495 --> 02:16:28,898 SKIN OF PIG USING 45 GRAY DOSE 3339 02:16:28,898 --> 02:16:30,966 OF RADIATION, AND THIS AGENT 3340 02:16:30,966 --> 02:16:32,935 SHOWN TO SPEED WOUND CLOSURE AND 3341 02:16:32,935 --> 02:16:36,772 AS A RESULT OF THESE STUDIES 3342 02:16:36,772 --> 02:16:39,375 PRIMARY ENDPOINT HAS BEEN 3343 02:16:39,375 --> 02:16:42,711 ESTABLISHED FOR PIVOTAL STUDIES 3344 02:16:42,711 --> 02:16:44,880 OF WOUND CLOSURE. 3345 02:16:44,880 --> 02:16:46,048 THIS IS INNOVATIVE FOR TREATING 3346 02:16:46,048 --> 02:16:50,619 GI INJURIES FOLLOWING EXPOSURE 3347 02:16:50,619 --> 02:16:53,088 TO RADIATION, CYTOKINES TO THE 3348 02:16:53,088 --> 02:17:02,865 GI TRACT, A PROBIOTIC PRODUCT 3349 02:17:02,865 --> 02:17:05,267 WHICH LACTOBACILLUS REUTERI, AND 3350 02:17:05,267 --> 02:17:08,771 UPON DELIVERY THE BACTERIA 3351 02:17:08,771 --> 02:17:18,948 EXPOSED, THAT INDUCE EXPRESSION 3352 02:17:18,948 --> 02:17:26,956 OF ENDOGENOUS PHAGES THAT LYSE 3353 02:17:26,956 --> 02:17:35,698 THE BACTERIA, BEING DEVELOPED BY 3354 02:17:35,698 --> 02:17:36,699 CHROMOLOGIC. 3355 02:17:36,699 --> 02:17:40,603 PROPOSED BAA TO PROMOTE 3356 02:17:40,603 --> 02:17:42,938 ACCELERATION OF PRE-CLINICAL 3357 02:17:42,938 --> 02:17:45,207 MCMS OR ASSAYS, SUPPORTS 3358 02:17:45,207 --> 02:17:46,642 EFFICACY STUDIES OF LARGE 3359 02:17:46,642 --> 02:17:53,949 ANIMALS AND SUPPORTS IND 3360 02:17:53,949 --> 02:17:54,884 SUBMISSIONS AND INVESTIGATIONAL 3361 02:17:54,884 --> 02:17:57,786 USE ONLY SUBMISSIONS FOR 3362 02:17:57,786 --> 02:17:58,187 LICENSURE. 3363 02:17:58,187 --> 02:17:58,888 BIOMECHANISM ALLOWS AUTHORS TO 3364 02:17:58,888 --> 02:18:01,290 PROPOSE THEIR OWN STATEMENT OF 3365 02:18:01,290 --> 02:18:02,725 WORK APPROPRIATE TO THE PRODUCT 3366 02:18:02,725 --> 02:18:06,996 THEY ARE PROPOSING TO WORK WITH 3367 02:18:06,996 --> 02:18:11,100 WE EXPECT 8 TO 10 PROPOSAL, 3368 02:18:11,100 --> 02:18:16,939 INTEND TO FUND 2 TO 3, THESE ARE 3369 02:18:16,939 --> 02:18:18,240 3-YEAR CONTRACTS. 3370 02:18:18,240 --> 02:18:20,876 IF ANYONE HAS SLIDES ALL BE 3371 02:18:20,876 --> 02:18:22,411 HAPPY TO ANSWER THEM. 3372 02:18:22,411 --> 02:18:24,079 IF THERE'S NO QUESTIONS I'LL 3373 02:18:24,079 --> 02:18:25,381 STOP SHARING AND TURN THE FLOOR 3374 02:18:25,381 --> 02:18:29,885 BACK OVER TO YOU. 3375 02:18:29,885 --> 02:18:32,354 >> OKAY, SEEMS LIKE THERE'S NO 3376 02:18:32,354 --> 02:18:34,256 DISCUSSION ON THAT. 3377 02:18:34,256 --> 02:18:36,091 JOE, YOU'RE UP NOW. 3378 02:18:36,091 --> 02:18:44,667 THANKS, TOM. 3379 02:18:44,667 --> 02:18:46,936 >> HERE WE GO. 3380 02:18:46,936 --> 02:18:49,905 GOOD AFTERNOON, I'M JOE BREEN, 3381 02:18:49,905 --> 02:18:53,075 SECTION CHIEF IN BASIC 3382 02:18:53,075 --> 02:18:53,842 IMMUNOLOGY BRANCH, WOLFGANG'S 3383 02:18:53,842 --> 02:18:57,246 PARTNER IN CRIME. 3384 02:18:57,246 --> 02:18:58,914 HE'S INNATE IMMUNE, I'M THE 3385 02:18:58,914 --> 02:18:59,114 OTHER. 3386 02:18:59,114 --> 02:19:01,517 I'M GOING TO TELL BUT AN 3387 02:19:01,517 --> 02:19:04,920 INITIATIVE CONCEPT, RENEWAL, 3388 02:19:04,920 --> 02:19:06,255 IMMUNE EPITOPE DATABASE AND 3389 02:19:06,255 --> 02:19:10,392 ANALYSIS RESOURCE, IT'S BEEN IN 3390 02:19:10,392 --> 02:19:12,494 EXISTENCE FOR SOME TIME. 3391 02:19:12,494 --> 02:19:15,664 SO, THIS SLIDE SHOWS THE 3392 02:19:15,664 --> 02:19:17,232 ENTRYWAY INTO THIS ANALYSIS 3393 02:19:17,232 --> 02:19:18,968 RESOURCE AND DATABASE. 3394 02:19:18,968 --> 02:19:21,503 THE OBJECTIVE IS TO PROVIDE 3395 02:19:21,503 --> 02:19:23,572 UNIQUE PUBLIC REPOSITORY OF 3396 02:19:23,572 --> 02:19:27,176 IMMUNE EPITOPE DATA AS WELL AS 3397 02:19:27,176 --> 02:19:29,812 ANALYSIS TOOLS TO SUPPORT 3398 02:19:29,812 --> 02:19:32,648 ACCELERATED OF THERAPEUTICS, 3399 02:19:32,648 --> 02:19:35,451 DIAGNOSTICS, VACCINES FOR 3400 02:19:35,451 --> 02:19:37,886 INFECTIOUS, ALLERGIC, IMMUNE 3401 02:19:37,886 --> 02:19:38,520 MEDIATED DISEASES COVERING ALL 3402 02:19:38,520 --> 02:19:39,989 OF NIAID WITH THE EXCEPTION OF 3403 02:19:39,989 --> 02:19:42,691 HIV BECAUSE THERE'S A COMPARABLE 3404 02:19:42,691 --> 02:19:44,827 DATABASE FUNDED SEPARATELY FOR 3405 02:19:44,827 --> 02:19:45,260 THAT PURPOSE. 3406 02:19:45,260 --> 02:19:50,165 AND IT REALLY IS A UNIQUE PUBLIC 3407 02:19:50,165 --> 02:19:50,499 DATABASE. 3408 02:19:50,499 --> 02:19:52,568 TO DATE THERE'S NOTHING LIKE IT 3409 02:19:52,568 --> 02:19:54,636 AVAILABLE TO THE PUBLIC. 3410 02:19:54,636 --> 02:19:55,304 THERE ARE COMMERCIAL VENTURES 3411 02:19:55,304 --> 02:20:00,342 AND IN FACT THE WHOLE DATABASE 3412 02:20:00,342 --> 02:20:02,211 HAS BEEN DOWNLOADED AND LICENSED 3413 02:20:02,211 --> 02:20:03,278 BY COMMERCIAL PARTNERS BUT WE 3414 02:20:03,278 --> 02:20:07,750 DON'T KNOW WHAT THEY DO WITH 3415 02:20:07,750 --> 02:20:08,350 THAT DATA. 3416 02:20:08,350 --> 02:20:11,086 ON THE RIGHT IS A SNAPSHOT HOW 3417 02:20:11,086 --> 02:20:12,721 FOLKS GET ACCESS TO IMMUNE 3418 02:20:12,721 --> 02:20:15,657 EPITOPES IN THE IMMUNE EPITOPE 3419 02:20:15,657 --> 02:20:18,827 DATABASE THROUGH A NUMBER OF 3420 02:20:18,827 --> 02:20:20,095 MEANS THAT ARE PRE-FILTERED OR 3421 02:20:20,095 --> 02:20:21,797 OPEN TEXT. 3422 02:20:21,797 --> 02:20:23,532 A LITTLE BIT OF THE NUMBERS OF 3423 02:20:23,532 --> 02:20:25,167 WHAT'S AVAILABLE IN THE 3424 02:20:25,167 --> 02:20:26,068 DATABASE, I'LL GO THROUGH THAT 3425 02:20:26,068 --> 02:20:28,237 IN THE NEXT SLIDE. 3426 02:20:28,237 --> 02:20:29,204 SO THE WEBSITE THAT REPRESENTS 3427 02:20:29,204 --> 02:20:31,974 THE WAY TO GET INTO THE DATABASE 3428 02:20:31,974 --> 02:20:34,810 PROPER HAS BEEN PUBLICLY 3429 02:20:34,810 --> 02:20:38,113 AVAILABLE SINCE 2005. 3430 02:20:38,113 --> 02:20:41,483 INITIALLY THIS CONTRACT WAS 3431 02:20:41,483 --> 02:20:43,252 ANNOTATING EPITOPES THAT WERE 3432 02:20:43,252 --> 02:20:46,855 GENERATED THROUGH B AND T CELL 3433 02:20:46,855 --> 02:20:47,956 EPITOPE DISCOVERY PROGRAMS BUT 3434 02:20:47,956 --> 02:20:51,026 THAT DATA -- AND THAT CONTINUES 3435 02:20:51,026 --> 02:20:52,661 TODAY BUT THAT REPRESENTS ABOUT 3436 02:20:52,661 --> 02:20:54,296 A QUARTER OF WHAT'S AVAILABLE IN 3437 02:20:54,296 --> 02:20:55,397 THE IDB. 3438 02:20:55,397 --> 02:20:57,733 MOST IS GENERATED BY CURATING 3439 02:20:57,733 --> 02:21:04,173 THE LITERATURE, SO THEY HAVE 3440 02:21:04,173 --> 02:21:05,908 CURATED 25 HOW REFERENCES, 3441 02:21:05,908 --> 02:21:10,045 PubMed CITATIONS THAT 3442 02:21:10,045 --> 02:21:10,512 CONTAIN EPITOPE DATA, 3443 02:21:10,512 --> 02:21:11,046 2.2 MILLION EPITOPES. 3444 02:21:11,046 --> 02:21:13,682 THE STRENGTH OF THAT, THOSE ARE 3445 02:21:13,682 --> 02:21:17,619 AVAILABLE TO COMPARE ACROSS MANY 3446 02:21:17,619 --> 02:21:19,455 DIFFERENT SPECIES, DATA TYPES, 3447 02:21:19,455 --> 02:21:20,789 ET CETERA. 3448 02:21:20,789 --> 02:21:23,192 AND FOR BOTH ANTIBODIES AND T 3449 02:21:23,192 --> 02:21:24,159 CELL EPITOPES. 3450 02:21:24,159 --> 02:21:26,028 SONG THAT HAS DEVELOPED OVER THE 3451 02:21:26,028 --> 02:21:28,530 LAST FIVE YEARS OF THE CONTRACT 3452 02:21:28,530 --> 02:21:32,401 IS CONNECTING EPITOPE DATA IN A 3453 02:21:32,401 --> 02:21:35,337 PAPER WITH B AND T-CELL RECEPTOR 3454 02:21:35,337 --> 02:21:36,772 REPERTOIRE DATA, INCREASINGLY 3455 02:21:36,772 --> 02:21:37,039 REPORTED. 3456 02:21:37,039 --> 02:21:39,408 WE DON'T STORE THAT DATA IN IDB 3457 02:21:39,408 --> 02:21:41,910 BUT DO REFERENCE IT SO YOU CAN 3458 02:21:41,910 --> 02:21:43,679 MAKE COMPARISONS. 3459 02:21:43,679 --> 02:21:46,648 IT REALLY CONNECTS TO OTHER NCBI 3460 02:21:46,648 --> 02:21:50,119 RESOURCES WHAT THAT DATA IS 3461 02:21:50,119 --> 02:21:50,652 COLLECTED. 3462 02:21:50,652 --> 02:21:53,989 AND THERE'S VERY BROAD IN TERMS 3463 02:21:53,989 --> 02:21:56,391 OF NUMBER OF ORGANISMS, MHC 3464 02:21:56,391 --> 02:21:58,961 ALLELES, AND THE GROUP 3465 02:21:58,961 --> 02:22:02,831 THEMSELVES HAVE PUBLISHED 130 3466 02:22:02,831 --> 02:22:03,932 PUBLICATIONS SINCE 2012, 3467 02:22:03,932 --> 02:22:05,901 PRIMARILY IN TOOL MAKING. 3468 02:22:05,901 --> 02:22:07,636 THIS IS REALLY A DATABASE WHICH 3469 02:22:07,636 --> 02:22:09,638 IS CURATION OF THE LITERATURE 3470 02:22:09,638 --> 02:22:11,907 AND THEN TOOLS WHICH ARE 3471 02:22:11,907 --> 02:22:14,009 GENERATED BY THE TEAM THAT HOLD 3472 02:22:14,009 --> 02:22:15,677 THE CONTRACT, OR IN FACT THEY 3473 02:22:15,677 --> 02:22:19,481 CAN TAKE IN TOOLS THAT ARE MADE 3474 02:22:19,481 --> 02:22:21,116 IN THE COMMUNITY, SO THAT MAKING 3475 02:22:21,116 --> 02:22:23,652 A SINGLE PLACE WHERE PEOPLE CAN 3476 02:22:23,652 --> 02:22:25,721 USE THOSE TOOLS WITH ALL OF THE 3477 02:22:25,721 --> 02:22:31,326 RICH DATA THAT'S IN THE IDB. 3478 02:22:31,326 --> 02:22:33,595 ANOTHER NEW DEVELOPMENT, 3479 02:22:33,595 --> 02:22:36,899 ACCOMPLISHMENT IS DEVELOPMENT OF 3480 02:22:36,899 --> 02:22:38,066 APPLICATION PROGRAMMING 3481 02:22:38,066 --> 02:22:40,502 INTERFACE, API, SO THAT THE 3482 02:22:40,502 --> 02:22:42,237 OTHER PROGRAMS AND NIAID THAT 3483 02:22:42,237 --> 02:22:43,772 CONTAIN VARIOUS DATA TYPES CAN 3484 02:22:43,772 --> 02:22:45,741 BASICALLY TALK TO EACH OTHER, 3485 02:22:45,741 --> 02:22:47,743 AND CAN BE ACCESSED TOGETHER, 3486 02:22:47,743 --> 02:22:51,680 INCREASE POWER OF EACH OF THEM 3487 02:22:51,680 --> 02:22:53,415 ACTUALLY, LIKE IMPORT, 3488 02:22:53,415 --> 02:22:58,487 BIOINFORMATICS RESOURCE CENTERS, 3489 02:22:58,487 --> 02:23:03,292 FUNDED FROM DMID AND THE IMMUNE 3490 02:23:03,292 --> 02:23:07,029 SPACE WHERE DATA CAN BE 3491 02:23:07,029 --> 02:23:09,097 VISUALIZED, INCREASING POWER OF 3492 02:23:09,097 --> 02:23:10,832 ANY SINGLE DATABASE, NIAID IS 3493 02:23:10,832 --> 02:23:15,103 GENERATING WHAT REQUIRES THIS 3494 02:23:15,103 --> 02:23:16,872 INTERFACE, API, AND NIH-WIDE 3495 02:23:16,872 --> 02:23:17,839 STRATEGY EVENTUALLY THAT'S HOW 3496 02:23:17,839 --> 02:23:19,374 THESE WILL BE CONNECTED. 3497 02:23:19,374 --> 02:23:24,079 AND THE LAST BULLET, SO THERE'S 3498 02:23:24,079 --> 02:23:27,149 THE DATABASE, THEN THE ANALYSIS 3499 02:23:27,149 --> 02:23:30,419 RESOURCE, TOOLS FOR ANTIBODY AND 3500 02:23:30,419 --> 02:23:32,621 T CELL EPITOPES, HOW TO GET 3501 02:23:32,621 --> 02:23:33,488 PEOPLE TO UTILIZE THIS, WE'VE 3502 02:23:33,488 --> 02:23:34,990 ALWAYS HAD AN ANNUAL WORKSHOP 3503 02:23:34,990 --> 02:23:36,858 FUNDED BY THE CONTRACT TO BRING 3504 02:23:36,858 --> 02:23:39,394 PEOPLE IN TO SHOW THEM HOW TO 3505 02:23:39,394 --> 02:23:42,030 USE THE TOOLS, AND TO REALLY 3506 02:23:42,030 --> 02:23:43,465 PROVIDE A USER WORKSHOP. 3507 02:23:43,465 --> 02:23:45,634 AND WE WERE SURPRISED AND 3508 02:23:45,634 --> 02:23:48,036 HAPPILY SO WITH THE PANDEMIC WE 3509 02:23:48,036 --> 02:23:52,541 COULDN'T DO THAT RESPONSIBLY SO 3510 02:23:52,541 --> 02:23:54,710 WE CONVERTED IT TO VIRTUAL AND 3511 02:23:54,710 --> 02:23:56,245 IT REALLY INCREASED -- INSTEAD 3512 02:23:56,245 --> 02:24:00,182 OF 50 PEOPLE IN A ROOM, NOW WE 3513 02:24:00,182 --> 02:24:04,019 HAVE 700 PEOPLE WORLDWIDE ACROSS 3514 02:24:04,019 --> 02:24:06,121 60 COUNTRIES, MANY LOW RESOURCE 3515 02:24:06,121 --> 02:24:06,421 COUNTRIES. 3516 02:24:06,421 --> 02:24:09,358 SO IT'S REALLY BEEN A VERY 3517 02:24:09,358 --> 02:24:09,725 STRONG OUTCOME. 3518 02:24:09,725 --> 02:24:10,926 I'M NOT CONVINCED WE SHOULDN'T 3519 02:24:10,926 --> 02:24:12,761 STILL BRING PEOPLE TOGETHER IN A 3520 02:24:12,761 --> 02:24:13,762 ROOM BECAUSE AS WE KNOW 3521 02:24:13,762 --> 02:24:15,964 DIFFERENT THINGS HAPPEN THERE. 3522 02:24:15,964 --> 02:24:21,770 BUT THE REACH HAS CERTAINLY BEEN 3523 02:24:21,770 --> 02:24:22,104 INCREASED. 3524 02:24:22,104 --> 02:24:25,507 SO, WHAT CAN DATA DO FOR THE 3525 02:24:25,507 --> 02:24:25,741 PUBLIC? 3526 02:24:25,741 --> 02:24:27,042 AND THE RESEARCH COMMUNITY? 3527 02:24:27,042 --> 02:24:28,677 THESE ARE THREE EXAMPLES. 3528 02:24:28,677 --> 02:24:30,212 I'M NOT GOING THROUGH IN DETAIL 3529 02:24:30,212 --> 02:24:33,048 BUT EVEN TODAY WE HEARD 3530 02:24:33,048 --> 02:24:35,350 DISCUSSIONS OF H1N1, HOW SIMILAR 3531 02:24:35,350 --> 02:24:38,620 IS THIS TO WHAT'S BEEN 3532 02:24:38,620 --> 02:24:39,855 CIRCULATING IN THE ANIMAL 3533 02:24:39,855 --> 02:24:40,822 COMMUNITY, HUMAN COMMUNITY, 3534 02:24:40,822 --> 02:24:46,628 COULD THERE BE UNIQUE EPITOPES 3535 02:24:46,628 --> 02:24:48,030 THAT ARE BETWEEN H 5 ON THE 3536 02:24:48,030 --> 02:24:50,932 ANTIBODY SIDE OR T CELL SIDE IN 3537 02:24:50,932 --> 02:24:54,336 FACT, AND WHAT SHOULD WE EXPECT 3538 02:24:54,336 --> 02:24:57,839 IN TERMS OF CROSS-PRESENTATION. 3539 02:24:57,839 --> 02:25:01,743 IEDB FOLKS DID A META-ANALYSIS, 3540 02:25:01,743 --> 02:25:05,914 THIS TIME AVIAN FLU SOME YEARS 3541 02:25:05,914 --> 02:25:07,716 AGO, THEY ARE DOING THIS NOW FOR 3542 02:25:07,716 --> 02:25:12,020 H 5 TO HELP US UNDERSTAND HOW 3543 02:25:12,020 --> 02:25:14,990 CLOSELY RELATED THE NEWER H 5s 3544 02:25:14,990 --> 02:25:16,358 ARE WITH WHAT'S CURRENTLY 3545 02:25:16,358 --> 02:25:17,959 CIRCULATING BASED ON WHAT'S 3546 02:25:17,959 --> 02:25:19,061 AVAILABLE IN THE DATABASE AND 3547 02:25:19,061 --> 02:25:22,664 SEQUENCES THAT THEY CAN GET 3548 02:25:22,664 --> 02:25:27,369 THEIR HANDS ON. 3549 02:25:27,369 --> 02:25:29,671 WHICH MANY ARE PUBLIC. 3550 02:25:29,671 --> 02:25:32,607 IDB TEAM HAS DONE WHICH THAT IDB 3551 02:25:32,607 --> 02:25:34,142 TO LOOK FOR UNIQUE T CELL 3552 02:25:34,142 --> 02:25:34,409 EPITOPES. 3553 02:25:34,409 --> 02:25:37,212 MOST RECENTLY FOR SARS AND 3554 02:25:37,212 --> 02:25:40,716 PANDEMIC EARLY ON THIS GROUP WAS 3555 02:25:40,716 --> 02:25:42,784 ABLE TO COMPUTATIONALLY 3556 02:25:42,784 --> 02:25:48,056 DETERMINE AREAS THAT MIGHT BE 3557 02:25:48,056 --> 02:25:49,124 UNIQUE TO SARS-COV-2, THOSE 3558 02:25:49,124 --> 02:25:50,992 AREAS, FOR EXAMPLE, FOR T CELL 3559 02:25:50,992 --> 02:25:55,897 EPITOPES WHICH MIGHT BE 3560 02:25:55,897 --> 02:25:57,466 CROSS-PRESENTED WITH SEASONAL 3561 02:25:57,466 --> 02:25:58,533 CORONAVIRUSES, AND INTERESTINGLY 3562 02:25:58,533 --> 02:26:00,435 THIS, THE T CELL MILIEU, SEEMED 3563 02:26:00,435 --> 02:26:03,271 TO BE MUCH MORE CONSTANTLY 3564 02:26:03,271 --> 02:26:04,806 SO-CALLED PAINTED WITH EPITOPES 3565 02:26:04,806 --> 02:26:07,242 THAN THE ANTIBODY SIDE WHERE WE 3566 02:26:07,242 --> 02:26:10,178 KNEW THERE WERE CHANGES WITH 3567 02:26:10,178 --> 02:26:10,612 VARIANTS. 3568 02:26:10,612 --> 02:26:12,047 SO LEADING US TO WHEN WE 3569 02:26:12,047 --> 02:26:14,683 UNDERSTOOD A LITTLE BIT MORE 3570 02:26:14,683 --> 02:26:16,351 ABOUT T CELL MEMORY, IMPORTANT 3571 02:26:16,351 --> 02:26:19,087 ISSUES WITH TRYING TO ADDRESS 3572 02:26:19,087 --> 02:26:20,422 WHOSE'S BEEN INFECTED, WHO HAS 3573 02:26:20,422 --> 02:26:20,589 NOT. 3574 02:26:20,589 --> 02:26:22,591 TURNS OUT THE T CELL MEMORY WAS 3575 02:26:22,591 --> 02:26:25,193 SUPER IMPORTANT IN HELPING TO 3576 02:26:25,193 --> 02:26:28,196 UNDERSTAND THAT BECAUSE OF THE 3577 02:26:28,196 --> 02:26:30,599 ISSUES WITH DURABLE ANTIBODIES 3578 02:26:30,599 --> 02:26:31,933 AND MEMORY IN FACT. 3579 02:26:31,933 --> 02:26:34,336 AND MY LAST SLIDE IS REALLY THE 3580 02:26:34,336 --> 02:26:38,039 SCOPE OF WHAT WE'RE PROPOSING 3581 02:26:38,039 --> 02:26:40,242 FOR THE RENEWAL REMAINS THE SAME 3582 02:26:40,242 --> 02:26:42,210 WITH CONTINUED EMPHASIS ON 3583 02:26:42,210 --> 02:26:42,944 INTEGRATION OF DATA TYPES 3584 02:26:42,944 --> 02:26:47,249 INCLUDING STRUCTURES PROPOSED 3585 02:26:47,249 --> 02:26:49,117 WITH HIGHER DEGREE OF CERTAINTY 3586 02:26:49,117 --> 02:26:59,628 USING ALPHA FOLD AND RECEPTOR 3587 02:27:01,997 --> 02:27:04,332 REPERTOIRE, A CONTRACT FOR FIVE 3588 02:27:04,332 --> 02:27:08,069 YEARS AND WE ANTICIPATE A SINGLE 3589 02:27:08,069 --> 02:27:08,270 AWARD. 3590 02:27:08,270 --> 02:27:10,906 BOTTOM SHOWS SOME REACH, EVEN 3591 02:27:10,906 --> 02:27:12,340 TODAY THERE ARE ABOUT 37,000 3592 02:27:12,340 --> 02:27:14,176 MONTHLY SITE VISITS TO THE 3593 02:27:14,176 --> 02:27:17,479 WEBSITE, ABOUT EQUALLY SPLIT 3594 02:27:17,479 --> 02:27:18,914 BETWEEN ANALYSIS RESOURCE AND 3595 02:27:18,914 --> 02:27:20,315 DATABASE, AND ACTUALLY KEEPS 3596 02:27:20,315 --> 02:27:21,349 GOING UP. 3597 02:27:21,349 --> 02:27:22,617 SO EVEN AFTER COVID OF COURSE 3598 02:27:22,617 --> 02:27:24,820 THERE WAS A HUGE BUMP BUT THE 3599 02:27:24,820 --> 02:27:26,555 USER BASE IS STILL CONTINUING TO 3600 02:27:26,555 --> 02:27:28,857 GROW SO WE HAVEN'T QUITE MET 3601 02:27:28,857 --> 02:27:31,927 SATURATION YET IN TERMS OF 3602 02:27:31,927 --> 02:27:33,328 NUMBER OF SCIENTISTS ACROSS THE 3603 02:27:33,328 --> 02:27:34,563 WORLD USING THE DATABASE. 3604 02:27:34,563 --> 02:27:36,198 AND I'LL STOP THERE AND BE HAPPY 3605 02:27:36,198 --> 02:27:37,032 TO TAKE ANY QUESTIONS. 3606 02:27:37,032 --> 02:27:45,574 THANK YOU. 3607 02:27:45,574 --> 02:27:51,079 3608 02:27:51,079 --> 02:27:51,713 >> OKAY. 3609 02:27:51,713 --> 02:27:59,287 IN THAT CASE, WE CAN REQUEST AN 3610 02:27:59,287 --> 02:28:00,489 EN BLOC RECOMMENDATION TO 3611 02:28:00,489 --> 02:28:03,658 PROCEED AND THEN I'LL ASK FOR A 3612 02:28:03,658 --> 02:28:03,892 SECOND. 3613 02:28:03,892 --> 02:28:06,828 >> SO MOVED. 3614 02:28:06,828 --> 02:28:07,496 >> GREAT. 3615 02:28:07,496 --> 02:28:07,829 OKAY. 3616 02:28:07,829 --> 02:28:13,201 THEN THAT WRAPS US UP, RIGHT 3617 02:28:13,201 --> 02:28:13,768 BEFORE 3:30. 3618 02:28:13,768 --> 02:28:17,606 >> IF I COULD ASK COUNCIL 3619 02:28:17,606 --> 02:28:18,573 MEMBERS INTO THE ELECTRONIC 3620 02:28:18,573 --> 02:28:20,442 COUNCIL BOOK FOR CONCEPT 3621 02:28:20,442 --> 02:28:25,347 CLEARANCES. 3622 02:28:25,347 --> 02:28:26,882 >> THEY HAVE TO DO THAT IN THE 3623 02:28:26,882 --> 02:28:27,115 ECB. 3624 02:28:27,115 --> 02:28:30,752 YOU NEED TO GO INTO THE 3625 02:28:30,752 --> 02:28:34,022 ELECTRONIC COUNCIL BOOK AND MAKE 3626 02:28:34,022 --> 02:28:35,156 YOUR APPROVALS EVIDENT THERE. 3627 02:28:35,156 --> 02:28:40,061 ONCE YOU DO THAT, WE ARE WRAPPED 3628 02:28:40,061 --> 02:28:42,130 UP AND WISH EVERYBODY SAFE 3629 02:28:42,130 --> 02:28:44,966 TRAVELS HOME AND THANK YOU FOR 3630 02:28:44,966 --> 02:28:55,143 PARTICIPATING TODAY. 3631 02:28:55,143 --> 02:28:57,879 [END OF PROGRAM] 3632 02:28:57,879 --> 02:29:03,919 3633 02:29:03,919 --> 02:29:13,962