1 00:00:05,920 --> 00:00:08,440 >>HELLO, WELCOME EVERYONE TO 2 00:00:08,440 --> 00:00:11,560 OUR LATEST LECTURE IN THE COVID 3 00:00:11,560 --> 00:00:13,520 INTEREST GROUP. 4 00:00:13,520 --> 00:00:16,360 IT IS REALLY A GREAT PLEASURE TO 5 00:00:16,360 --> 00:00:18,920 INTRODUCE OUR SPEAKER, DR. ALI 6 00:00:18,920 --> 00:00:20,680 ELLEBEDY, WHO IS A FACULTY IN 7 00:00:20,680 --> 00:00:23,200 THE DEPARTMENT OF PATHOLOGY AND 8 00:00:23,200 --> 00:00:26,160 IMMUNOLOGY AND CO-DIRECTOR FOR 9 00:00:26,160 --> 00:00:29,600 THE CENTER FOR VACCINES AND 10 00:00:29,600 --> 00:00:30,800 IMMUNITY AT THE WASHINGTON 11 00:00:30,800 --> 00:00:31,960 UNIVERSITY SCHOOL OF MEDICINE IN 12 00:00:31,960 --> 00:00:33,040 ST. LOUIS. 13 00:00:33,040 --> 00:00:34,560 STARTING WITH HIS GRADUATE WORK 14 00:00:34,560 --> 00:00:36,480 AT THE UNIVERSITY OF TENNESSEE 15 00:00:36,480 --> 00:00:39,720 AND POST DOCTORAL WORK AT EMRY, 16 00:00:39,720 --> 00:00:41,960 DR. ELLEBEDY HAS BEEN AT THE 17 00:00:41,960 --> 00:00:45,080 FOREFRONT OF ELUCIDATING 18 00:00:45,080 --> 00:00:46,000 MECHANISMS OF SUCCESSFUL 19 00:00:46,000 --> 00:00:48,480 RESPONSING TO IMMUNIZATION. 20 00:00:48,480 --> 00:00:51,960 FIRST FOCUSING ON INFLUENZA, HE 21 00:00:51,960 --> 00:00:53,480 DESCRIBED AS HIS FIRST AND REAL 22 00:00:53,480 --> 00:00:54,560 LOVE. 23 00:00:54,560 --> 00:00:56,840 MORE RECENTLY ON VACCINATION FOR 24 00:00:56,840 --> 00:00:57,160 SARS-COV-2. 25 00:00:57,160 --> 00:00:58,680 IN HIS OWN LAB AT WASHINGTON 26 00:00:58,680 --> 00:01:00,000 UNIVERSITY WHERE HE HAS BEEN 27 00:01:00,000 --> 00:01:02,640 SINCE 2017, ACTUALLY, VERY 28 00:01:02,640 --> 00:01:04,600 RECENT, STARTING HIS LAB, DR. 29 00:01:04,600 --> 00:01:06,920 ELLEBEDY'S WORK HAS BEEN NOTABLE 30 00:01:06,920 --> 00:01:08,840 FOR HIS GROUNDBREAKING STUDIES 31 00:01:08,840 --> 00:01:13,480 OF IMMUNE RESPONSES TO 32 00:01:13,480 --> 00:01:14,400 VACCINATIONS. 33 00:01:14,400 --> 00:01:16,880 NOT ONLY IN THE BLOOD WHERE MOST 34 00:01:16,880 --> 00:01:18,680 STUDIES HAVE BEEN CARRIED OUT, 35 00:01:18,680 --> 00:01:23,360 BUT ALSO IN THE TISSUE BY TAKING 36 00:01:23,360 --> 00:01:26,480 THE BRAVE STEP IN SERIAL LIMP 37 00:01:26,480 --> 00:01:30,880 NODE BIOPSIES AND BONE MARROW 38 00:01:30,880 --> 00:01:36,480 BUY -- BIOPSIES. 39 00:01:36,480 --> 00:01:39,640 THIS IS AN AMAZING STEP IN, I 40 00:01:39,640 --> 00:01:41,440 THINK, HUMAN IMMUNOLOGY AND 41 00:01:41,440 --> 00:01:45,880 SERVES AS A MODEL FOR ALL OF US. 42 00:01:45,880 --> 00:01:49,680 TOGETHER HIS WORK HAS HELPED TO 43 00:01:49,680 --> 00:01:53,120 DESIGN SCLAR AND MOLECULAR 44 00:01:53,120 --> 00:01:55,280 MECHANISMS, HELPED US UNDERSTAND 45 00:01:55,280 --> 00:01:58,920 THE HETEROGENEITY OF MEMORY B 46 00:01:58,920 --> 00:02:00,440 CELL RESPONSES AND DERNLING THE 47 00:02:00,440 --> 00:02:04,080 RULES FOR ELICITING LARGELY 48 00:02:04,080 --> 00:02:07,080 NEUTRAL B CELL RESPONSES AGAINST 49 00:02:07,080 --> 00:02:08,880 PATHOGENS SUCH AS INFLEW ENDSA 50 00:02:08,880 --> 00:02:12,680 AND SARS-COV-2. 51 00:02:12,680 --> 00:02:16,680 DR. ELLEBEDY'S WORK IS AT THE 52 00:02:16,680 --> 00:02:18,760 FOREFRONT OF TECHNOLOGIES USING 53 00:02:18,760 --> 00:02:19,720 TECHNIQUES THAT WOULDN'T HAVE 54 00:02:19,720 --> 00:02:21,200 BEEN POSSIBLE JUST A FEW YEARS 55 00:02:21,200 --> 00:02:25,640 AGO AND I THINK IT IS REALLY A 56 00:02:25,640 --> 00:02:28,280 TESTIMONY TO HOW THIS FIELD HAS 57 00:02:28,280 --> 00:02:31,320 MOVED TO HELP US UNDERSTAND WHY 58 00:02:31,320 --> 00:02:32,440 VACCINES WORK. 59 00:02:32,440 --> 00:02:34,680 WE LOOK FORWARD TO HEARING HIS 60 00:02:34,680 --> 00:02:36,520 EXCITING FINDINGS. 61 00:02:36,520 --> 00:02:38,800 SO WELCOME, DR. ELLEBEDY. 62 00:02:38,800 --> 00:02:40,200 >>THANK YOU SO MUCH FOR THE 63 00:02:40,200 --> 00:02:41,720 VERY, VERY KIND INTRODUCTION. 64 00:02:41,720 --> 00:02:45,000 AND THANK YOU FOR THE 65 00:02:45,000 --> 00:02:45,280 INVITATION. 66 00:02:45,280 --> 00:02:48,160 I'M REALLY HAPPY AND THRILLED TO 67 00:02:48,160 --> 00:02:51,040 BE SHARING OUR WORK WITH THIS 68 00:02:51,040 --> 00:02:52,280 GROUP. 69 00:02:52,280 --> 00:02:52,640 YEAH. 70 00:02:52,640 --> 00:02:54,360 IT IS -- I'M GOING TO GO 71 00:02:54,360 --> 00:02:57,800 THROUGH -- I SEE THAT WE HAVE 72 00:02:57,800 --> 00:02:59,440 ALREADY THE DISCLOSURE, SO I 73 00:02:59,440 --> 00:03:06,960 WILL SKIP THE DISCLOSURE PART. 74 00:03:06,960 --> 00:03:08,280 I'M GOING TO TELL YOU THE STORY 75 00:03:08,280 --> 00:03:10,120 OF WHAT I HAVE LEARNED SO FAR IN 76 00:03:10,120 --> 00:03:12,080 THE LAST FEW YEARS AND ONE OF 77 00:03:12,080 --> 00:03:13,280 THE THINGS YOU GET ASKED WHEN 78 00:03:13,280 --> 00:03:17,240 YOU APPLY FOR A POSITION TO 79 00:03:17,240 --> 00:03:20,240 START YOUR OWN LAB, TELL US WHAT 80 00:03:20,240 --> 00:03:21,840 YOU ARE GOING TO DO IN THE NEXT 81 00:03:21,840 --> 00:03:22,880 FIVE YEARS. 82 00:03:22,880 --> 00:03:25,400 I LOOK BACK AND I ACTUALLY 83 00:03:25,400 --> 00:03:27,440 LOOKED BACK AT MY PLAN, WHATEVER 84 00:03:27,440 --> 00:03:29,680 THE PLAN WAS AT THE TIME, AND, 85 00:03:29,680 --> 00:03:35,440 OF COURSE, IT HAS NOTHING TO DO 86 00:03:35,440 --> 00:03:36,720 WITH WHAT I HAVE DONE IN THE 87 00:03:36,720 --> 00:03:38,720 LAST FIVE YEARS OR WHAT WE HAVE 88 00:03:38,720 --> 00:03:40,440 LEARNED IN THE LAST FIVE YEARS. 89 00:03:40,440 --> 00:03:43,360 THERE ARE THINGS YOU CANNOT 90 00:03:43,360 --> 00:03:44,760 REALLY PLAN FOR. 91 00:03:44,760 --> 00:03:45,760 REALLY, EVERYTHING CHANGED. 92 00:03:45,760 --> 00:03:47,560 AS YOU WILL SEE, EVERYTHING 93 00:03:47,560 --> 00:03:49,040 CHANGED QUICKLY AND WE HAD TO 94 00:03:49,040 --> 00:03:51,800 ADAPT TO BE ABLE TO LEARN MORE 95 00:03:51,800 --> 00:03:53,880 IN THE ONGOING STUDIES. 96 00:03:53,880 --> 00:03:56,360 I KNOW WE ARE ALL EXPECTING 97 00:03:56,360 --> 00:03:58,400 SARS-COV-2 AND MY FIRST SLIDES 98 00:03:58,400 --> 00:04:00,760 ARE ABOUT A DIFFERENT VIRUS. 99 00:04:00,760 --> 00:04:04,080 ABOUT THE -- IT IS AN EPIDEMIC 100 00:04:04,080 --> 00:04:06,000 THAT HAD BEEN TALKED ABOUT AND 101 00:04:06,000 --> 00:04:09,960 WROTE ABOUT A LOT IN THE MEASLES 102 00:04:09,960 --> 00:04:12,280 EPIDEMIC IN THE FARE ISLANDS IN 103 00:04:12,280 --> 00:04:12,640 1846. 104 00:04:12,640 --> 00:04:15,280 THESE ARE A GROUP OF ISLANDS 105 00:04:15,280 --> 00:04:17,000 THAT ARE SELF-GOVERNING ISLANDS 106 00:04:17,000 --> 00:04:20,160 IN THE ATLANTIC OCEAN BETWEEN 107 00:04:20,160 --> 00:04:21,400 ICELAND AND NORWAY. 108 00:04:21,400 --> 00:04:23,400 THE REASON I'M BRINGING THIS UP, 109 00:04:23,400 --> 00:04:26,640 VERY INTERESTINGLY AT THE TIME, 110 00:04:26,640 --> 00:04:32,480 STARTING FROM 1,500, THE DANISH 111 00:04:32,480 --> 00:04:34,080 DYNASTIES OR WHOEVER WAS RULING 112 00:04:34,080 --> 00:04:36,440 AT THE TIME WAS REALLY CONCERNED 113 00:04:36,440 --> 00:04:38,200 ABOUT THE POPULATION FOR MANY, 114 00:04:38,200 --> 00:04:39,480 MANY OBVIOUS REASONS. 115 00:04:39,480 --> 00:04:42,120 SO THEY STARTED MONITORING THE 116 00:04:42,120 --> 00:04:47,360 OUTBREAKS AND AT THE TIME THEY 117 00:04:47,360 --> 00:04:57,880 SENT A DANISH EPIDEMIOLOGYIST. 118 00:04:58,800 --> 00:05:00,440 THERE WAS A HUGE OUTBREAK. 119 00:05:00,440 --> 00:05:10,800 BUT ONE OF THE FAMOUS 120 00:05:11,960 --> 00:05:13,200 EPIDEMIOLOGIST, WHAT HE WROTE 121 00:05:13,200 --> 00:05:14,560 WHEN HE INVESTIGATING THAT 122 00:05:14,560 --> 00:05:17,320 OUTBREAK, I LIKED SOME OF THE 123 00:05:17,320 --> 00:05:17,520 WRITING. 124 00:05:17,520 --> 00:05:19,760 HE MADE FEW OBSERVATIONS THAT 125 00:05:19,760 --> 00:05:20,760 REMAIN TRUE TO NOW. 126 00:05:20,760 --> 00:05:24,240 IT REALLY TELLS YOU HOW 127 00:05:24,240 --> 00:05:26,600 INSIGHTFUL IT CAN BE CAREFULLY 128 00:05:26,600 --> 00:05:28,640 DONE EPIDEMIOLOGY FOR THE 129 00:05:28,640 --> 00:05:32,960 STUDIES. 130 00:05:32,960 --> 00:05:36,120 THE FIRST VERSION IS VIRGIN 131 00:05:36,120 --> 00:05:37,440 POPULATIONS OR NAIVE 132 00:05:37,440 --> 00:05:37,720 POPULATIONS. 133 00:05:37,720 --> 00:05:39,640 WHEN THERE IS AN OUTBREAK WITH A 134 00:05:39,640 --> 00:05:41,520 VIRUS, EVERYONE GETS INFECTED. 135 00:05:41,520 --> 00:05:44,440 THE REASON HE SAID NEARLY ALL 136 00:05:44,440 --> 00:05:46,760 WOULD BE INFECTED IS THERE WAS 137 00:05:46,760 --> 00:05:50,640 AN OUTBREAK IN 1781 DOCUMENTED 138 00:05:50,640 --> 00:05:52,240 IN THE ISLANDS. 139 00:05:52,240 --> 00:05:54,800 IT WAS A MEASLES OUTBREAK. 140 00:05:54,800 --> 00:05:57,320 PEOPLE WHO ARE 65 OR OLDER DID 141 00:05:57,320 --> 00:06:00,800 NOT GET AFFECTED BY THE 1846 142 00:06:00,800 --> 00:06:01,080 OUTBREAK. 143 00:06:01,080 --> 00:06:02,840 AT THAT TIME IT WAS AN 144 00:06:02,840 --> 00:06:05,200 INTERESTING OBSERVATION ABOUT 145 00:06:05,200 --> 00:06:06,000 EXPERIENCING OUTBREAK BEFORE CAN 146 00:06:06,000 --> 00:06:09,000 PROTECT YOU. 147 00:06:09,000 --> 00:06:11,840 AND THEN HE MADE THAT 148 00:06:11,840 --> 00:06:13,200 OBSERVATION THAT NATURAL 149 00:06:13,200 --> 00:06:14,280 INFECTION CAN GIVE YOU LIFE-LONG 150 00:06:14,280 --> 00:06:15,080 IMMUNITY. 151 00:06:15,080 --> 00:06:17,640 WELL, I GUESS WE WILL GO 152 00:06:17,640 --> 00:06:22,200 STRAIGHT TO THE FAROE ISLANDS, 153 00:06:22,200 --> 00:06:27,640 I WAS SHOWING WHERE THEY ARE AND 154 00:06:27,640 --> 00:06:37,360 THE EPIDEMIOLOGIST FROM DENMARK. 155 00:06:37,360 --> 00:06:45,640 I SAID THE INSIGHT OF BEING 156 00:06:45,640 --> 00:06:49,040 EXPOSED TO AN EPIDEMIC HELPED 157 00:06:49,040 --> 00:06:50,680 PEOPLE. 158 00:06:50,680 --> 00:06:53,760 THE VIRUS DIDN'T CHANGE BUT YOU 159 00:06:53,760 --> 00:06:55,120 GET THIS LIFE-LONG IMMUNITY. 160 00:06:55,120 --> 00:06:57,200 THAT IS BASICALLY IT. 161 00:06:57,200 --> 00:06:58,880 I'M GLAD WE TAUGHT THIS. 162 00:06:58,880 --> 00:07:02,280 THIS LIFE-LONG IMMUNITY COME 163 00:07:02,280 --> 00:07:03,640 FROM TWO MAIN POPULATION OF B 164 00:07:03,640 --> 00:07:04,720 CELL POPULATION. 165 00:07:04,720 --> 00:07:09,600 THE BONE MARROW PLASMA CELLS, 166 00:07:09,600 --> 00:07:18,480 THE ANTIBODY SECRETING CELLS. 167 00:07:18,480 --> 00:07:21,040 IF THOSE AREN'T ENOUGH IN TERMS 168 00:07:21,040 --> 00:07:24,640 OF PROVIDING PROTECTION, WE HAVE 169 00:07:24,640 --> 00:07:26,320 CIRCULATING B-CELLS. 170 00:07:26,320 --> 00:07:32,360 BOTH OF THESE POPULATION COME 171 00:07:32,360 --> 00:07:33,880 FROM REACTION. 172 00:07:33,880 --> 00:07:36,120 THIS IS A REACTION THAT 173 00:07:36,120 --> 00:07:37,960 HAPPENED, A VERY UNIQUE ACTION, 174 00:07:37,960 --> 00:07:39,880 I WILL DISCUSS IN DETAIL IN THE 175 00:07:39,880 --> 00:07:40,640 NEXT SLIDE. 176 00:07:40,640 --> 00:07:42,360 THIS REACTION IS CRITICAL FOR 177 00:07:42,360 --> 00:07:45,600 THE GENERATION OF THOSE TWO 178 00:07:45,600 --> 00:07:45,880 POPULATIONS. 179 00:07:45,880 --> 00:07:47,320 ESPECIALLY HIGH AGENERAL FI, OR 180 00:07:47,320 --> 00:07:49,440 HIGH BINDING AFFINITY POPULATION 181 00:07:49,440 --> 00:07:50,440 OF THOSE CELLS. 182 00:07:50,440 --> 00:07:53,840 SO YOU CAN THINK OF ALL OF OUR 183 00:07:53,840 --> 00:07:55,080 SUCCESSFUL VACCINATIONS IN THE 184 00:07:55,080 --> 00:07:57,080 LAST FEW HUNDRED YEARS. 185 00:07:57,080 --> 00:07:59,560 THINKING ABOUT SMALLPOX, POLIO, 186 00:07:59,560 --> 00:08:03,080 YELLOW FEVER, TETANUS, 187 00:08:03,080 --> 00:08:05,800 DIPHTHERIA, MMR, SAVING MILLIONS 188 00:08:05,800 --> 00:08:07,560 AND MILLIONS OF LIVES. 189 00:08:07,560 --> 00:08:10,920 WHILE WE HAVEN'T REALLY STUDIED 190 00:08:10,920 --> 00:08:14,720 THE IMMUNE RESPONSE -- OR AT 191 00:08:14,720 --> 00:08:19,040 LEAST THE GERMINAL RESPONSE WE 192 00:08:19,040 --> 00:08:21,360 CAN ASSUME THEY HAVE A ROBUST 193 00:08:21,360 --> 00:08:21,640 RESPONSE. 194 00:08:21,640 --> 00:08:23,160 WE HAVE OBSERVED THESE 195 00:08:23,160 --> 00:08:25,440 POPULATIONS TO SURVIVE FOR A 196 00:08:25,440 --> 00:08:28,280 LONG TIME. 197 00:08:28,280 --> 00:08:31,120 GERMINAL CENTER REACTION IS A 198 00:08:31,120 --> 00:08:32,720 CRITICAL REACTION FOR THE 199 00:08:32,720 --> 00:08:32,920 MEMORY. 200 00:08:32,920 --> 00:08:43,480 THIS IS OVERSIMPLIFIED, IF YOU 201 00:08:47,560 --> 00:08:50,000 GET IMMUNIZED, YOU WILL SEE WHY 202 00:08:50,000 --> 00:08:52,240 I THINK THIS IS OVERSIMPLIFIED 203 00:08:52,240 --> 00:08:54,920 BECAUSE IN HUMANS WE HAVE MORE 204 00:08:54,920 --> 00:09:03,240 THAN ONE LYNCH NODE DRAINING. 205 00:09:03,240 --> 00:09:06,200 ASSUMING THERE IS A DRAINAGE, 206 00:09:06,200 --> 00:09:09,560 THE B-CELLS WILL REACT TO 207 00:09:09,560 --> 00:09:11,680 PLASMA, THOSE ARE SHORT LIVED 208 00:09:11,680 --> 00:09:13,440 AND THOSE DON'T PROVIDE THE 209 00:09:13,440 --> 00:09:16,440 FIRST WAVE OF PROTECTIVE 210 00:09:16,440 --> 00:09:17,720 ANTIBODIES. 211 00:09:17,720 --> 00:09:20,560 THEY ARE NOT AFFINITY MATURE, 212 00:09:20,560 --> 00:09:23,080 WHICH HAPPENS IN THE GERMINAL 213 00:09:23,080 --> 00:09:23,440 SYSTEM. 214 00:09:23,440 --> 00:09:31,520 SOME OF THE RESPONDING BCELLS, 215 00:09:31,520 --> 00:09:33,720 THEY WILL HAVE REACTION IN THE 216 00:09:33,720 --> 00:09:35,960 CORTEX, IN THE CENTER OF THE 217 00:09:35,960 --> 00:09:40,120 B-CELL FOLLICLES. 218 00:09:40,120 --> 00:09:41,920 B-CELLS WILL UNDERGO MULTIPLE 219 00:09:41,920 --> 00:09:43,960 ROUNDS OF PROLIFERATION, 220 00:09:43,960 --> 00:09:46,360 REGULATE THE IDEAS, ALLOWED TO 221 00:09:46,360 --> 00:09:51,680 INTRODUCE MUTATIONS IN THE BCR. 222 00:09:51,680 --> 00:09:55,960 THOSE SHOW THE BINDING AFFINITY 223 00:09:55,960 --> 00:09:59,840 TO THE ANTI GERKS ENS, 224 00:09:59,840 --> 00:10:01,440 SPECIALIZED CELLS IN THE 225 00:10:01,440 --> 00:10:02,560 DRAINING LIMP NODES. 226 00:10:02,560 --> 00:10:04,720 SO NOW YOU HAVE DETAILED, IF YOU 227 00:10:04,720 --> 00:10:06,720 GO CLOSER, THERE ARE TWO 228 00:10:06,720 --> 00:10:07,800 DIFFERENT ZONES. 229 00:10:07,800 --> 00:10:09,920 ONE ZONE REALLY SPECIALIZED FOR 230 00:10:09,920 --> 00:10:15,200 THE AMPLIFICATION OF THE B-CELLS 231 00:10:15,200 --> 00:10:19,920 AND INTRODUCTION OF THE B-CELL 232 00:10:19,920 --> 00:10:23,000 RECEPTOR MUTATIONS. 233 00:10:23,000 --> 00:10:28,760 EVERYTHING HAPPENED HERE WITH 234 00:10:28,760 --> 00:10:31,960 THE HELP OF A VERY CONTROLLED 235 00:10:31,960 --> 00:10:34,080 AND HELP FROM T-CELLS. 236 00:10:34,080 --> 00:10:36,680 RESPONDING B-CELLS, OR AT LEAST 237 00:10:36,680 --> 00:10:40,120 THE B-CELLS EXITING, SO THEY CAN 238 00:10:40,120 --> 00:10:42,880 COME OUT AS CIRCULATING MEMORY 239 00:10:42,880 --> 00:10:45,000 B-CELLS OR LONG LIVE PLASMA 240 00:10:45,000 --> 00:10:46,120 CELLS THAT WILL MIGRATE TO THE 241 00:10:46,120 --> 00:10:48,520 BOTTOM NOW. 242 00:10:48,520 --> 00:10:50,720 THIS IS THE REACTION, WHAT WE 243 00:10:50,720 --> 00:10:52,960 LEARNED FROM ANIMAL MODELS, 244 00:10:52,960 --> 00:10:55,360 ACTUALLY, IN THE LAST 50 TO 245 00:10:55,360 --> 00:10:59,600 MAYBE 60 TO 70 YEARS SINCE WE 246 00:10:59,600 --> 00:11:02,600 STARTED LEARNING IN RABBITS AND 247 00:11:02,600 --> 00:11:03,920 SMALLER RATS AND MICE. 248 00:11:03,920 --> 00:11:08,640 WE REALLY LEARNED MOST OF THESE 249 00:11:08,640 --> 00:11:10,080 DETAILS FROM THESE REALLY 250 00:11:10,080 --> 00:11:12,480 IMPORTANT EXPERIMENTS IN ANIMAL 251 00:11:12,480 --> 00:11:12,720 MODELS. 252 00:11:12,720 --> 00:11:15,680 BUT THEN IN HUMANS, HOW CAN 253 00:11:15,680 --> 00:11:18,920 WE -- GIVEN HOW CRITICAL THIS 254 00:11:18,920 --> 00:11:20,880 REACTION IS AND GIVEN THESE 255 00:11:20,880 --> 00:11:22,640 CELLS DO NOT CIRCULATE IN BLOOD, 256 00:11:22,640 --> 00:11:24,520 HAVING THESE CELLS CONFINED TO 257 00:11:24,520 --> 00:11:26,920 THIS MICROATOMIC STRUCTURES IN 258 00:11:26,920 --> 00:11:29,520 THE DRAINING INFLUENCE, HOW CAN 259 00:11:29,520 --> 00:11:31,360 WE KNOW, FOR EXAMPLE, IN THE 260 00:11:31,360 --> 00:11:34,160 CASE OF INFLUENZA VACCINE, HOW 261 00:11:34,160 --> 00:11:37,600 CAN WE IMPROVE THE VACCINE IF WE 262 00:11:37,600 --> 00:11:39,600 DON'T HAVE A GENERAL REACTION. 263 00:11:39,600 --> 00:11:41,760 IN MY TALK I WILL TELL YOU MY 264 00:11:41,760 --> 00:11:43,840 JOURNEY OF HOW I STARTED ASKING 265 00:11:43,840 --> 00:11:47,680 THESE IMPORTANT QUESTIONS. 266 00:11:47,680 --> 00:11:49,200 THIS IS WHAT DROVE REALLY THE 267 00:11:49,200 --> 00:11:51,440 TOOLS AND TECHNIQUES THAT WE 268 00:11:51,440 --> 00:11:53,760 TRIED TO ANSWER THESE QUESTIONS. 269 00:11:53,760 --> 00:11:57,560 I WILL START FIRST WITH THE 270 00:11:57,560 --> 00:12:00,360 PLASMA -- THIS IS MY POST DOC I 271 00:12:00,360 --> 00:12:00,760 MENTIONED. 272 00:12:00,760 --> 00:12:03,960 HE DID THIS STUDY 15 YEARS AGO, 273 00:12:03,960 --> 00:12:06,200 PUBLISHED VERY SIMPLE ONE, 274 00:12:06,200 --> 00:12:08,720 LOOKING AT HEALTHY YOUNG 275 00:12:08,720 --> 00:12:09,200 DIFFICULTS. 276 00:12:09,200 --> 00:12:14,240 THE REL INFLUENZA VACCINE. 277 00:12:14,240 --> 00:12:18,040 THEY NOTICED THIS POPULATION OF 278 00:12:18,040 --> 00:12:22,200 COMING VERY QUICKLY PLASMABLAST, 279 00:12:22,200 --> 00:12:28,760 ANTIBODIES ARE RESPONDING TO THE 280 00:12:28,760 --> 00:12:32,640 VACCINE AND HE MADE THE NOTE 281 00:12:32,640 --> 00:12:35,360 THESE ARE COMING FROM MEMORY 282 00:12:35,360 --> 00:12:35,720 CELLS. 283 00:12:35,720 --> 00:12:38,840 FIRST EVERY ONE OF US HAS A POOL 284 00:12:38,840 --> 00:12:44,280 OF MEMORY B-CELLS FOR INFLUENZA. 285 00:12:44,280 --> 00:12:47,640 IF YOU PUT THIS ON PLATES COATED 286 00:12:47,640 --> 00:12:51,600 WITH THE ANTIGEN, YOU WILL SEE 287 00:12:51,600 --> 00:12:53,280 THEY ARE MOSTLY SECRETING. 288 00:12:53,280 --> 00:12:54,680 THEY COME QUICKLY. 289 00:12:54,680 --> 00:12:57,160 THAT IS A FAST KIND. 290 00:12:57,160 --> 00:12:59,400 AND THEY HAVE ACCUMULATED LARGE 291 00:12:59,400 --> 00:13:01,640 NUMBER OF MUTATIONS, RELATIVELY. 292 00:13:01,640 --> 00:13:04,120 SO THAT MEANS THEY ARE MOST 293 00:13:04,120 --> 00:13:06,160 LIKELY CAME FROM MEMORY CELLS. 294 00:13:06,160 --> 00:13:09,920 THESE MEMORY SELLS WENT THROUGH 295 00:13:09,920 --> 00:13:11,600 INTERACTION IN THE PAST AND 296 00:13:11,600 --> 00:13:13,280 ACCUMULATED THESE MUTATIONS. 297 00:13:13,280 --> 00:13:16,000 THESE MUTATIONS HAPPEN AS I 298 00:13:16,000 --> 00:13:16,280 DISCUSSED. 299 00:13:16,280 --> 00:13:17,880 SO WHAT I WANT YOU TO LEARN FROM 300 00:13:17,880 --> 00:13:20,920 SO FAR IS THAT WE HAD, BY 301 00:13:20,920 --> 00:13:22,800 LOOKING AT BLOOD, WE CAN LEARN A 302 00:13:22,800 --> 00:13:23,640 LOT OF THINGS. 303 00:13:23,640 --> 00:13:27,320 WE CAN ISOLATE THE RESPONDING 304 00:13:27,320 --> 00:13:27,640 PLASMABLAST. 305 00:13:27,640 --> 00:13:29,680 WE CAN LEARN A LITTLE BIT ABOUT 306 00:13:29,680 --> 00:13:31,240 THEIR ORIGIN. 307 00:13:31,240 --> 00:13:35,400 WE CAN LOOK AT THE IGG, THE 308 00:13:35,400 --> 00:13:36,920 ISOTYPE THEY ARE SPEAKING. 309 00:13:36,920 --> 00:13:44,400 WE COULDN'T LEARN IF WE CAN 310 00:13:44,400 --> 00:13:46,520 GENER 311 00:13:46,520 --> 00:13:47,800 GENERATE 312 00:13:47,800 --> 00:13:53,760 [ INDISCERNIBLE ] 313 00:13:53,760 --> 00:13:58,160 CAN WE ACTUALLY LOOKED A OTHER 314 00:13:58,160 --> 00:14:01,440 CELLS IN THE BLOOD, THAT ARE NOT 315 00:14:01,440 --> 00:14:03,040 DIFFERENTIATING THROUGH 316 00:14:03,040 --> 00:14:03,320 PLASMABLAST. 317 00:14:03,320 --> 00:14:05,280 I CALL THEM ACTIVATED B-CELLS AT 318 00:14:05,280 --> 00:14:05,760 THE TIME. 319 00:14:05,760 --> 00:14:11,080 THOSE ARE THE CELLS YOU CAN 320 00:14:11,080 --> 00:14:13,760 DEFINE THEM AS 71 HIGH CELLS, 321 00:14:13,760 --> 00:14:18,880 THEY ARE PROLIFERATING BUT DON'T 322 00:14:18,880 --> 00:14:19,200 DIFFERENTIATE. 323 00:14:19,200 --> 00:14:20,960 THESE ARE ALL DETAILED IN THIS 324 00:14:20,960 --> 00:14:22,560 PAPER. 325 00:14:22,560 --> 00:14:25,640 IF YOU DID THE SEQUENCE ANALYSIS 326 00:14:25,640 --> 00:14:27,920 OF THE RESPONDING B-CELLS, THE 327 00:14:27,920 --> 00:14:29,640 LEVEL OF MUTATIONS DIDN'T CHANGE 328 00:14:29,640 --> 00:14:31,440 MUCH AND THIS IS JUST LOOKING AT 329 00:14:31,440 --> 00:14:33,840 AVERAGE MUTATION FOR THE SAME 330 00:14:33,840 --> 00:14:36,240 EXACT CLONE THAT ARE RESPONDING 331 00:14:36,240 --> 00:14:38,160 TO A CHANGE OVER TIME. 332 00:14:38,160 --> 00:14:40,240 AT THE TIME IT WAS INTRIGUING TO 333 00:14:40,240 --> 00:14:40,440 ME. 334 00:14:40,440 --> 00:14:45,760 I WAS FINISHING MY POST DOC 335 00:14:45,760 --> 00:14:48,560 FOLLOWSHIP, IF WE HAVE A GOOD 336 00:14:48,560 --> 00:14:53,040 RESPONSE WHY DON'T WE HAVE A 337 00:14:53,040 --> 00:14:55,400 GERMINAL CENTER. 338 00:14:55,400 --> 00:14:58,400 SO THIS REALLY, THAT QUESTION 339 00:14:58,400 --> 00:15:00,040 REMAINED WITH ME AS I MOVED FROM 340 00:15:00,040 --> 00:15:01,440 ATLANTA TO ST. LOUIS AND I 341 00:15:01,440 --> 00:15:02,880 THOUGHT THE FIRST QUESTION I 342 00:15:02,880 --> 00:15:09,360 WANTED TO ASK IS CAN WE STUDY 343 00:15:09,360 --> 00:15:13,480 THE GERMAL CENTER IN VACCINE. 344 00:15:13,480 --> 00:15:19,120 WE KNOW THAT IT IS A SUB -- 345 00:15:19,120 --> 00:15:22,280 VACCINE, BUT DOESN'T INDUCE A 346 00:15:22,280 --> 00:15:24,320 GERMINAL CENTER REACTION. 347 00:15:24,320 --> 00:15:26,200 IF IT DOESN'T, WE NEED TO 348 00:15:26,200 --> 00:15:30,760 IMPROVE, IF IT DOES, HOW MANY? 349 00:15:30,760 --> 00:15:33,000 AT THE TIME A LAB PUBLISHED A 350 00:15:33,000 --> 00:15:35,480 COUPLE OF PAPERS OF SAMPLING 351 00:15:35,480 --> 00:15:38,200 LYNCH NODES FINDING -- SO THIS 352 00:15:38,200 --> 00:15:43,000 IS ONE OF THE THINGS THAT REALLY 353 00:15:43,000 --> 00:15:44,960 BEING MORE OR LESS NAIVE ABOUT 354 00:15:44,960 --> 00:15:49,520 HOW THINGS GO, I JUST WENT TO 355 00:15:49,520 --> 00:15:53,280 OUR GEOLOGIST AT WASH U, IN 356 00:15:53,280 --> 00:15:56,600 2017, ONE WEEK AFTER I STARTED 357 00:15:56,600 --> 00:15:58,160 BY LAB. 358 00:15:58,160 --> 00:16:01,240 I WALKED INTO THE RADIOLOGIST 359 00:16:01,240 --> 00:16:04,400 OFFICE AND SAID I SAW THIS PAPER 360 00:16:04,400 --> 00:16:07,280 THAT IT CAN DO THIS TECHNIQUE 361 00:16:07,280 --> 00:16:14,440 AND I READ YOU DO THIS DYING -- 362 00:16:14,440 --> 00:16:16,680 DIAGNO 363 00:16:16,680 --> 00:16:17,080 DIAGNOSTICALLY. 364 00:16:17,080 --> 00:16:18,480 I WOULD LIKE YOUR HELP IN 365 00:16:18,480 --> 00:16:20,720 SAMPLING THE NODES. 366 00:16:20,720 --> 00:16:22,640 OBVIOUSLY, IT TOOK SOME TIME TO 367 00:16:22,640 --> 00:16:24,120 CONVINCE THAT THIS IS AN 368 00:16:24,120 --> 00:16:25,960 IMPORTANT QUESTION, BUT AT THE 369 00:16:25,960 --> 00:16:32,240 SAME TIME I LEARNED THAT HUMANS 370 00:16:32,240 --> 00:16:34,600 HAVE MULTIPLE LYNCH NODES. 371 00:16:34,600 --> 00:16:36,000 IT TOOK US THE FIRST YEAR TO 372 00:16:36,000 --> 00:16:37,600 LEARN HOW TO DO THIS TECHNIQUE 373 00:16:37,600 --> 00:16:42,000 AND HOW TO ACTUALLY SAMPLE 374 00:16:42,000 --> 00:16:44,440 RELIABLELY THE GENE. 375 00:16:44,440 --> 00:16:48,480 THIS IS AN ULTRA SOUND GUIDED 376 00:16:48,480 --> 00:16:49,720 AUXILIARY NODE. 377 00:16:49,720 --> 00:16:51,560 WE SAMPLE THE CORTEX REASON. 378 00:16:51,560 --> 00:16:53,680 WE DO NOT APPLY SUCTION SO WE 379 00:16:53,680 --> 00:16:55,400 TRY TO KEEP THE STRUCTURE OF THE 380 00:16:55,400 --> 00:16:59,120 NODE INTACT SO WE CAN DO THIS 381 00:16:59,120 --> 00:16:59,520 MULTIPLE TIMES. 382 00:16:59,520 --> 00:17:01,440 SO 2017-18 WAS THE YEAR WE 383 00:17:01,440 --> 00:17:02,960 LEARNED HOW TO DO THIS. 384 00:17:02,960 --> 00:17:06,200 SO WE DIDN'T REALLY GENERATE ANY 385 00:17:06,200 --> 00:17:08,360 MEANINGFUL DATA IN THAT TIME. 386 00:17:08,360 --> 00:17:10,800 IN 2018-19, NOW WE HAVE BEEN 387 00:17:10,800 --> 00:17:13,440 REALLY SET UP TO DO THIS, WE 388 00:17:13,440 --> 00:17:15,280 LEARNED WE CAN ACTUALLY PREDICT 389 00:17:15,280 --> 00:17:17,640 WHICH NODES WILL BE RESPONDING 390 00:17:17,640 --> 00:17:18,640 TO VACCINE. 391 00:17:18,640 --> 00:17:21,160 THESE ARE THE LATERAL CLUSTER, 392 00:17:21,160 --> 00:17:22,360 THROUGH TRIAL OR ERROR, THOSE 393 00:17:22,360 --> 00:17:24,480 ARE THE NODES WE SHOULD SAMPLE 394 00:17:24,480 --> 00:17:26,120 BECAUSE THEY ARE NOT DRAINING 395 00:17:26,120 --> 00:17:28,200 THE UPPER ARM. 396 00:17:28,200 --> 00:17:30,800 YOU CAN SEE ONE OF THE NODES WE 397 00:17:30,800 --> 00:17:32,400 CORRECTLY PREDICTED WOULD 398 00:17:32,400 --> 00:17:33,680 RESPOND TO THE VACCINE, THE 399 00:17:33,680 --> 00:17:37,080 CORTEX IS VERY THIN, BUT OVER 400 00:17:37,080 --> 00:17:39,040 TIME AT VACCINATION, THE CORTEX 401 00:17:39,040 --> 00:17:40,000 GETS MUCH THICKER. 402 00:17:40,000 --> 00:17:42,880 THAT IS A GOOD SIGN THERE MUST 403 00:17:42,880 --> 00:17:44,000 BE GOING ON. 404 00:17:44,000 --> 00:17:46,760 IF YOU LOOK AT THE SAME TIME 405 00:17:46,760 --> 00:17:55,680 POINTS, WEEK ONE IS BLAST MA -- 406 00:17:55,680 --> 00:17:57,000 PLASMABLAST ARE WORKING. 407 00:17:57,000 --> 00:18:00,560 THESE ARE B-CELLS RESPONDING TO 408 00:18:00,560 --> 00:18:02,240 SOME STIMULATION OR MEMORY 409 00:18:02,240 --> 00:18:02,440 CELLS. 410 00:18:02,440 --> 00:18:09,040 WEEK TWO WE STARTED SEEING THE 411 00:18:09,040 --> 00:18:10,560 GERMINAL CENTER REACTION, SOME 412 00:18:10,560 --> 00:18:12,560 POUND TO THE HA, THE MAIN 413 00:18:12,560 --> 00:18:15,200 PROTEIN IN THE INFLUENZA 414 00:18:15,200 --> 00:18:15,400 VACCINE. 415 00:18:15,400 --> 00:18:20,400 THIS IS THE FIRST DETECTION OF 416 00:18:20,400 --> 00:18:21,840 B-CELLS AFTER VACCINATION. 417 00:18:21,840 --> 00:18:24,040 ALLOWED US TO ANSWER A SIMPLE 418 00:18:24,040 --> 00:18:24,480 QUESTION. 419 00:18:24,480 --> 00:18:28,520 REMEMBER, I MENTIONED 420 00:18:28,520 --> 00:18:30,160 PLASMABLAST ALMOST COME FROM THE 421 00:18:30,160 --> 00:18:35,440 MEMORY B-CELL COMPARTMENT 422 00:18:35,440 --> 00:18:37,400 BECAUSE THE VACCINE IS NOT -- IT 423 00:18:37,400 --> 00:18:41,880 RELIES ON STEM LATING THE MEMORY 424 00:18:41,880 --> 00:18:42,400 B-CELLS. 425 00:18:42,400 --> 00:18:43,840 WE SEE MULTIMILLION TIME POINTS 426 00:18:43,840 --> 00:18:46,760 OF THE SAME CLONES, RESPONDING 427 00:18:46,760 --> 00:18:48,680 TO VACCINATION WITH THE 428 00:18:48,680 --> 00:18:50,080 INFLUENZA CAN BECOME PART OF THE 429 00:18:50,080 --> 00:18:53,800 GC OR A COMPLETELY DIFFERENT 430 00:18:53,800 --> 00:18:55,320 NODE OR WE HAVE A MIX. 431 00:18:55,320 --> 00:18:57,720 TO ANSWER THIS QUESTION WE 432 00:18:57,720 --> 00:19:01,360 SINGLE SOURCED PLASMABLAST FROM 433 00:19:01,360 --> 00:19:01,560 BLOOD. 434 00:19:01,560 --> 00:19:06,560 WE DID THE SAME FOR THE GC 435 00:19:06,560 --> 00:19:07,720 B-CELLS. 436 00:19:07,720 --> 00:19:08,720 TOTAL GC. 437 00:19:08,720 --> 00:19:11,720 ONCE YOU HAVE THE ANTIBODIES YOU 438 00:19:11,720 --> 00:19:13,440 CAN CONFIRM ITS BINDING. 439 00:19:13,440 --> 00:19:15,320 ONCE YOU HAVE IT CONFIRMED TO 440 00:19:15,320 --> 00:19:21,080 THE VACCINE, YOU NOW HAVE THIS 441 00:19:21,080 --> 00:19:22,760 REARRANGED FROM THAT PARTICULAR 442 00:19:22,760 --> 00:19:24,560 CLONE AS YOUR I.D. OR 443 00:19:24,560 --> 00:19:25,960 FINGERPRINT, YOU CAN TRACK THE 444 00:19:25,960 --> 00:19:26,240 EVOLUTION. 445 00:19:26,240 --> 00:19:27,520 THIS IS WHAT WE DID HERE. 446 00:19:27,520 --> 00:19:34,960 THIS IS A SINGLE CELL ANALYSIS 447 00:19:34,960 --> 00:19:37,640 OF ONE INDIVIDUAL, B-CELLS OR 448 00:19:37,640 --> 00:19:39,160 LIMP NODE B-CELLS. 449 00:19:39,160 --> 00:19:41,600 WE TRACKED THAT OVER TIME. 450 00:19:41,600 --> 00:19:44,120 YOU CAN HAVE THE TRANSCRIPTION 451 00:19:44,120 --> 00:19:48,320 TO DIVIDE B-CELLS PLASMABLAST, 452 00:19:48,320 --> 00:19:52,000 MEMORY AND SAME IN THE LIMP NODE 453 00:19:52,000 --> 00:19:55,600 BUT YOU ADD THE GERMINAL CENTER 454 00:19:55,600 --> 00:19:58,080 IN BLUE. 455 00:19:58,080 --> 00:20:04,440 THESE AT BASELINE WERE ANGI 456 00:20:04,440 --> 00:20:04,680 SPECIFIC. 457 00:20:04,680 --> 00:20:06,920 THAT BRC COMPLIED WITH THAT. 458 00:20:06,920 --> 00:20:09,040 FIRST WEEK EVERYTHING HERE IN 459 00:20:09,040 --> 00:20:12,400 THE PLASMABLAST IS SPECIFIC 460 00:20:12,400 --> 00:20:14,360 BECAUSE THAT IS WHAT WE KNEW. 461 00:20:14,360 --> 00:20:16,720 THE EXPECTATION AND THOSE ARE 462 00:20:16,720 --> 00:20:19,120 COMING FROM MEMORY, THOSE ARE 463 00:20:19,120 --> 00:20:20,800 HIGH LEVEL OF MUTATIONS. 464 00:20:20,800 --> 00:20:23,960 THEY ARE FROM BLOOD, ACTIVATED 465 00:20:23,960 --> 00:20:26,320 B-CELLS WHICH IS THE WORK I DID 466 00:20:26,320 --> 00:20:28,600 WITH RAFY AS A POST DOC. 467 00:20:28,600 --> 00:20:30,640 THOSE BECOME RESTING CELLS AND 468 00:20:30,640 --> 00:20:33,240 SLOWLY BECOME OUR MEMORY CELLS. 469 00:20:33,240 --> 00:20:42,640 THE LYMPH NODE IN THE GERMINAL 470 00:20:42,640 --> 00:20:44,160 YOU CAN SEE THEM FOR TWO MONTHS. 471 00:20:44,160 --> 00:20:48,120 SOME CLONES I COLORED IN BLUE 472 00:20:48,120 --> 00:20:52,400 THAT ARE RECORDING IN THE 473 00:20:52,400 --> 00:20:52,720 PLASMABLAST. 474 00:20:52,720 --> 00:20:55,240 ANYONE WE SHARED I COLORED 475 00:20:55,240 --> 00:20:55,480 PURPLE. 476 00:20:55,480 --> 00:20:59,240 THERE ARE SOME CLONES GOING BOTH 477 00:20:59,240 --> 00:21:02,560 WAYS, THE MEMORY SELLS ARE THE 478 00:21:02,560 --> 00:21:06,440 MAJOR PRECURSOR FOR THE 479 00:21:06,440 --> 00:21:08,320 PLASMABLAST, THOSE CELLS IN BLUE 480 00:21:08,320 --> 00:21:10,480 ARE COMING FROM NAIVE. 481 00:21:10,480 --> 00:21:12,160 THEY WILL HAVE LOWER MUTATIONS 482 00:21:12,160 --> 00:21:13,080 IN THAT CASE. 483 00:21:13,080 --> 00:21:15,360 WE DID THE ANALYSIS FROM THREE 484 00:21:15,360 --> 00:21:16,480 INDIVIDUALS AND IN THAT CASE, 485 00:21:16,480 --> 00:21:18,840 THIS IS LOOKING AT MUTATION 486 00:21:18,840 --> 00:21:22,880 LEVEL AND PLASMABLAST OR SHARED 487 00:21:22,880 --> 00:21:25,560 PLASMABLAST AND GCs ARE 488 00:21:25,560 --> 00:21:27,320 SIGNIFICANTLY HIGHER MUTATED 489 00:21:27,320 --> 00:21:27,520 CELLS. 490 00:21:27,520 --> 00:21:37,320 WE MADE THE CORRESPONDING MONO 491 00:21:37,320 --> 00:21:37,720 CLO 492 00:21:37,720 --> 00:21:37,960 CLONES. 493 00:21:37,960 --> 00:21:39,400 WE CAN GENERATE B-CELLS TO THE 494 00:21:39,400 --> 00:21:40,640 REACTION AND WHY THIS IS 495 00:21:40,640 --> 00:21:41,200 IMPORTANT. 496 00:21:41,200 --> 00:21:44,240 IN THE CASE OF RAPIDLY INVOLVING 497 00:21:44,240 --> 00:21:47,680 VIRUSS OR ANTIGENS YOU GET 498 00:21:47,680 --> 00:21:49,720 EXPOSED TO REPEATEDLY, YOU WANT 499 00:21:49,720 --> 00:22:00,160 TO UPDATE YOUR REP -- R 500 00:22:02,520 --> 00:22:02,920 REPRETOIRE. 501 00:22:02,920 --> 00:22:04,760 IF YOU HAVE A ROBUST YOU CAN 502 00:22:04,760 --> 00:22:10,080 ENGAGE THE CELLS LATER IN THE 503 00:22:10,080 --> 00:22:10,360 RESPONSE. 504 00:22:10,360 --> 00:22:13,400 AND THEY ARE TARGETING NOVT 505 00:22:13,400 --> 00:22:14,640 ISOTOPES AND WE SHOWED THAT IN 506 00:22:14,640 --> 00:22:16,640 THIS PAPER. 507 00:22:16,640 --> 00:22:18,320 SO THIS IS NOW JUST TO PUT YOU 508 00:22:18,320 --> 00:22:22,640 IN THE CONTEXT OF THE TIME AND 509 00:22:22,640 --> 00:22:24,120 THE SYSTEM, PROFESSOR, TWO AND A 510 00:22:24,120 --> 00:22:27,320 HALF YEARS AND I WAS SO EXCITED. 511 00:22:27,320 --> 00:22:29,560 WE HAVE OUR FIRST BIG PAPER AND 512 00:22:29,560 --> 00:22:33,200 WE ARE REALLY EXCITED AND WE CAN 513 00:22:33,200 --> 00:22:36,360 ADDRESS QUESTIONS ABOUT GERMINAL 514 00:22:36,360 --> 00:22:38,160 CENTER DYNAMICS IN HUMANS. 515 00:22:38,160 --> 00:22:40,880 I WANTED TO LOOK AT THE BONE 516 00:22:40,880 --> 00:22:42,080 MARROW PLASMA CELLS. 517 00:22:42,080 --> 00:22:44,080 THAT IS WHERE THE ULTIMATE 518 00:22:44,080 --> 00:22:49,520 TARGET OF HAVING THIS I ENLISTED 519 00:22:49,520 --> 00:22:52,080 SOME HELP WITH ONCOLOGISTS. 520 00:22:52,080 --> 00:22:58,240 WE CAN DO A VACCINE STUDY TO 521 00:22:58,240 --> 00:23:04,160 SAMPLE LYMP NODE, BLOOD AND THIS 522 00:23:04,160 --> 00:23:05,400 IS SO EXCITING. 523 00:23:05,400 --> 00:23:07,040 WE ARE VERY READY TO GO. 524 00:23:07,040 --> 00:23:08,600 OF COURSE, AS YOU ALL KNOW THIS 525 00:23:08,600 --> 00:23:10,120 HAPPENED AND I GOT THIS CALL IN 526 00:23:10,120 --> 00:23:12,400 MARCH 2020, THIS WAS A VERY, 527 00:23:12,400 --> 00:23:14,800 VERY DEPRESSING WEEK WHERE WE 528 00:23:14,800 --> 00:23:16,000 HAD EVERYTHING HAS TO BE 529 00:23:16,000 --> 00:23:16,280 STOPPED. 530 00:23:16,280 --> 00:23:18,480 WE HAVE TO SWITCH. 531 00:23:18,480 --> 00:23:26,080 NO WORK ON INFLUENZA ANYMORE. 532 00:23:26,080 --> 00:23:28,040 ALL OF MY DREAMS, ALL OF MY 533 00:23:28,040 --> 00:23:29,960 PLANS SO EXCITED TO START, BUT 534 00:23:29,960 --> 00:23:32,720 THEN I REALIZED RIGHT AWAY THIS 535 00:23:32,720 --> 00:23:34,560 IS A GOOD OPPORTUNITY BECAUSE 536 00:23:34,560 --> 00:23:38,640 OBVIOUSLY INFECTION WITH THE 537 00:23:38,640 --> 00:23:40,720 SARS-COV-2 AS A NOVEL VIRUS IN A 538 00:23:40,720 --> 00:23:42,520 WAY, BUT THE VACCINATION PART. 539 00:23:42,520 --> 00:23:44,720 THIS IS A VACCINE PLATFORM NEVER 540 00:23:44,720 --> 00:23:46,200 TESTED IN HUMANS. 541 00:23:46,200 --> 00:23:48,000 IF PEOPLE HAVEN'T BEEN INFECTED, 542 00:23:48,000 --> 00:23:50,240 THIS COULD BE CLOSER TO A 543 00:23:50,240 --> 00:23:51,800 PRIMARY RESPONSE I NEVER GET A 544 00:23:51,800 --> 00:23:54,040 CHANCE TO STUDY IN HUMANS 545 00:23:54,040 --> 00:23:57,320 BECAUSE INFLUENZA MODELS IS 546 00:23:57,320 --> 00:23:59,280 ALWAYS REALIZING THE -- 547 00:23:59,280 --> 00:23:59,640 RESPONSE. 548 00:23:59,640 --> 00:24:03,520 WE HAVE THE SAME QUESTION WITH 549 00:24:03,520 --> 00:24:05,080 THE SARS-COV-2 VACCINE. 550 00:24:05,080 --> 00:24:06,600 PFIZER LOOKING AT PEOPLE GETTING 551 00:24:06,600 --> 00:24:07,720 TWO DOSES. 552 00:24:07,720 --> 00:24:10,040 IN DECEMBER 2020, LIKE MANY 553 00:24:10,040 --> 00:24:12,960 OTHER GROUPS AROUND THE WORLD. 554 00:24:12,960 --> 00:24:15,160 QUESTION RECRUITED INDIVIDUALS. 555 00:24:15,160 --> 00:24:17,040 THE ONLY DIFFERENCE IS WE 556 00:24:17,040 --> 00:24:20,200 SAMPLED BLOOD AND LYMPH NODE 557 00:24:20,200 --> 00:24:30,680 OVER TIME THEN WE ASKED FOR 558 00:24:32,680 --> 00:24:36,000 BLOOD FOR LOOKING AT THE 559 00:24:36,000 --> 00:24:36,280 PLASMABLAST. 560 00:24:36,280 --> 00:24:38,160 THERE ARE SOME RESPONSES 561 00:24:38,160 --> 00:24:40,360 DETECTED AT THREE WEEKS. 562 00:24:40,360 --> 00:24:43,000 THIS IS PROTEIN IGG. 563 00:24:43,000 --> 00:24:44,520 ONE WEEK AFTER SECOND DOSE 564 00:24:44,520 --> 00:24:46,360 EVERYONE RESPONDED WELL. 565 00:24:46,360 --> 00:24:47,720 YOU CAN SEE SOMETHING VERY 566 00:24:47,720 --> 00:24:51,560 SIMPLE AS TWO DOSES NEEDED TO 567 00:24:51,560 --> 00:24:53,680 GET REALLY HIGH, BUT IF YOU HAVE 568 00:24:53,680 --> 00:24:56,480 BEEN INFECTED WITH THE VIRUS, 569 00:24:56,480 --> 00:24:58,200 ONE DOSE IS ENOUGH BECAUSE YOU 570 00:24:58,200 --> 00:25:00,400 HAVE MEMORY CELLS FROM THE VIRUS 571 00:25:00,400 --> 00:25:00,640 INFECTION. 572 00:25:00,640 --> 00:25:02,720 THIS IS THE DATA THAT HAS BEEN 573 00:25:02,720 --> 00:25:05,280 SHOWN A THOUSAND TIMES NOW BY 574 00:25:05,280 --> 00:25:06,840 MANY, MANY DIFFERENT GROUPS. 575 00:25:06,840 --> 00:25:10,160 WHAT ABOUT THE GERMINAL CENTER? 576 00:25:10,160 --> 00:25:13,520 AT THE TIME, INFLUENZA VACCINE 577 00:25:13,520 --> 00:25:17,960 IN HUMANS IN THE U.S. IS REALLY 578 00:25:17,960 --> 00:25:19,640 POORLY MANAGED VACCINE IF IT 579 00:25:19,640 --> 00:25:23,160 WASN'T JUST RELYING ON MEMORY 580 00:25:23,160 --> 00:25:23,880 CELLS. 581 00:25:23,880 --> 00:25:26,120 THE LYMPH NODE RESPONSE WAS MORE 582 00:25:26,120 --> 00:25:27,920 ROBUST HERE. 583 00:25:27,920 --> 00:25:30,000 ROBUST IS MUCH BIGGER NODE, MUCH 584 00:25:30,000 --> 00:25:32,320 MORE ACTIVE, REACTIVE NODES. 585 00:25:32,320 --> 00:25:34,240 I GOT THE PHONE CALL YOU NEED TO 586 00:25:34,240 --> 00:25:35,920 COME AND SEE THIS BECAUSE THIS 587 00:25:35,920 --> 00:25:37,080 IS SOMETHING WE HAVEN'T SEEN 588 00:25:37,080 --> 00:25:37,840 WITH FLU BEFORE. 589 00:25:37,840 --> 00:25:41,400 JUST TO GIVE YOU THE EXAMPLE, 590 00:25:41,400 --> 00:25:47,920 THIS IS OUR LYMPH NODE RESPONSE 591 00:25:47,920 --> 00:25:51,920 TO -- ISOTOPE B-CELLS. 592 00:25:51,920 --> 00:25:55,800 THIS IS BEFORE VACCINATION. 593 00:25:55,800 --> 00:25:58,240 B-CELL IS THE MAIN 594 00:25:58,240 --> 00:25:59,760 TRANSSCRIPTURE FACTOR. 595 00:25:59,760 --> 00:26:01,480 YOU CAN TELL THERE IS AN 596 00:26:01,480 --> 00:26:02,040 INCREASE. 597 00:26:02,040 --> 00:26:04,240 THE SAME POPULATION ONE WEEK 598 00:26:04,240 --> 00:26:06,440 AFTER THE SECOND PFIZER 599 00:26:06,440 --> 00:26:07,760 IMMUNIZATION, WHICH IS BASICALLY 600 00:26:07,760 --> 00:26:09,640 THE TWO DOSES THAT WERE THREE 601 00:26:09,640 --> 00:26:11,520 WEEKS APART, ONE WEEK AFTER THAT 602 00:26:11,520 --> 00:26:14,120 SECOND DOSE, THIS IS THE 603 00:26:14,120 --> 00:26:15,480 POPULATION OF THE LYMPH NODES. 604 00:26:15,480 --> 00:26:16,600 THIS IS OUR FIRST VOLUNTEERS. 605 00:26:16,600 --> 00:26:19,800 WE ARE LOOKING AT SOMETHING 606 00:26:19,800 --> 00:26:20,720 COMPLETELY DIFFERENT. 607 00:26:20,720 --> 00:26:22,480 PEOPLE FELT THERE IS A VERY 608 00:26:22,480 --> 00:26:23,640 ROBUST RESPONSE AND SOME PEOPLE 609 00:26:23,640 --> 00:26:26,800 SAID THE NODES WERE REALLY, YOU 610 00:26:26,800 --> 00:26:34,960 CAN FEEL THEM, I GUESS. 611 00:26:34,960 --> 00:26:37,200 THAT ACTUALLY -- WE PUBLISHED 612 00:26:37,200 --> 00:26:40,040 THIS AND SAID WE ARE A ROBUST 613 00:26:40,040 --> 00:26:40,440 RESPONSE. 614 00:26:40,440 --> 00:26:41,840 HOW LONG WILL THAT RESPONSE 615 00:26:41,840 --> 00:26:42,440 LAST? 616 00:26:42,440 --> 00:26:44,360 WE HAD 15 PEOPLE PARTICIPATING 617 00:26:44,360 --> 00:26:45,080 IN THIS. 618 00:26:45,080 --> 00:26:47,240 NONE OF THEM WAS INFECTED AND 619 00:26:47,240 --> 00:26:49,800 NONE OF THEM WAS INFECTED DURING 620 00:26:49,800 --> 00:26:52,520 THE PERIOD OF THE STUDY SO 621 00:26:52,520 --> 00:26:53,920 EVERYTHING HERE IS VACCINE 622 00:26:53,920 --> 00:26:54,120 INDUCED. 623 00:26:54,120 --> 00:26:56,680 WE TRACKED THE SAME NODES SIX 624 00:26:56,680 --> 00:26:58,160 TIMES FOR SIX MONTHS AFTER 625 00:26:58,160 --> 00:27:00,360 SECONDS IMMUNIZATION. 626 00:27:00,360 --> 00:27:01,760 HOW LONG THAT GERMINAL CENTER 627 00:27:01,760 --> 00:27:02,760 CAN LAST? 628 00:27:02,760 --> 00:27:04,160 THIS IS AN EXAMPLE WHERE A 629 00:27:04,160 --> 00:27:06,400 REALLY SURPRISING FINDING FOR US 630 00:27:06,400 --> 00:27:08,960 AT THE TIME THAT FOR SIX MONTHS, 631 00:27:08,960 --> 00:27:12,480 10 OUT OF THE 15, HAD A REALLY 632 00:27:12,480 --> 00:27:14,880 ROBUST GERMINAL CENTER GOING ON. 633 00:27:14,880 --> 00:27:21,880 THIS IS GATED IN GC B-CELLS, 80% 634 00:27:21,880 --> 00:27:23,040 TO THE SPIKE PROTEIN. 635 00:27:23,040 --> 00:27:25,760 THIS IS A DRIVEN RESPONSE. 636 00:27:25,760 --> 00:27:27,520 AND THE SUMMARY DATA SO THE 637 00:27:27,520 --> 00:27:28,680 DETAILS ARE REALLY OUT THERE. 638 00:27:28,680 --> 00:27:31,280 WE HAVE SOMETHING WE HAVE NEVER 639 00:27:31,280 --> 00:27:32,800 EXPERIENCED IN ANY ANIMAL THAT 640 00:27:32,800 --> 00:27:34,760 YOU CAN HAVE THE TIME. 641 00:27:34,760 --> 00:27:37,720 SUCH A ROBUST AND PERSISTENT 642 00:27:37,720 --> 00:27:39,440 GERMINAL CENTER REACTION IN 643 00:27:39,440 --> 00:27:39,680 HUMANS. 644 00:27:39,680 --> 00:27:42,040 BUT THEN ANOTHER THING WE 645 00:27:42,040 --> 00:27:44,480 NOTICED IS EVERY TIME WE SEE THE 646 00:27:44,480 --> 00:27:46,400 GERMINAL CENTER WE SEE LYMPH 647 00:27:46,400 --> 00:27:47,920 NODE PLASMA CENTERS. 648 00:27:47,920 --> 00:27:52,880 YOU CAN DETECT PLASMA BLAST 649 00:27:52,880 --> 00:27:55,000 EARLY IN BLOOD, BUT PLASMA CELLS 650 00:27:55,000 --> 00:27:57,680 IN THE LYMPH NODE, I ASSUME, 651 00:27:57,680 --> 00:27:59,240 THESE ARE COMING OUT OF THE GC. 652 00:27:59,240 --> 00:28:01,120 THAT IS ONE OF THE OUTCOMES OF 653 00:28:01,120 --> 00:28:03,400 THE GCs. 654 00:28:03,400 --> 00:28:08,960 WE DETECT THESE AS 38 HIGH, 655 00:28:08,960 --> 00:28:09,240 POSITIVE. 656 00:28:09,240 --> 00:28:12,160 SOME OF THEM BIND TO THE SPIKE. 657 00:28:12,160 --> 00:28:16,000 THE VCR GETTING DOWN REGULATED. 658 00:28:16,000 --> 00:28:17,920 WE POSTULATED THOSE CELLS ARE 659 00:28:17,920 --> 00:28:19,120 LIKELY GOING TO BECOME THE ONES 660 00:28:19,120 --> 00:28:21,160 THAT EXIST THE GC AND GO THROUGH 661 00:28:21,160 --> 00:28:21,960 THE LYMPH NODE. 662 00:28:21,960 --> 00:28:24,120 AT THE TIME WE DIDN'T HAVE SOLID 663 00:28:24,120 --> 00:28:25,080 DATA FOR THAT. 664 00:28:25,080 --> 00:28:28,480 WHAT HAPPENS IN THE BONE MARROW? 665 00:28:28,480 --> 00:28:35,120 11 OUT OF THE 15, GIVE US ANS 666 00:28:35,120 --> 00:28:38,240 ASPIRATE, WE ISOLATED THE BONE 667 00:28:38,240 --> 00:28:40,080 MARROW CELLS AND THOSE, THINK OF 668 00:28:40,080 --> 00:28:43,760 THEM AS CONTINUOUSLY ANTIBODIES 669 00:28:43,760 --> 00:28:44,920 SECRETING MACHINES. 670 00:28:44,920 --> 00:28:47,600 YOU DON'T NEED TO STIMULATE 671 00:28:47,600 --> 00:28:49,160 THEM, PUT THEM OVERNIGHT ON 672 00:28:49,160 --> 00:28:54,400 PLATES WITH THE ANTIGEN. 673 00:28:54,400 --> 00:28:57,040 EVERY SINGLE PERSON IN THOSE 11 674 00:28:57,040 --> 00:29:00,120 HAD A REALLY, LOTS OF PLASMA 675 00:29:00,120 --> 00:29:02,000 CELLS AGAINST INFLUENZA. 676 00:29:02,000 --> 00:29:05,680 1 IN 100 OF OUR PLASMA CELLS ARE 677 00:29:05,680 --> 00:29:09,600 SPECIFIC TO INFLUENZA ANTIGEN, 678 00:29:09,600 --> 00:29:13,920 MUCH LESS IN TETANUS DIPHTHERIA, 679 00:29:13,920 --> 00:29:18,880 FOR NOSE 9 OF 11, VERY LOW, BUT 680 00:29:18,880 --> 00:29:20,400 DETECTABLE SPIKE SPECIFIC PLASMA 681 00:29:20,400 --> 00:29:20,600 CELLS. 682 00:29:20,600 --> 00:29:21,880 WE THOUGHT THIS IS GREAT. 683 00:29:21,880 --> 00:29:23,440 WE CAN DETECT THE PLASMA. 684 00:29:23,440 --> 00:29:26,160 IT IS MUCH LOWER THAN INFLUENZA, 685 00:29:26,160 --> 00:29:28,040 UH BUT IT IS THERE. 686 00:29:28,040 --> 00:29:31,000 CAN WE, IF YOU LOOK AT BLOOD, 687 00:29:31,000 --> 00:29:32,200 YOU WILL SEE THIS IS LIKE 688 00:29:32,200 --> 00:29:34,240 EVERYONE ELSE YOU HAVE A VERY 689 00:29:34,240 --> 00:29:36,240 NICE INCREASE EARLY ON, BUT THEN 690 00:29:36,240 --> 00:29:38,280 YOU HAVE THIS DECAY WHICH GOT 691 00:29:38,280 --> 00:29:40,360 SOME PEOPLE CONCERNED AFTER THE 692 00:29:40,360 --> 00:29:41,240 PEAK RESPONSES. 693 00:29:41,240 --> 00:29:42,560 WE THOUGHT THIS IS NORMAL 694 00:29:42,560 --> 00:29:45,480 BECAUSE THIS WILL BE THE PLASMA 695 00:29:45,480 --> 00:29:51,280 PLUS DRIVEN ANTIBODIES AND THESE 696 00:29:51,280 --> 00:29:53,320 PLASMABLASTS WILL DIE, BUT LATER 697 00:29:53,320 --> 00:29:55,480 YOU HAVE GERMINAL CENTER AND 698 00:29:55,480 --> 00:29:57,280 BONE MARROW CELLS. 699 00:29:57,280 --> 00:29:59,760 THESE ANTIBODIES SHOULD BE MORE 700 00:29:59,760 --> 00:30:00,160 MATURE. 701 00:30:00,160 --> 00:30:02,120 BETWEEN THESE TWO TIME POINTS 702 00:30:02,120 --> 00:30:04,440 THERE IS ROBUST GERMINAL CENTER 703 00:30:04,440 --> 00:30:04,680 REACTION. 704 00:30:04,680 --> 00:30:06,960 TO ENSURE THIS IS THE CASE, SO 705 00:30:06,960 --> 00:30:10,040 WE PICKED EIGHT INDIVIDUALS THAT 706 00:30:10,040 --> 00:30:14,720 GIVE US THE THREE TIME POINTS, 707 00:30:14,720 --> 00:30:16,560 BLOOD, LYMPH NODE AND BONE 708 00:30:16,560 --> 00:30:18,400 MARROW AND SEQUENCE THE GERMINAL 709 00:30:18,400 --> 00:30:20,560 CENTER FROM THE LYMPH NODE AND 710 00:30:20,560 --> 00:30:23,000 THE LYMPH NODE PLASMA CELLS. 711 00:30:23,000 --> 00:30:27,640 WE MADE THE CORRESPONDING 712 00:30:27,640 --> 00:30:30,160 MONOBJECTION CLONAL ANTIBODIES 713 00:30:30,160 --> 00:30:32,800 AND TESTED THAT. 714 00:30:32,800 --> 00:30:35,160 THAT GAVE US MORE THAN 1,500 715 00:30:35,160 --> 00:30:37,040 CLONES COMBINED BETWEEN THE 716 00:30:37,040 --> 00:30:38,760 EIGHT INDIVIDUALS BINDING TO THE 717 00:30:38,760 --> 00:30:39,680 SPIKE PROTEIN. 718 00:30:39,680 --> 00:30:43,400 NOW WE HAVE MORE THAN 15,000 719 00:30:43,400 --> 00:30:44,040 FINGERPRINT FROM EIGHT 720 00:30:44,040 --> 00:30:46,960 INDIVIDUALS WE CAN FOLLOW OVER 721 00:30:46,960 --> 00:30:47,320 TIME. 722 00:30:47,320 --> 00:30:50,440 DOES THIS ROBUST GERMINAL CENTER 723 00:30:50,440 --> 00:30:51,640 REACTION GIVE YOU THIS 724 00:30:51,640 --> 00:30:54,400 ENHANCEMENT OF YOUR CAPACITY TO 725 00:30:54,400 --> 00:30:55,840 ACTUALLY NEUTRALIZE THE VIRUS. 726 00:30:55,840 --> 00:30:58,920 WHAT IS THE POINT OF INVESTING, 727 00:30:58,920 --> 00:31:02,240 OF HAVING THIS ROBUST GERMINAL 728 00:31:02,240 --> 00:31:02,720 CENTER REACTION. 729 00:31:02,720 --> 00:31:05,600 TO GO BACK TO THE SEQUENCING 730 00:31:05,600 --> 00:31:05,880 DATA. 731 00:31:05,880 --> 00:31:08,120 EVERYTHING I'M GOING TO SHOW YOU 732 00:31:08,120 --> 00:31:10,000 IS ANGO SPECIFIC. 733 00:31:10,000 --> 00:31:11,760 WE TESTED THESE MODELS AND ASKED 734 00:31:11,760 --> 00:31:14,400 THE SAME QUESTION, IF WE LOOK AT 735 00:31:14,400 --> 00:31:17,000 THE PLASMABLAST IN BLOOD EARLY 736 00:31:17,000 --> 00:31:18,560 ON, HOW MUCH OF THAT RESPONSE 737 00:31:18,560 --> 00:31:20,120 OVERLAPS WITH THE GC? 738 00:31:20,120 --> 00:31:22,360 IN THE EIGHT INDIVIDUALS WE SEE 739 00:31:22,360 --> 00:31:23,520 VARIABLE FRACTIONS. 740 00:31:23,520 --> 00:31:24,920 EVERYONE SHOWED SOME OVERLAP. 741 00:31:24,920 --> 00:31:28,240 THIS IS CONFIRMING WHAT WE SAW 742 00:31:28,240 --> 00:31:30,600 WITH INFLUENZA. 743 00:31:30,600 --> 00:31:33,120 YOU CAN HAVE MEMORY CELLS IN THE 744 00:31:33,120 --> 00:31:33,640 GC. 745 00:31:33,640 --> 00:31:36,640 IN THE PLASMABLAST AND -- 746 00:31:36,640 --> 00:31:40,400 BUT IMPORTANTLY, WE CAN TRACK IF 747 00:31:40,400 --> 00:31:44,200 A SAME CLONE BECAME A 748 00:31:44,200 --> 00:31:45,000 PLASMABLAST. 749 00:31:45,000 --> 00:31:53,400 A CRONE WILL PRORIFF PROLIFERATE 750 00:31:53,400 --> 00:31:54,840 AND WE CAN TRACK THE SAME CLONE. 751 00:31:54,840 --> 00:31:59,600 IF IT IS A PLASMA BLAST IS THE 752 00:31:59,600 --> 00:32:03,360 LEVEL OF MUTATIONS. 753 00:32:03,360 --> 00:32:06,240 PLASMA BLAST DETECTED ONE WEEK 754 00:32:06,240 --> 00:32:06,440 AFTER. 755 00:32:06,440 --> 00:32:08,560 GC HAS ALMOST THE SAME MUTATION. 756 00:32:08,560 --> 00:32:10,400 IF YOU CHECK THIS OVER TIME, YOU 757 00:32:10,400 --> 00:32:13,560 SEE THE SAME CLONE IN THE 758 00:32:13,560 --> 00:32:15,440 GERMINAL CENTER EMANATED MUCH 759 00:32:15,440 --> 00:32:18,520 MORE SIGNIFICANT MUTATIONS. 760 00:32:18,520 --> 00:32:21,400 HAVING THAT GERMINAL CENTER IS 761 00:32:21,400 --> 00:32:23,880 GREAT BECAUSE IT IS WHAT WE 762 00:32:23,880 --> 00:32:25,320 SHOULD EXPECT. 763 00:32:25,320 --> 00:32:27,120 LYMPH NODE PLASMA KROLLS, I 764 00:32:27,120 --> 00:32:28,800 MEENGSED THEY ARE LIKELY COMING 765 00:32:28,800 --> 00:32:29,760 FROM THE GC. 766 00:32:29,760 --> 00:32:31,800 IF THIS IS THE CASE THEY SHOULD 767 00:32:31,800 --> 00:32:34,520 BE IDENTICAL AND MUTATION RATES 768 00:32:34,520 --> 00:32:37,240 SHOULD NOT HAVE THAT DYNAMICS. 769 00:32:37,240 --> 00:32:42,800 IF WE ARE COMPARING THEM TO GC B 770 00:32:42,800 --> 00:32:46,240 CELLS THEY SHOULD BE ON THE SAME 771 00:32:46,240 --> 00:32:51,640 LEVEL. 772 00:32:51,640 --> 00:32:53,520 WHAT YOU SEE HERE IS THE 773 00:32:53,520 --> 00:32:54,400 MUTATION RATE. 774 00:32:54,400 --> 00:32:56,080 WHAT ABOUT THE BONE MARROW 775 00:32:56,080 --> 00:32:56,960 PLASMA CELLS. 776 00:32:56,960 --> 00:32:59,320 ARE THE CELLS THAT ARE SPIKE 777 00:32:59,320 --> 00:33:00,800 SPECIFIC, ARE THEY COMING FROM 778 00:33:00,800 --> 00:33:03,240 HIGH LEVEL OF MUTATIONS OR LOW 779 00:33:03,240 --> 00:33:03,440 LEVEL? 780 00:33:03,440 --> 00:33:07,360 SO WE DID THIS ANALYSIS 781 00:33:07,360 --> 00:33:09,880 COMPARING PLASMA BLAST, LYMPH 782 00:33:09,880 --> 00:33:12,480 NODE AND BONE MARROW AT THE 783 00:33:12,480 --> 00:33:13,680 SIX-MONTH TIME POINT. 784 00:33:13,680 --> 00:33:17,040 THAT IS WHAT WE SEE HERE, A 785 00:33:17,040 --> 00:33:18,400 RESPONDING PLASMA BLAST, 786 00:33:18,400 --> 00:33:20,240 MUTATIONS OVER TIME AND 787 00:33:20,240 --> 00:33:23,120 STRIKINGLY BONE MARROW PLASMA 788 00:33:23,120 --> 00:33:24,520 CELLS HAVE ALMOST THE SAME 789 00:33:24,520 --> 00:33:26,120 MUTATIONS AT THE LYMPH NODE AT 790 00:33:26,120 --> 00:33:26,960 THE SAME TIME POINT. 791 00:33:26,960 --> 00:33:29,120 THIS GIVES US THIS IDEA THAT, 792 00:33:29,120 --> 00:33:32,400 WELL, ACTUALLY, IT IS LIKELY 793 00:33:32,400 --> 00:33:33,960 THOSE LYMPH NODE PLASMA CELLS 794 00:33:33,960 --> 00:33:35,480 ARE SHIPPED TO THE BONE MARROW, 795 00:33:35,480 --> 00:33:36,040 WHICH IS GREAT. 796 00:33:36,040 --> 00:33:38,760 THE CELLS THAT ARE COMING OUT 797 00:33:38,760 --> 00:33:40,280 HERE, THE ANTIBODIES PRODUCED BY 798 00:33:40,280 --> 00:33:50,800 THOSE CELLS SHOULD BE HIGHER 799 00:33:52,360 --> 00:33:52,840 QUALITY. 800 00:33:52,840 --> 00:33:55,240 WE HAVE ALL THE SEQUENCES AND WE 801 00:33:55,240 --> 00:33:59,280 KNOW THERE ARE ANGI SPECIFIC. 802 00:33:59,280 --> 00:34:02,680 WE CAN EXPRESS THE ANTIBODIES AS 803 00:34:02,680 --> 00:34:04,800 A PLASMA BLAST. 804 00:34:04,800 --> 00:34:06,960 WE CAN EXPRESS IT AS A BONE 805 00:34:06,960 --> 00:34:10,080 MARROW PLASMA CELLS ADDING THE 806 00:34:10,080 --> 00:34:13,880 MUTATIONS NATURALLY ACCUMULATED. 807 00:34:13,880 --> 00:34:16,800 THE FIRST ANTIBODY BINDING 808 00:34:16,800 --> 00:34:17,240 AFFINITY. 809 00:34:17,240 --> 00:34:18,760 OR BY NEUTRALIZATION. 810 00:34:18,760 --> 00:34:23,600 YOU CAN SEE IN BOTH CASES 811 00:34:23,600 --> 00:34:26,080 ANTIBODY THAT BECAME STRONGER 812 00:34:26,080 --> 00:34:29,400 BINDING FOR THE MOST PARTS IT 813 00:34:29,400 --> 00:34:31,480 BECAME BETTER NEUTRALIZERS. 814 00:34:31,480 --> 00:34:33,120 AFTER THESE TWO DOSES, THIS IS 815 00:34:33,120 --> 00:34:35,800 THE FIRST TWO DOSES WERKS HAD A 816 00:34:35,800 --> 00:34:36,880 REALLY ROBUST RESPONSE. 817 00:34:36,880 --> 00:34:39,440 MOST OF THE EARLY ANTIBODIES 818 00:34:39,440 --> 00:34:42,960 WERE DRAWN FROM SHORT LIVED 819 00:34:42,960 --> 00:34:44,040 PLASMA BLAST. 820 00:34:44,040 --> 00:34:46,600 AFTER A ROBUST GERMINAL CENTERS 821 00:34:46,600 --> 00:34:52,360 WHERE B CELLS ARE RESPONDING 822 00:34:52,360 --> 00:34:54,440 ALLOWED THEM TO BECOME LATER 823 00:34:54,440 --> 00:34:57,680 LIKELY THE BONE MARROW CELLS. 824 00:34:57,680 --> 00:34:59,320 THE ANTIBODY WILL BE LESS IN 825 00:34:59,320 --> 00:35:00,880 MAGNITUDE, BUT HIGHER IN 826 00:35:00,880 --> 00:35:01,480 QUALITY. 827 00:35:01,480 --> 00:35:04,440 WE PUBLISHED THIS YEAR LAST WEEK 828 00:35:04,440 --> 00:35:08,000 AND OBVIOUSLY, WE ALL KNOW WHAT 829 00:35:08,000 --> 00:35:08,280 HAPPENED. 830 00:35:08,280 --> 00:35:10,680 THE VIRUS DIDN'T -- AND WE GOT 831 00:35:10,680 --> 00:35:13,000 TO LEARN MORE LESSONS FROM THE 832 00:35:13,000 --> 00:35:14,600 FAROE ISLANDS. 833 00:35:14,600 --> 00:35:17,760 A PREPRINT CAME OUT IN DECEMBER 834 00:35:17,760 --> 00:35:20,200 2021 ABOUT A MEETING IN HEALTH 835 00:35:20,200 --> 00:35:23,640 CARE WORKERS IN THESE ISLANDS OF 836 00:35:23,640 --> 00:35:25,560 PEOPLE, 33 HEALTH CARE WORKERS 837 00:35:25,560 --> 00:35:27,360 HAD THIS SOCIAL GATHERING. 838 00:35:27,360 --> 00:35:32,760 ALL OF THEM HAVE BEEN TRIPLE 839 00:35:32,760 --> 00:35:37,120 VACCINATED WITH THE PFIZER 840 00:35:37,120 --> 00:35:39,600 VACCINE, TRIPLE VACCINATED AND 841 00:35:39,600 --> 00:35:39,840 BOOSTED. 842 00:35:39,840 --> 00:35:42,200 ALL OF THEM TESTED NEGATIVE 843 00:35:42,200 --> 00:35:44,280 BEFORE THAT SOCIAL GATHERING. 844 00:35:44,280 --> 00:35:48,200 WE KNOW WHAT HAPPENED. 845 00:35:48,200 --> 00:35:52,120 OMICRON CAME IN. 846 00:35:52,120 --> 00:35:54,120 OUR VACCINE DIDN'T BLOCK THE 847 00:35:54,120 --> 00:35:55,360 INFECTION, EVEN THREE DOSES 848 00:35:55,360 --> 00:35:57,800 AFTER ALL OF THESE RESPONSES. 849 00:35:57,800 --> 00:36:00,000 I'M NOT GOING TO DISCUSS WHY 850 00:36:00,000 --> 00:36:01,000 THIS IS THE CASE BECAUSE THERE 851 00:36:01,000 --> 00:36:02,440 ARE SO MANY REASONS. 852 00:36:02,440 --> 00:36:04,600 I'M NOT GOING TO STUDY THAT, BUT 853 00:36:04,600 --> 00:36:06,480 THERE'S MANY REASONS WHY WE CAN 854 00:36:06,480 --> 00:36:10,040 HAVE A GOOD IMMUNE RESPONSE BUT 855 00:36:10,040 --> 00:36:20,560 ONCE THE VIRUS ANTIGENETICALLY 856 00:36:23,360 --> 00:36:25,920 CHANGED. 857 00:36:25,920 --> 00:36:26,440 OMCRON HAS SIGNIFICANT 858 00:36:26,440 --> 00:36:30,920 MUTATIONS. 859 00:36:30,920 --> 00:36:34,840 MODERNA MADE THE BIVALUE LENT. 860 00:36:34,840 --> 00:36:36,840 MODERNA ASKED CAN WE SEE IF 861 00:36:36,840 --> 00:36:40,560 HAVING A BIVALENT VACCINE WILL 862 00:36:40,560 --> 00:36:43,960 HELP IN REDUCING NAIVE B-CELLS? 863 00:36:43,960 --> 00:36:46,120 IF YOU BOOST PEOPLE THAT HAVE 864 00:36:46,120 --> 00:36:49,720 ALREADY BEEN IMMUNIZED WITH MRNA 865 00:36:49,720 --> 00:36:51,480 VACCINE, THEY HAVE THIS REALLY 866 00:36:51,480 --> 00:36:56,840 NICE MEMORY B-CELL COMPARTMENT, 867 00:36:56,840 --> 00:36:59,560 IF YOU BOOST THEM WITH A VACCINE 868 00:36:59,560 --> 00:37:02,920 WITH NOVEL SPIKE, CAN WE GET A 869 00:37:02,920 --> 00:37:03,160 RESPONSE? 870 00:37:03,160 --> 00:37:06,040 WE RECRUITED NINE PEOPLE, GAVE 871 00:37:06,040 --> 00:37:11,400 THEM THE BIVALENT VACCINE AND 872 00:37:11,400 --> 00:37:13,080 EVERYBODY RESPONDED ROBUSTLY TO 873 00:37:13,080 --> 00:37:15,320 THE PLASMA BLAST. 874 00:37:15,320 --> 00:37:16,560 HOW ABOUT THE GERMINAL CENTER. 875 00:37:16,560 --> 00:37:18,840 EIGHT WEEKS, THIS IS TWO MONTHS. 876 00:37:18,840 --> 00:37:20,800 REMEMBER, MY EXPERIENCE WITH 877 00:37:20,800 --> 00:37:23,120 INFLUENZA IS THE GERMINAL CENTER 878 00:37:23,120 --> 00:37:24,800 IS WHERE IT SHOULD BE. 879 00:37:24,800 --> 00:37:27,760 WE HAVE THIS WINDOW TO INDUCE 880 00:37:27,760 --> 00:37:30,120 NAIVE B-CELLS. 881 00:37:30,120 --> 00:37:36,640 LET'S INVESTIGATOR -- LET'S GO 882 00:37:36,640 --> 00:37:44,680 FOR THE GERMINAL CENTER. 883 00:37:44,680 --> 00:37:46,160 AND WE MADE SURE THAT NONE OF 884 00:37:46,160 --> 00:37:51,840 THE INDIVIDUALS GOT INFECTED. 885 00:37:51,840 --> 00:37:53,960 WE LOOKED AT THE RESPONSE 886 00:37:53,960 --> 00:37:55,800 AGAINST SARS-COV-2 AND IT WAS A 887 00:37:55,800 --> 00:37:56,080 FLATLINE. 888 00:37:56,080 --> 00:37:58,040 AFTER THE NINE PEOPLE, FEW 889 00:37:58,040 --> 00:38:00,400 RESPONDED, WELL, WE ALMOST SAW 890 00:38:00,400 --> 00:38:01,160 RESPONSES IN EVERYONE EXCEPT 891 00:38:01,160 --> 00:38:01,680 THIS PERSON. 892 00:38:01,680 --> 00:38:03,880 FIVE IN THE MIDDLE HERE 893 00:38:03,880 --> 00:38:05,960 RESPONDED VERY ROBUSTLY AGAINST 894 00:38:05,960 --> 00:38:09,160 THE SPIKE PROTEIN. 895 00:38:09,160 --> 00:38:13,040 GC B-CELLS, THE SPIKE PROTEIN. 896 00:38:13,040 --> 00:38:15,640 WE DON'T KNOW HOW MANY OF THOSE, 897 00:38:15,640 --> 00:38:17,560 WITH THE ORIGINAL SPIKE. 898 00:38:17,560 --> 00:38:19,120 WE DON'T KNOW HOW MANY OF THOSE 899 00:38:19,120 --> 00:38:21,440 COULD BE NAIVE OR COULD BE 900 00:38:21,440 --> 00:38:25,920 COMING AGAINST THE OMICRON 901 00:38:25,920 --> 00:38:26,120 SPIKE. 902 00:38:26,120 --> 00:38:29,240 WE WENT BACK TO THE GC B-CELLS 903 00:38:29,240 --> 00:38:31,160 FROM THE FIVE INDIVIDUALS AND 904 00:38:31,160 --> 00:38:33,480 SINGLE CELL SORTED EVERY SINGLE 905 00:38:33,480 --> 00:38:33,840 ONE. 906 00:38:33,840 --> 00:38:35,400 AND THIS IS WHAT I'M SHOWING YOU 907 00:38:35,400 --> 00:38:35,600 HERE. 908 00:38:35,600 --> 00:38:40,760 WE LOOKED AT THE LYMPH NODES, 909 00:38:40,760 --> 00:38:43,760 AND THE 10X, SINGLE CELL 910 00:38:43,760 --> 00:38:46,640 SEQUENCE OF B 10X ANALYSIS OF 911 00:38:46,640 --> 00:38:47,920 THOSE RESPONDING B-CELLS. 912 00:38:47,920 --> 00:38:50,200 WE CAN LOOK AT THE GERMINAL 913 00:38:50,200 --> 00:38:50,400 CENTER. 914 00:38:50,400 --> 00:38:52,840 TOOK EVERY ONE OF THEM, MADE THE 915 00:38:52,840 --> 00:38:54,440 CORRESPONDING ANTIBODIES, TESTED 916 00:38:54,440 --> 00:38:55,840 AGAINST THE SPIKES AND MAKE SURE 917 00:38:55,840 --> 00:38:58,440 THEY ARE ALL BINDING TO THE 918 00:38:58,440 --> 00:38:58,680 SPIKE. 919 00:38:58,680 --> 00:39:01,600 BUT WE TESTED THEM AGAINST BOTH 920 00:39:01,600 --> 00:39:03,440 SPIKES, ARE THEY BINDING TO THE 921 00:39:03,440 --> 00:39:07,120 ORIGINAL SPIKE OR BINDING TO THE 922 00:39:07,120 --> 00:39:08,520 OMICRON SPIKE OR BINDING TO 923 00:39:08,520 --> 00:39:17,760 BOTH? 924 00:39:17,760 --> 00:39:20,600 WE EXPECT A LOT TO BE CROSS 925 00:39:20,600 --> 00:39:21,240 REACTIVE BECAUSE THOSE PEOPLE 926 00:39:21,240 --> 00:39:22,440 ARE IMMUNE. 927 00:39:22,440 --> 00:39:25,000 WE DIDN'T GET A SINGLE YAENT 928 00:39:25,000 --> 00:39:30,520 BODY THAT BOUND TO B1, OMICRON, 929 00:39:30,520 --> 00:39:32,040 BUT NOT TO THE ORIGINAL. 930 00:39:32,040 --> 00:39:33,960 THIS IS NOT ABOUT DETECTION. 931 00:39:33,960 --> 00:39:37,160 WE SEQUENCED EVERY CELL AND MADE 932 00:39:37,160 --> 00:39:40,000 THEM MONOCLONAL. 933 00:39:40,000 --> 00:39:42,080 IT IS NOT THAT WE COULDN'T 934 00:39:42,080 --> 00:39:44,000 DETECT THEM BECAUSE WE DIDN'T GO 935 00:39:44,000 --> 00:39:44,640 DEEP ENOUGH. 936 00:39:44,640 --> 00:39:47,320 WE WENT AS DEEP AS WE COULD GO 937 00:39:47,320 --> 00:39:49,200 IN THIS FIVE INDIVIDUALS AND 938 00:39:49,200 --> 00:39:53,960 COULDN'T DETECT A SINGLE B1 939 00:39:53,960 --> 00:39:54,600 SPECIFIC. 940 00:39:54,600 --> 00:39:56,960 SO I THOUGHT MAYBE WE WENT TOO 941 00:39:56,960 --> 00:39:57,160 EARLY. 942 00:39:57,160 --> 00:39:59,360 HERE EIGHT WEEKS IS MAYBE TOO 943 00:39:59,360 --> 00:39:59,720 EARLY. 944 00:39:59,720 --> 00:40:02,440 AND ALSO THE OTHER THING IS THIS 945 00:40:02,440 --> 00:40:06,880 VACCINE HAS A 50% ORIGINAL 946 00:40:06,880 --> 00:40:08,000 STRAIN MRNA SO MAYBE THAT 947 00:40:08,000 --> 00:40:10,440 BIASSED THE RESPONSE TO THE 948 00:40:10,440 --> 00:40:12,160 CROSS REACTIVE ANTIBODIES WE SEE 949 00:40:12,160 --> 00:40:14,760 HERE, THE 71% HERE. 950 00:40:14,760 --> 00:40:17,920 I REACH OUT TO MODERNA AND I 951 00:40:17,920 --> 00:40:21,360 SAID YOU HAVE THE MONO VALENT 952 00:40:21,360 --> 00:40:21,720 VACCINE. 953 00:40:21,720 --> 00:40:25,080 SO IF I COMPARE THAT AND INSTEAD 954 00:40:25,080 --> 00:40:28,520 OF LOOKING AT EIGHT WEEKS LOOK 955 00:40:28,520 --> 00:40:29,800 AT FOUR MONTHS AFTER BOOST, I 956 00:40:29,800 --> 00:40:32,840 CAN SEE IF THERE IS A CHANCE OF 957 00:40:32,840 --> 00:40:34,640 GETTING THE NAIVE RESPONSE TO BE 958 00:40:34,640 --> 00:40:34,840 ENGAGED. 959 00:40:34,840 --> 00:40:37,760 I COMPARED THAT TO PEOPLE WHO 960 00:40:37,760 --> 00:40:41,000 GOT LIKE MOST OF US THE ORIGINAL 961 00:40:41,000 --> 00:40:43,360 VACCINE AS A BOOSTER 962 00:40:43,360 --> 00:40:43,680 IMMUNIZATION. 963 00:40:43,680 --> 00:40:46,000 SO WE HAVE THE EIGHT PEOPLE THAT 964 00:40:46,000 --> 00:40:50,400 WE GOT THE MONO VALENT AND WE 965 00:40:50,400 --> 00:40:52,360 PICKED THREE PEOPLE FROM EACH 966 00:40:52,360 --> 00:40:54,760 AND SORTED THEIR MEMORY CELLS AT 967 00:40:54,760 --> 00:40:56,640 FOUR MONTHS' TIME POINT. 968 00:40:56,640 --> 00:40:59,720 WE LOOKED AT TOTAL MEMORY 969 00:40:59,720 --> 00:41:03,080 WHATEVER BOUND TO EITHER SPIKE, 970 00:41:03,080 --> 00:41:04,160 SINGLE CELL THEM AND ASKED THE 971 00:41:04,160 --> 00:41:06,360 SAME QUESTION, CAN ANY OF THE 972 00:41:06,360 --> 00:41:08,120 ANTIBODIES BIND TO THE OMICRON? 973 00:41:08,120 --> 00:41:10,440 WELL, IF YOU HAVE BEEN ONLY 974 00:41:10,440 --> 00:41:12,480 IMMUNIZED WITH THE ORIGINAL 975 00:41:12,480 --> 00:41:14,760 STRAIN, SO FOR EXAMPLE, TWO 976 00:41:14,760 --> 00:41:16,920 PFIZER, TWO MODERNA EARLY ON AND 977 00:41:16,920 --> 00:41:22,360 GOT THE THIRD, THE MONOCLONAL IS 978 00:41:22,360 --> 00:41:23,600 COMING OUT. 979 00:41:23,600 --> 00:41:25,120 YOU SHOULDN'T EXPECT ANYTHING TO 980 00:41:25,120 --> 00:41:26,880 BE OMICRON SPECIFIC AND THAT IS 981 00:41:26,880 --> 00:41:27,960 WHAT WE SEE HERE. 982 00:41:27,960 --> 00:41:31,320 IF YOU HAVE BEEN EXPOSED TO THE 983 00:41:31,320 --> 00:41:34,720 ORIGINAL STREAM, PFIZER OR 984 00:41:34,720 --> 00:41:37,360 MODERNA, YOU HAVE 2/3, BUT 1/3 985 00:41:37,360 --> 00:41:41,240 SPECIFIC TO ORIGINAL. 986 00:41:41,240 --> 00:41:42,920 AS YOU WOULD EXPECT, THERE IS 987 00:41:42,920 --> 00:41:44,400 NOTHING HERE SPECIFIC TO THE 988 00:41:44,400 --> 00:41:46,600 OMICRON BY ITSELF. 989 00:41:46,600 --> 00:41:49,560 BUT NOW I PREDICTED THAT WE HAVE 990 00:41:49,560 --> 00:41:53,320 WAY MORE ANTIBODIES AGAINST BA1 991 00:41:53,320 --> 00:41:54,240 AND I WAS WRONG. 992 00:41:54,240 --> 00:41:57,120 NONE OF THE ANTIBODIES -- SO IF 993 00:41:57,120 --> 00:42:02,080 YOU HAVE BEEN BOOSTED WITH MONO 994 00:42:02,080 --> 00:42:05,120 VALENT BA1 AND WAIT FOUR MONTHS, 995 00:42:05,120 --> 00:42:06,640 THERE IS STILL SIGNIFICANT CROSS 996 00:42:06,640 --> 00:42:10,640 REACTIVE ANTIBODIES, BUT NONE 997 00:42:10,640 --> 00:42:11,960 BOUND TO THE BA1. 998 00:42:11,960 --> 00:42:13,600 I THOUGHT THIS IS VERY DIFFERENT 999 00:42:13,600 --> 00:42:15,800 FROM WHAT WE EXPECT, FROM WHAT I 1000 00:42:15,800 --> 00:42:16,120 EXPECTED. 1001 00:42:16,120 --> 00:42:17,680 SO I THOUGHT MAYBE BECAUSE WE 1002 00:42:17,680 --> 00:42:20,760 ARE LOOKING AT MEMORY, WE ARE 1003 00:42:20,760 --> 00:42:22,080 NOT GOING DEEP ENOUGH. 1004 00:42:22,080 --> 00:42:24,560 TO GO DEEPER IN THIS COMPARTMENT 1005 00:42:24,560 --> 00:42:28,120 AND DETECT ANY BA1 SPECIFIC, I 1006 00:42:28,120 --> 00:42:33,040 SORTED THE BA1 SPECIFIC MEMORY 1007 00:42:33,040 --> 00:42:33,240 CELLS. 1008 00:42:33,240 --> 00:42:35,880 THIS IS VERY TARGETED TO BA1. 1009 00:42:35,880 --> 00:42:41,000 FROM THOSE CELLS, THE ONE THAT 1010 00:42:41,000 --> 00:42:42,560 TENDED TO NOT BIND FROM THE 1011 00:42:42,560 --> 00:42:43,120 WASHINGTON STRAIN. 1012 00:42:43,120 --> 00:42:49,000 WE MADE THE MONOCLONALS AND CAN 1013 00:42:49,000 --> 00:42:52,120 WE SEE THE BA1 CELLS? 1014 00:42:52,120 --> 00:42:57,080 AFTER DOING THAT, SIX 1015 00:42:57,080 --> 00:43:00,080 MONOCLONALS THAT ONLY BOUND TO 1016 00:43:00,080 --> 00:43:10,360 BA1 NOT THE WA1. 1017 00:43:10,360 --> 00:43:12,680 THEY SHOULD HAVE SLIGHTLY LOWER 1018 00:43:12,680 --> 00:43:14,640 MUTATIONS AND INDEED HAVE LOWER 1019 00:43:14,640 --> 00:43:16,440 MUTATIONS COMPARED TO THE CROSS 1020 00:43:16,440 --> 00:43:17,680 REACTIVE ONES. 1021 00:43:17,680 --> 00:43:20,240 ONE COULD ASK, WHY DO WE CARE? 1022 00:43:20,240 --> 00:43:23,920 WHY THE INSISTENCE OF SHOWING WE 1023 00:43:23,920 --> 00:43:26,920 HAVE THESE NAIVE RESPONSES? 1024 00:43:26,920 --> 00:43:30,720 BECAUSE THOSE SIX MONOCLONALS, 1025 00:43:30,720 --> 00:43:31,480 RESIST BA1. 1026 00:43:31,480 --> 00:43:33,040 IT IS NOT A LUXURY. 1027 00:43:33,040 --> 00:43:35,360 YOU ACTUALLY INCREASE YOUR 1028 00:43:35,360 --> 00:43:41,760 ABILITY TO ADD TO YOUR 1029 00:43:41,760 --> 00:43:43,600 NEUTRALIZING BA SPOBSS TO THE 1030 00:43:43,600 --> 00:43:44,600 ORIGINAL STRAIN. 1031 00:43:44,600 --> 00:43:50,080 THE FACT BECAUSE THEY ARE 1032 00:43:50,080 --> 00:43:53,640 NEUTRALIZING, WE WERE ABLE TO 1033 00:43:53,640 --> 00:43:54,080 MAP WHERE THEY BIND. 1034 00:43:54,080 --> 00:43:57,360 THIS IS WITH THE VSV, NOT THE 1035 00:43:57,360 --> 00:43:58,800 REAL VIRUS, PSEUDOTYPE. 1036 00:43:58,800 --> 00:44:02,560 THE VSV WERE PSEUDOTYPE WITH BA1 1037 00:44:02,560 --> 00:44:09,520 AND WE GENERATED, WE SEQUENCED 1038 00:44:09,520 --> 00:44:14,400 FROM THIS NEUTRALIZATION AND WE 1039 00:44:14,400 --> 00:44:17,160 WERE ABLE TO SHOW THE RESIDUES 1040 00:44:17,160 --> 00:44:18,960 THEY ARE LIKELY RECOGNIZING ARE 1041 00:44:18,960 --> 00:44:23,720 ONLY SPECIFIC TO BA1. 1042 00:44:23,720 --> 00:44:25,680 SO AFTER ALL OF THAT, WHAT WE 1043 00:44:25,680 --> 00:44:28,760 LEARNED IS THE BA1 RESPONSE OR 1044 00:44:28,760 --> 00:44:34,960 THE OMICRON RESPONSE CAN ENGAGE 1045 00:44:34,960 --> 00:44:39,560 IS VERY IMMUNOGENI THAT 1046 00:44:39,560 --> 00:44:41,000 GENERATED MANY B-CELLS. 1047 00:44:41,000 --> 00:44:44,160 A BOOSTER ENGAGED THE MEMORY 1048 00:44:44,160 --> 00:44:46,960 B-CELLS AND BROUGHT THEM BABLG 1049 00:44:46,960 --> 00:44:48,160 TO THE GERMINAL CENTER REACTION. 1050 00:44:48,160 --> 00:44:51,160 WE SHOWED WITH INFLUENZA AND 1051 00:44:51,160 --> 00:44:54,200 SHOWED WITH THE BA1 VACCINE. 1052 00:44:54,200 --> 00:44:57,320 CHANGING THE VACCINE CAN ALLOW 1053 00:44:57,320 --> 00:45:03,840 ENGAGEMENT OF BA CELLS. 1054 00:45:03,840 --> 00:45:07,520 THIS ENGAGEMENT CAN BE NOT VERY 1055 00:45:07,520 --> 00:45:07,800 EFFICIENT. 1056 00:45:07,800 --> 00:45:09,880 IF YOU ARE CLOSELY RELATED 1057 00:45:09,880 --> 00:45:11,480 SEQUENCE WISE TO THE ORIGINAL 1058 00:45:11,480 --> 00:45:13,160 STRAIN, THIS WILL ALLOW A LOT OF 1059 00:45:13,160 --> 00:45:15,960 MEMORY CELLS TO BE ENGAGED. 1060 00:45:15,960 --> 00:45:18,880 AND THEN ALSO WE KNEW FROM OUR 1061 00:45:18,880 --> 00:45:20,840 PREVIOUS WORK WITH RAFY, ONE 1062 00:45:20,840 --> 00:45:22,560 DOSE MIGHT NOT BE ENOUGH TO GET 1063 00:45:22,560 --> 00:45:27,640 A DETECTABLE RESPONSE. 1064 00:45:27,640 --> 00:45:30,880 ONE DOSE LIKELY MULTIPLE 1065 00:45:30,880 --> 00:45:33,000 RESPONSE TO OMICRON WILL 1066 00:45:33,000 --> 00:45:35,680 INCREASE AND MORE DETECTABLE IN 1067 00:45:35,680 --> 00:45:39,080 THE NYE VEEF RESPONSES. 1068 00:45:39,080 --> 00:45:40,320 ANOTHER SURPRISE WE LEARNED IN 1069 00:45:40,320 --> 00:45:44,400 OUR STUDY, WE DIDN'T PREDICT AT 1070 00:45:44,400 --> 00:45:47,080 ALL, IS GERMINAL RESPONSE IN 1071 00:45:47,080 --> 00:45:49,520 HUMAN CANS BE PERSISTENT AND 1072 00:45:49,520 --> 00:45:51,480 LONGER THAN ANY PREDICTION FROM 1073 00:45:51,480 --> 00:45:52,720 SMALL ANIMAL MODELS. 1074 00:45:52,720 --> 00:45:55,160 WE WERE THINKING THIS IS 1075 00:45:55,160 --> 00:45:56,800 SOMETHING SPECIFIC TO THE MRNA 1076 00:45:56,800 --> 00:45:57,760 PLATFORM, BUT WE DON'T THINK 1077 00:45:57,760 --> 00:45:58,760 THIS IS THE CASE. 1078 00:45:58,760 --> 00:45:59,960 WE THINK THIS IS REALLY 1079 00:45:59,960 --> 00:46:02,640 SOMETHING THAT RELIES ON THE 1080 00:46:02,640 --> 00:46:04,000 CONTEXT WHERE THE VACCINE WAS 1081 00:46:04,000 --> 00:46:05,680 GIVEN OR WHO GETS THE VACCINE 1082 00:46:05,680 --> 00:46:07,640 AND THE PREEXISTING IMMUNITY. 1083 00:46:07,640 --> 00:46:12,000 THIS WORK COMES FROM -- LAB AS 1084 00:46:12,000 --> 00:46:12,320 WELL. 1085 00:46:12,320 --> 00:46:14,880 THE PREEXISTS BASELINE SITS 1086 00:46:14,880 --> 00:46:17,920 THERE AT THE ROBUSTNESS AND 1087 00:46:17,920 --> 00:46:24,120 DURATION OF THE RESPONSE. 1088 00:46:24,120 --> 00:46:29,240 LE INDUCTION OF PERSISTENT GC IS 1089 00:46:29,240 --> 00:46:30,360 WHAT KEEPS IT GOING. 1090 00:46:30,360 --> 00:46:31,920 WE REALLY DON'T KNOW. 1091 00:46:31,920 --> 00:46:34,240 WE WOULD LIKE TO SHOW THAT. 1092 00:46:34,240 --> 00:46:38,240 AND ALSO THIS BRINGS ME TO 1093 00:46:38,240 --> 00:46:40,560 SOMETHING THAT IS NOT IDEAL. 1094 00:46:40,560 --> 00:46:42,160 YOU ONLY LOOK AT CELL 1095 00:46:42,160 --> 00:46:47,480 SUSPENSION, SO YOU CANNOT GET 1096 00:46:47,480 --> 00:46:49,880 ANY INFORMATION ABOUT 1097 00:46:49,880 --> 00:46:50,600 PERSISTENCE. 1098 00:46:50,600 --> 00:46:52,920 OVER THE LAST YEAR WE OPTIMIZED 1099 00:46:52,920 --> 00:46:56,760 OUR TOOLS INSTEAD OF GETTING 1100 00:46:56,760 --> 00:47:01,240 ASPIRATES, WE GET ASPIRATED PLUS 1101 00:47:01,240 --> 00:47:02,280 CORE WITH THESE. 1102 00:47:02,280 --> 00:47:04,080 I WILL SHOW YOU DATA WE JUST GOT 1103 00:47:04,080 --> 00:47:06,000 THE LAST COUPLE OF WEEKS, AFTER 1104 00:47:06,000 --> 00:47:10,600 SOME TRIALS AND ERRORS WE CAN 1105 00:47:10,600 --> 00:47:14,840 GET CORE BIOPSIES. 1106 00:47:14,840 --> 00:47:17,040 WE CAN STAIN FOR THE GERMINAL 1107 00:47:17,040 --> 00:47:17,280 CENTER. 1108 00:47:17,280 --> 00:47:19,320 THIS WAS VERY EXCITING FOR US TO 1109 00:47:19,320 --> 00:47:22,800 BE ABLE TO SEE THAT WITHIN THE 1110 00:47:22,800 --> 00:47:26,720 B-CELL FOLLICLES WE CAN SEE A 1111 00:47:26,720 --> 00:47:31,760 RESPONDING GC FROM SOMEONE 1112 00:47:31,760 --> 00:47:33,160 IMMUNIZED WITH MRNA VACCINE. 1113 00:47:33,160 --> 00:47:35,920 THE NEXT QUESTION FOR US IS CAN 1114 00:47:35,920 --> 00:47:39,960 WE SEE HOW LONG THE ANTEGEN CAN 1115 00:47:39,960 --> 00:47:41,920 PERSIST AND HOPEFULLY THIS WILL 1116 00:47:41,920 --> 00:47:42,920 BE COMING NEXT. 1117 00:47:42,920 --> 00:47:44,760 I MENTIONED A LOT OF 1118 00:47:44,760 --> 00:47:46,760 EXPERIMENTS, A LOT OF WORK I 1119 00:47:46,760 --> 00:47:47,320 DID. 1120 00:47:47,320 --> 00:47:48,800 I DIDN'T GENERATE ANY SINGLE 1121 00:47:48,800 --> 00:47:49,920 PIECE OF DATA. 1122 00:47:49,920 --> 00:47:51,840 I AM REPRESENTING THE TERRIFIC 1123 00:47:51,840 --> 00:47:53,440 TEAM THAT DID ALL THE WORK IN MY 1124 00:47:53,440 --> 00:47:54,840 LAB. 1125 00:47:54,840 --> 00:47:58,520 OBVIOUSLY, YOU CAN ASSUME THERE 1126 00:47:58,520 --> 00:48:00,640 IS A LOT OF COLLABORATORS THAT 1127 00:48:00,640 --> 00:48:04,640 ARE BRILLIANT AND TERRIFIC, NOT 1128 00:48:04,640 --> 00:48:06,520 ONLY TAKING CARE OF PATIENTS, 1129 00:48:06,520 --> 00:48:07,760 BUT HELPING US WITH THESE 1130 00:48:07,760 --> 00:48:10,360 STUDIES. 1131 00:48:10,360 --> 00:48:12,760 A LOT OF COORDINATORS THAT WERE 1132 00:48:12,760 --> 00:48:18,400 VERY KRCRITICAL. 1133 00:48:18,400 --> 00:48:22,640 INSIDE AND OUTSIDE OF WSU. 1134 00:48:22,640 --> 00:48:25,000 FUNDING, YOU CANNOT DO THIS 1135 00:48:25,000 --> 00:48:26,440 WITHOUT GENEROUS VOLUNTEERS. 1136 00:48:26,440 --> 00:48:29,240 I'M HAPPY TO TAKE QUESTIONS. 1137 00:48:29,240 --> 00:48:31,920 >>THANK YOU, ALI, VERY 1138 00:48:31,920 --> 00:48:32,400 FASCINATING TALK. 1139 00:48:32,400 --> 00:48:38,200 BEFORE WE START, THE CMA CODE 1140 00:48:38,200 --> 00:48:45,120 FOR TODAY'S TALK IS 44480. 1141 00:48:45,120 --> 00:48:47,560 SO THE FIRST QUESTION IS YOUR 1142 00:48:47,560 --> 00:48:50,440 STUDIES HAVE SHOWNED THAT GC 1143 00:48:50,440 --> 00:48:52,040 REACTIONS ARE MAINTAINED FOR A 1144 00:48:52,040 --> 00:48:56,600 LONG TIME, SIX MONTHS OR LONGER, 1145 00:48:56,600 --> 00:48:57,920 ALLOWING INFECTIONAL 1146 00:48:57,920 --> 00:48:58,360 VACCINATION. 1147 00:48:58,360 --> 00:49:01,320 OTHER STUDIES HAVE SHOWN THERE 1148 00:49:01,320 --> 00:49:05,280 IS A WANING OF NEUTRALIZING 1149 00:49:05,280 --> 00:49:07,160 ANTIBODIES OR VACCINE EFFICACY 1150 00:49:07,160 --> 00:49:09,560 TWO TO MONTHS FOLLOWING 1151 00:49:09,560 --> 00:49:09,880 VACCINATION. 1152 00:49:09,880 --> 00:49:12,560 HOW DO YOU RECONCILE THOSE TWO 1153 00:49:12,560 --> 00:49:14,680 FINDINGS THAT LONG LASTING LYMPH 1154 00:49:14,680 --> 00:49:19,360 NODE B-CELL ACTIVITY WITH THE 1155 00:49:19,360 --> 00:49:20,840 ANTIBODIES RESPONSE AND VACCINE 1156 00:49:20,840 --> 00:49:21,200 EFFICACY? 1157 00:49:21,200 --> 00:49:23,200 >>THAT IS A VERY IMPORTANT AND 1158 00:49:23,200 --> 00:49:27,480 VERY COMMON QUESTION I GET ABOUT 1159 00:49:27,480 --> 00:49:28,120 THIS. 1160 00:49:28,120 --> 00:49:29,680 SO WE HAVE TO DISTINGUISH A 1161 00:49:29,680 --> 00:49:33,320 COUPLE OF POINTS. 1162 00:49:33,320 --> 00:49:36,480 WANING IS SOMETHING I'M NOT 1163 00:49:36,480 --> 00:49:36,760 MEASURING. 1164 00:49:36,760 --> 00:49:39,760 THE VIRUS IS DIFFERENT, CHANGED 1165 00:49:39,760 --> 00:49:41,440 SIGNIFICANTLY IN THE CASE OF 1166 00:49:41,440 --> 00:49:41,720 OMICRON. 1167 00:49:41,720 --> 00:49:45,520 IN CASE OF DELTA THE VIRUS 1168 00:49:45,520 --> 00:49:46,640 INTRINSICALLY BECAME MORE 1169 00:49:46,640 --> 00:49:46,960 INFECTIOUS. 1170 00:49:46,960 --> 00:49:50,240 SO THERE ARE OTHER FACTORS THAT 1171 00:49:50,240 --> 00:49:54,240 DECIDES WHAT THE OUTCOME OF 1172 00:49:54,240 --> 00:50:00,520 EXPOSURE, IN TERMS OF 1173 00:50:00,520 --> 00:50:00,840 SYMPTOMATIC. 1174 00:50:00,840 --> 00:50:01,800 IT IS VERY DIFFERENT THINGS. 1175 00:50:01,800 --> 00:50:03,520 WHAT I'M LOOKING AT IS DETECTION 1176 00:50:03,520 --> 00:50:04,960 OF ANTIBODIES. 1177 00:50:04,960 --> 00:50:06,120 NOW, YOUR FIRST QUESTION, WHICH 1178 00:50:06,120 --> 00:50:09,800 IS A VERY IMPORTANT QUESTION, SO 1179 00:50:09,800 --> 00:50:12,960 MRNA VACCINES, THIS IS THE 1180 00:50:12,960 --> 00:50:14,240 THEORETICAL FRAMEWORK I'M 1181 00:50:14,240 --> 00:50:17,160 CURRENTLY THINKING ABOUT, MRNA 1182 00:50:17,160 --> 00:50:18,640 VACCINES DELIVER A LARGE DOSE OF 1183 00:50:18,640 --> 00:50:20,560 PROTEIN EARLY ON. 1184 00:50:20,560 --> 00:50:23,880 THAT DRIVES A LOT OF PLASMA 1185 00:50:23,880 --> 00:50:24,960 BLAST RESPONSE. 1186 00:50:24,960 --> 00:50:28,360 ALMOST DISPROPORTIONATE 1187 00:50:28,360 --> 00:50:29,200 PLASMABLAST RESPONSE. 1188 00:50:29,200 --> 00:50:31,920 WE GET THIS NICE SPIKE EARLY ON 1189 00:50:31,920 --> 00:50:34,320 IN ANTIBODIES YOU CAN SEE A VERY 1190 00:50:34,320 --> 00:50:35,600 NICE INCREASE. 1191 00:50:35,600 --> 00:50:37,840 AND ONCE THESE CELLS, NOT ALL OF 1192 00:50:37,840 --> 00:50:40,520 THOSE CLONES, RESPONDING CLONES, 1193 00:50:40,520 --> 00:50:42,480 SO ONCE THOSE CELLS START TO 1194 00:50:42,480 --> 00:50:44,720 DIE, YOU CAN SEE THIS, AGAIN, 1195 00:50:44,720 --> 00:50:46,440 DRAMATIC DECAY, WHICH I THINK 1196 00:50:46,440 --> 00:50:47,360 GOT PEOPLE CONCERNED. 1197 00:50:47,360 --> 00:50:49,560 WHAT I THINK IS IF YOU JUST LOOK 1198 00:50:49,560 --> 00:50:51,520 IN TERMS OF -- UNFORTUNATELY, WE 1199 00:50:51,520 --> 00:50:53,760 DIDN'T HAVE A CHANCE TO HAVE A 1200 00:50:53,760 --> 00:50:55,880 THREE, FOUR-YEAR-LONG STUDY TO 1201 00:50:55,880 --> 00:50:58,920 SEE THERE IS A PLATEAU OF THE 1202 00:50:58,920 --> 00:51:01,280 ANTIBODY RESPONSE YOU CAN DETECT 1203 00:51:01,280 --> 00:51:03,720 AFTER SIX TO SEVENTH RESPONSE. 1204 00:51:03,720 --> 00:51:06,400 YOU CAN SEE THE ANTIBODY 1205 00:51:06,400 --> 00:51:09,520 REACHING PLATEAU, NO MORE DECAY, 1206 00:51:09,520 --> 00:51:11,840 BUT AT THE TIME, IF YOU GOT 1207 00:51:11,840 --> 00:51:13,400 INFECT OR BOOSTED YOU COULDN'T 1208 00:51:13,400 --> 00:51:15,080 SEE THAT FOR A LONG PERIOD, BUT 1209 00:51:15,080 --> 00:51:15,840 IT WAS THERE. 1210 00:51:15,840 --> 00:51:18,680 SO I THINK THERE ARE INDUCTION 1211 00:51:18,680 --> 00:51:20,720 OF PLASMA BLASTS. 1212 00:51:20,720 --> 00:51:23,120 BUT IF YOU COMPARE IN THE SHORT 1213 00:51:23,120 --> 00:51:25,040 TIME PERIOD. 1214 00:51:25,040 --> 00:51:26,560 I KNOW SIX MONTHS DOESN'T SOUND 1215 00:51:26,560 --> 00:51:32,360 LIKE A SHORT TIME, BUT IF YOU 1216 00:51:32,360 --> 00:51:34,000 COMPARE WITH SUCCESSFUL 1217 00:51:34,000 --> 00:51:39,240 VACCINES, SMALLPOX AND HVC, 10 1218 00:51:39,240 --> 00:51:40,640 YEARS ARE FLATLINES. 1219 00:51:40,640 --> 00:51:43,120 THAT IS YEARS COMPARED TO SIX 1220 00:51:43,120 --> 00:51:43,440 MONTHS. 1221 00:51:43,440 --> 00:51:46,040 YEAH, IF YOU DO THE HALF LIFE 1222 00:51:46,040 --> 00:51:49,920 DECAY, IT WOULD LOOK REALLY 1223 00:51:49,920 --> 00:51:51,120 DRAMATICALLY BAD FOR MRNA 1224 00:51:51,120 --> 00:51:51,440 VACCINATION. 1225 00:51:51,440 --> 00:51:53,560 I DON'T THINK THERE IS SOMETHING 1226 00:51:53,560 --> 00:51:57,520 ISO INHERENTLY IN HUMANS THAT 1227 00:51:57,520 --> 00:52:01,440 MRNA CANNOT DELIVER A LONG TERM 1228 00:52:01,440 --> 00:52:01,760 ANTIBODY. 1229 00:52:01,760 --> 00:52:04,560 >>TO FOLLOW UP ON THAT PART, 1230 00:52:04,560 --> 00:52:08,880 SINCE YOU MOSTLY, AT LEAST 1231 00:52:08,880 --> 00:52:10,480 SHOWED MRNA BASED VACCINES, 1232 00:52:10,480 --> 00:52:12,800 RIGHT, HAVE YOU LOOKED AT FOR 1233 00:52:12,800 --> 00:52:16,320 COVID MRNA AS A PROTEIN OR ADD 1234 00:52:16,320 --> 00:52:17,320 FIVE BASE VACCINES. 1235 00:52:17,320 --> 00:52:19,360 DO THE GC RESPONSES DIFFER? 1236 00:52:19,360 --> 00:52:20,880 >>YEAH. 1237 00:52:20,880 --> 00:52:23,000 WE DID THE SMALL TRIAL, AS YOU 1238 00:52:23,000 --> 00:52:25,240 MIGHT RECALL DURING THE TIME 1239 00:52:25,240 --> 00:52:29,200 THERE WAS PAUSE IN USING IT. 1240 00:52:29,200 --> 00:52:30,880 WE COULDN'T REALLY, IDEALLY, WE 1241 00:52:30,880 --> 00:52:32,640 WOULD HAVE LOVED TO DO THAT 1242 00:52:32,640 --> 00:52:38,400 STUDY HEAD TO HEAD, MRNA VERSUS 1243 00:52:38,400 --> 00:52:41,280 NOVA VAX AND JNJ BASED. 1244 00:52:41,280 --> 00:52:43,240 RIGHT NOW IT IS VERY HARD 1245 00:52:43,240 --> 00:52:49,440 BECAUSE OF THE DIVERSE AND 1246 00:52:49,440 --> 00:52:50,440 HETEROGENEITY IN THE POPULATION. 1247 00:52:50,440 --> 00:52:52,400 IT IS HARD TO DO IT HEAD TO 1248 00:52:52,400 --> 00:52:52,680 HEAD. 1249 00:52:52,680 --> 00:52:53,640 UNFORTUNATELY, WE DIDN'T HAVE 1250 00:52:53,640 --> 00:52:54,600 THE OPPORTUNITY. 1251 00:52:54,600 --> 00:52:57,320 WE ARE DOING IT NOW BUT NOT WITH 1252 00:52:57,320 --> 00:52:59,680 SARS-COV-2. 1253 00:52:59,680 --> 00:53:03,320 INFLUENZA MRNA AND REGULAR. 1254 00:53:03,320 --> 00:53:05,320 THAT HOPEFULLY WILL BE COMING 1255 00:53:05,320 --> 00:53:06,120 OUT SOON. 1256 00:53:06,120 --> 00:53:08,680 >>IN THAT CONTEST, FOR THE FLU, 1257 00:53:08,680 --> 00:53:14,000 HAVE YOU LOOKED AT AT 1258 00:53:14,000 --> 00:53:16,360 [ INDISCERNIBLE ] 1259 00:53:16,360 --> 00:53:17,600 >>GREAT QUESTION. 1260 00:53:17,600 --> 00:53:20,200 ONE OF THE STUDIES I STARTED 1261 00:53:20,200 --> 00:53:21,520 BEFORE THE PANDEMIC AND ONE OF 1262 00:53:21,520 --> 00:53:25,800 THE STUDIES WHY I HATED TO 1263 00:53:25,800 --> 00:53:27,080 PANDEMIC, IT GOT CUT. 1264 00:53:27,080 --> 00:53:29,560 WE WERE COMPARING THE FLU VIRUS 1265 00:53:29,560 --> 00:53:30,280 AND THE REGULAR. 1266 00:53:30,280 --> 00:53:31,800 AND THAT IS THE SAME 1267 00:53:31,800 --> 00:53:32,080 FORMULATION. 1268 00:53:32,080 --> 00:53:34,280 I WOULD LOVE TO GO BACK AND DO 1269 00:53:34,280 --> 00:53:40,960 THAT STUDY AGAIN. 1270 00:53:40,960 --> 00:53:43,880 WE ARE NOW COMPARING MRNA WHICH 1271 00:53:43,880 --> 00:53:46,400 ARE DIFFERENT, BUT COMPARING TO 1272 00:53:46,400 --> 00:53:49,920 THE CONVENTIONAL. 1273 00:53:49,920 --> 00:53:51,960 ADDING MRNA TO THAT WOULD BE 1274 00:53:51,960 --> 00:53:52,160 GREAT. 1275 00:53:52,160 --> 00:53:54,640 >>IN THIS CONTEST OF VACCINES, 1276 00:53:54,640 --> 00:54:01,040 HAVE YOU LOOKED AT ELDERLY 1277 00:54:01,040 --> 00:54:03,880 POPULATION TO SEE IF RESPONSE IN 1278 00:54:03,880 --> 00:54:05,280 GCs OR LYMPH NODE DIFFER? 1279 00:54:05,280 --> 00:54:06,280 >>YEAH. 1280 00:54:06,280 --> 00:54:07,480 AGAIN, ANOTHER GREAT QUESTION. 1281 00:54:07,480 --> 00:54:11,480 IN THE BOOSTER STUDIES, THIS IS 1282 00:54:11,480 --> 00:54:14,160 THE DATA THAT -- OH, HERE IT IS. 1283 00:54:14,160 --> 00:54:15,560 THREE OUT OF THOSE FIVE 1284 00:54:15,560 --> 00:54:17,960 INDIVIDUALS WERE 65 AND ABOVE. 1285 00:54:17,960 --> 00:54:21,400 WHICH IS REALLY, FOR ME, ANOTHER 1286 00:54:21,400 --> 00:54:23,040 FASCINATING ASPECT THAT WE CAN 1287 00:54:23,040 --> 00:54:25,120 SEE SUCH A ROBUST RESPONSE. 1288 00:54:25,120 --> 00:54:26,840 BUT WE DON'T HAVE NUMBERS REALLY 1289 00:54:26,840 --> 00:54:30,280 TO BE ALLOWED TO SAY SOMETHING 1290 00:54:30,280 --> 00:54:30,640 DEFINITIVELY. 1291 00:54:30,640 --> 00:54:32,800 WE HAVE A STUDY THAT IS PLANNING 1292 00:54:32,800 --> 00:54:34,720 TO ENROLL HOPEFULLY IN THE FALL 1293 00:54:34,720 --> 00:54:38,200 WHERE WE ARE DIRECTLY ASKING 1294 00:54:38,200 --> 00:54:38,680 THAT. 1295 00:54:38,680 --> 00:54:39,960 SAME VACCINE. 1296 00:54:39,960 --> 00:54:42,600 MRNA VERSUS CONVENTIONAL, 65 1297 00:54:42,600 --> 00:54:45,120 ABOVE FOR OLDER INDIVIDUALS OR 1298 00:54:45,120 --> 00:54:48,360 18-50 FOR YOUNG ADULTS. 1299 00:54:48,360 --> 00:54:49,920 >>SO A QUESTION ON THIS SLIDE, 1300 00:54:49,920 --> 00:54:54,320 SINCE YOU ARE SHOWING THE FNA, 1301 00:54:54,320 --> 00:54:56,800 DID YOU LOOK AT BONE MARROW AND 1302 00:54:56,800 --> 00:55:00,760 IF YOU SEE CHANGE IN BOOSTING 1303 00:55:00,760 --> 00:55:01,040 EFFECTS 1304 00:55:01,040 --> 00:55:01,680 >>WE DID. 1305 00:55:01,680 --> 00:55:03,720 I HAVE THAT IN EXTRA SLIDES. 1306 00:55:03,720 --> 00:55:05,840 I DIDN'T KNOW IF I WILL GO OVER 1307 00:55:05,840 --> 00:55:06,160 TIME. 1308 00:55:06,160 --> 00:55:13,280 SO BONE MARROW IS HERE. 1309 00:55:13,280 --> 00:55:15,480 SO THIS IS THE BONE MARROW LEVEL 1310 00:55:15,480 --> 00:55:16,920 AGAINST THE SPIKE. 1311 00:55:16,920 --> 00:55:19,360 IF YOU HAVE NEVER BEEN INFECTED 1312 00:55:19,360 --> 00:55:22,240 OR VACCINATED FOR SARS-COV-2, 1313 00:55:22,240 --> 00:55:24,960 THESE PEOPLE ARE HARD TO FIND. 1314 00:55:24,960 --> 00:55:28,000 YOU HAVE ALMOST BASICALLY AN 1315 00:55:28,000 --> 00:55:30,200 UNDETECTABLE BONE MARROW AGAINST 1316 00:55:30,200 --> 00:55:31,800 THE SPIKE PROTEIN. 1317 00:55:31,800 --> 00:55:34,240 IF YOU HAVE BEEN INFECTED ONCE 1318 00:55:34,240 --> 00:55:36,160 AND NEVER BEEN VACCINATED, THIS 1319 00:55:36,160 --> 00:55:39,200 IS ONE IN 1,000, YOU HAVE SPIKE 1320 00:55:39,200 --> 00:55:40,840 SPECIFIC, NOTHING COMPARED TO 1321 00:55:40,840 --> 00:55:41,080 FLU. 1322 00:55:41,080 --> 00:55:43,880 IF YOU HAVE BEEN VACCINATEDMAN 1323 00:55:43,880 --> 00:55:46,120 WITH TWO DOSES AND NOT INFECTED 1324 00:55:46,120 --> 00:55:47,720 YOU ALMOST HAVE THE SAME LEVEL 1325 00:55:47,720 --> 00:55:48,920 AS INFECTED. 1326 00:55:48,920 --> 00:55:51,120 IF YOU HAVE BEEN VACCINATED AND 1327 00:55:51,120 --> 00:55:52,760 BOOSTED, THIS IS YOUR LEVEL. 1328 00:55:52,760 --> 00:55:56,240 SO, YES, BOOSTING NOT ONLY GETS 1329 00:55:56,240 --> 00:55:58,160 YOU A GERMINAL CENTER REACTION 1330 00:55:58,160 --> 00:56:00,040 IT CAN INCREASE FREQUENCY OF 1331 00:56:00,040 --> 00:56:01,840 BONE MARROW PLASMA CELLS. 1332 00:56:01,840 --> 00:56:04,680 THIS IS A YEAR AND A HALF OLD. 1333 00:56:04,680 --> 00:56:06,800 RIGHT NOW MANY PEOPLE GOT NOT 1334 00:56:06,800 --> 00:56:08,960 ONLY TRIPLE IMMUNIZATION, BUT 1335 00:56:08,960 --> 00:56:11,440 GOT INFECTED, INFECTED TWICE, 1336 00:56:11,440 --> 00:56:13,240 FOUR IMMUNIZATION. 1337 00:56:13,240 --> 00:56:16,280 WE ARE VERY CLOSE TO INFLUENZA 1338 00:56:16,280 --> 00:56:17,000 FOR SARS-COV-2. 1339 00:56:17,000 --> 00:56:19,560 >>IN TERMS OF GC, THE QUESTION 1340 00:56:19,560 --> 00:56:22,800 COMES IS THERE A RELATIONSHIP OF 1341 00:56:22,800 --> 00:56:25,160 DURATION OF GC ANDEAN YAN AT 1342 00:56:25,160 --> 00:56:26,120 EACH TIME POINT. 1343 00:56:26,120 --> 00:56:28,960 DO SOME OF THE B-CELLS MORE 1344 00:56:28,960 --> 00:56:30,440 MATURE TEND TO LEAVE EARLY 1345 00:56:30,440 --> 00:56:33,880 COMPARED TO OTHERS IN THE 1346 00:56:33,880 --> 00:56:35,000 OPPORTUNITY IN DIFFERENT 1347 00:56:35,000 --> 00:56:35,760 INDIVIDUALS IS DIFFERENT OR 1348 00:56:35,760 --> 00:56:36,360 EVERYBODY THE SAME? 1349 00:56:36,360 --> 00:56:36,800 >>YES. 1350 00:56:36,800 --> 00:56:38,680 ALL THE QUESTIONS ARE BEAUTIFUL 1351 00:56:38,680 --> 00:56:38,960 TODAY. 1352 00:56:38,960 --> 00:56:44,160 IT IS HARD -- IT IS A TOUGH ONE. 1353 00:56:44,160 --> 00:56:47,040 IF WE DO SEE, OBVIOUSLY, FROM 1354 00:56:47,040 --> 00:56:49,520 THE LEVEL HERE OF MUTATION OVER 1355 00:56:49,520 --> 00:56:52,160 TIME, WE DO SEE, SORRY, I'M 1356 00:56:52,160 --> 00:56:53,800 MOVING THE SLIDES TOO FAST BUT 1357 00:56:53,800 --> 00:56:55,320 I'M TRYING TO GET TO THE SLIDE 1358 00:56:55,320 --> 00:56:57,120 THAT -- OH, HERE IT IS. 1359 00:56:57,120 --> 00:56:59,520 SO GC OVER TIME, THESE ARE THE 1360 00:56:59,520 --> 00:57:01,520 LYMPH NODE PLASMA CELLS I SHOWED 1361 00:57:01,520 --> 00:57:06,160 YOU EARLIER, SAME LEVEL OF GC 1362 00:57:06,160 --> 00:57:06,440 B-CELLS. 1363 00:57:06,440 --> 00:57:09,280 WE MADE MONOCLONAL FROM THE SAME 1364 00:57:09,280 --> 00:57:10,760 CLONE OVER TIME. 1365 00:57:10,760 --> 00:57:13,480 SOMETIMES YOU CAN DETECT THE 1366 00:57:13,480 --> 00:57:15,920 GRADUAL INCREASE IN BINDING 1367 00:57:15,920 --> 00:57:16,200 AFFINITY. 1368 00:57:16,200 --> 00:57:20,640 WHETHER THIS AFFECTS THE OVERALL 1369 00:57:20,640 --> 00:57:21,720 SERUM RESPONSE, WE HAVEN'T 1370 00:57:21,720 --> 00:57:22,840 LOOKED AT THAT. 1371 00:57:22,840 --> 00:57:25,600 TO BE HONEST, I DOUBT WE WILL BE 1372 00:57:25,600 --> 00:57:28,120 ABLE TO DETECT THAT IN A GRADUAL 1373 00:57:28,120 --> 00:57:28,520 FASHION. 1374 00:57:28,520 --> 00:57:31,680 I THINK WE CAN DETECT IT FROM 1375 00:57:31,680 --> 00:57:36,760 ZERO, BASELINE VERSUS SIX 1376 00:57:36,760 --> 00:57:37,000 MONTHS. 1377 00:57:37,000 --> 00:57:40,560 TO SEE THAT IMPACT OVERALL IN 1378 00:57:40,560 --> 00:57:44,120 SERUM, THESE HAVE TO 1379 00:57:44,120 --> 00:57:46,120 DIFFERENTIATE FROM THE -- CELLS 1380 00:57:46,120 --> 00:57:48,040 AND HAS TO BE A SIGNIFICANT 1381 00:57:48,040 --> 00:57:53,640 FRACTION OF POLY CLONE 1382 00:57:53,640 --> 00:57:53,960 ALRESPONSE. 1383 00:57:53,960 --> 00:57:56,240 >>TO FOLLOW ON THAT, WE COMBINE 1384 00:57:56,240 --> 00:57:58,240 TWO QUESTIONS. 1385 00:57:58,240 --> 00:58:01,520 IN THE LYMPH NODE OF POST 1386 00:58:01,520 --> 00:58:04,320 VACCINATED SUBJECTS, DO YOU 1387 00:58:04,320 --> 00:58:08,280 DETECT ATYPICAL B-CELLS AND HAVE 1388 00:58:08,280 --> 00:58:10,960 YOU LOOKED AT AUTOANTIBODIES 1389 00:58:10,960 --> 00:58:12,240 RESPONSES IN THE LYMPH NODE 1390 00:58:12,240 --> 00:58:12,440 CELL? 1391 00:58:12,440 --> 00:58:14,440 >>I WILL START WITH THE SECOND 1392 00:58:14,440 --> 00:58:14,800 ONE. 1393 00:58:14,800 --> 00:58:16,400 WE DID NOT TEST THAT. 1394 00:58:16,400 --> 00:58:19,360 WE DID NOT, I MEAN, WE HAVE THE 1395 00:58:19,360 --> 00:58:19,920 MONOCLONALS. 1396 00:58:19,920 --> 00:58:22,480 WE DID NOT -- WE DON'T DO THIS 1397 00:58:22,480 --> 00:58:24,520 ROUTINELY IN OUR LAB SO WE DID 1398 00:58:24,520 --> 00:58:25,720 NOT TEST -- I DON'T KNOW WHAT 1399 00:58:25,720 --> 00:58:27,480 WILL BE THE DEFINITION. 1400 00:58:27,480 --> 00:58:33,280 I GUESS BINDING TO SOME OF THE 1401 00:58:33,280 --> 00:58:34,600 ANTIGEN STRAND OF DNA. 1402 00:58:34,600 --> 00:58:37,360 WE HAVEN'T DONE THAT SO I DON'T 1403 00:58:37,360 --> 00:58:40,800 KNOW. 1404 00:58:40,800 --> 00:58:42,920 THE FIRST QUESTION ABOUT -- THE 1405 00:58:42,920 --> 00:58:44,240 FIRST QUESTION WAS -- CAN YOU 1406 00:58:44,240 --> 00:58:46,320 REMIND ME, ACTUALLY? 1407 00:58:46,320 --> 00:58:50,040 >>IN YOUR LYMPH NODE STUDIES 1408 00:58:50,040 --> 00:58:52,360 ARE THERE VACCINATION FOLLOWING 1409 00:58:52,360 --> 00:58:54,560 INFECTION, HAVE YOU DETECTED ANY 1410 00:58:54,560 --> 00:58:55,200 ATYPICAL MEMORY -- 1411 00:58:55,200 --> 00:58:58,960 >>OH, YES. 1412 00:58:58,960 --> 00:59:04,280 THE DEFINITION IS THE -- I'M 1413 00:59:04,280 --> 00:59:04,600 ASSUMING. 1414 00:59:04,600 --> 00:59:09,440 WE DID SEE THOSE CELLS. 1415 00:59:09,440 --> 00:59:11,520 I CAN'T REMEMBER MAINLY IN BLOOD 1416 00:59:11,520 --> 00:59:15,000 OR LYMPH NODES, WE CAN DETECT 1417 00:59:15,000 --> 00:59:16,960 THEM, WE CAN SEE THEM. 1418 00:59:16,960 --> 00:59:18,720 THE FREQUENCY IS NOT AS HIGH. 1419 00:59:18,720 --> 00:59:21,440 ONE OF THE THINGS WE ARE TRYING 1420 00:59:21,440 --> 00:59:24,040 TO LEARN AND WE DON'T HAVE A 1421 00:59:24,040 --> 00:59:25,240 DEFINITIVE ANSWER IS ARE THOSE 1422 00:59:25,240 --> 00:59:27,960 CELLS REALLY COMING OUT FROM THE 1423 00:59:27,960 --> 00:59:31,240 GC OR ARE THESE CELLS GOING INTO 1424 00:59:31,240 --> 00:59:34,680 THE GC. 1425 00:59:34,680 --> 00:59:39,200 IT IS HARD FOR US TO TELL WHERE 1426 00:59:39,200 --> 00:59:41,320 ARE THESE CELLS COMING FROM OR 1427 00:59:41,320 --> 00:59:45,120 ARE THESE CELLS GOING TO THE GC. 1428 00:59:45,120 --> 00:59:49,240 ARE THESE PHENOTYPE ACQUIRED 1429 00:59:49,240 --> 00:59:51,400 BEFORE OR AFTER THE GC. 1430 00:59:51,400 --> 00:59:53,360 WE CAN SEE THEM, BUT WE DON'T 1431 00:59:53,360 --> 00:59:55,400 HAVE A DEFINITIVE ANSWER YET. 1432 00:59:55,400 --> 00:59:59,360 >>A LOT OF QUESTIONS. 1433 00:59:59,360 --> 01:00:03,200 THE LAST TWO QUESTIONS, WE YOU 1434 01:00:03,200 --> 01:00:13,760 COMPARE HOMOLOGOUS OR 1435 01:00:13,760 --> 01:00:17,440 HETEROLOGOUS, ARE THEY THE SAME? 1436 01:00:17,440 --> 01:00:19,000 >>WE DIDN'T DETECT A DIFFERENCE 1437 01:00:19,000 --> 01:00:19,320 THERE. 1438 01:00:19,320 --> 01:00:21,600 IT IS NOT THE SAME. 1439 01:00:21,600 --> 01:00:22,840 IT LOOKED THE SAME. 1440 01:00:22,840 --> 01:00:25,720 >>SO THE LAST QUESTION IS BASED 1441 01:00:25,720 --> 01:00:31,960 ON WHAT YOU HAVE SHOWN IN TERMS 1442 01:00:31,960 --> 01:00:33,320 OF OKAY KRON VACCINATION AND 1443 01:00:33,320 --> 01:00:37,240 SMALL NUMBER OF B-CELLS SPECIFIC 1444 01:00:37,240 --> 01:00:38,240 FOR BA1 ONLY. 1445 01:00:38,240 --> 01:00:40,640 WHAT ARE THE IMPLICATIONS OF 1446 01:00:40,640 --> 01:00:42,120 THAT FINDING? 1447 01:00:42,120 --> 01:00:44,720 LET'S SAY DOWN THE ROAD WE WANT 1448 01:00:44,720 --> 01:00:47,640 TO HAVE THE NEWLY EMERGING 1449 01:00:47,640 --> 01:00:50,080 VARIANTS, THAT WILL TEND TO 1450 01:00:50,080 --> 01:00:51,480 GENERATE MOST ANTIBODIES THAT 1451 01:00:51,480 --> 01:00:55,040 ARE CROSS REACTIVE OR MORE 1452 01:00:55,040 --> 01:00:57,320 SPECIFIC FOR THE PROTOTYPE WA1 1453 01:00:57,320 --> 01:00:57,800 STRAIN. 1454 01:00:57,800 --> 01:01:00,560 HOW DO WE OVERCOME THAT? 1455 01:01:00,560 --> 01:01:02,240 HOW DO WE HAVE VACCINES 1456 01:01:02,240 --> 01:01:03,200 GENERATING MORE ANTIBODIES 1457 01:01:03,200 --> 01:01:07,240 AGAINST THE EMERGING STRAINS? 1458 01:01:07,240 --> 01:01:09,840 >>SO THE VERY FIRST PART, THE 1459 01:01:09,840 --> 01:01:11,520 VERY FIRST THING I LEARNED IS WE 1460 01:01:11,520 --> 01:01:14,200 DON'T REALLY NEED THE ORIGINAL 1461 01:01:14,200 --> 01:01:16,560 STRAIN IN THE VACCINE ANYMORE. 1462 01:01:16,560 --> 01:01:18,520 OMICRON BY ITSELF, IT IS VERY 1463 01:01:18,520 --> 01:01:21,840 CLEAR, CAN REENGAGE MEMORY CELLS 1464 01:01:21,840 --> 01:01:22,200 EFFICIENTLY. 1465 01:01:22,200 --> 01:01:25,760 AT LEAST AS A BOOSTER, NOT AS A 1466 01:01:25,760 --> 01:01:26,080 PRIMING. 1467 01:01:26,080 --> 01:01:28,720 AS A BOOSTER IMMUNIZATION, WE 1468 01:01:28,720 --> 01:01:31,280 DON'T NEED THE BIVALENT AND IN 1469 01:01:31,280 --> 01:01:35,200 MY OPINION WE CAN GO WITH THE -- 1470 01:01:35,200 --> 01:01:42,680 WE SEED A VARIANT ANTIGENICALLY 1471 01:01:42,680 --> 01:01:43,400 DIFFERENT. 1472 01:01:43,400 --> 01:01:47,320 OMICRON IS 97.5% SIMILAR TO THE 1473 01:01:47,320 --> 01:01:51,880 ORIGINAL IN TERMS OF HEMOLOGY. 1474 01:01:51,880 --> 01:01:56,200 IF WE THINK WE NEEDED TO SEE A 1475 01:01:56,200 --> 01:01:57,720 SIGNIFICANT ENGAGEMENT, I THINK 1476 01:01:57,720 --> 01:01:59,400 WE NEED EITHER TWO DOSES OR 1477 01:01:59,400 --> 01:02:00,320 SOMETHING THAT IS SIGNIFICANTLY 1478 01:02:00,320 --> 01:02:02,160 DIFFERENT. 1479 01:02:02,160 --> 01:02:03,920 AND THE SIGNIFICANTLY DIFFERENT 1480 01:02:03,920 --> 01:02:06,760 PART IS HARD TO MEASURE, BUT 1481 01:02:06,760 --> 01:02:09,600 OBVIOUSLY, OUR EXPERIENCE WITH 1482 01:02:09,600 --> 01:02:13,600 THE 97.5% WHICH IS OBVIOUSLY 1483 01:02:13,600 --> 01:02:14,960 DIFFERENT STILL NOT DIFFERENT 1484 01:02:14,960 --> 01:02:17,240 ENOUGH FOR ONE DOSE TO DO THE 1485 01:02:17,240 --> 01:02:17,560 JOB. 1486 01:02:17,560 --> 01:02:20,160 >>YOU BRIEFLY MENTIONED ABOUT 1487 01:02:20,160 --> 01:02:22,720 YOU ARE LOOKING AT OTHER 1488 01:02:22,720 --> 01:02:23,760 PLATFORMS. 1489 01:02:23,760 --> 01:02:24,440 >>YES. 1490 01:02:24,440 --> 01:02:27,720 >>IN TERMS OF BOOSTING, IS A 1491 01:02:27,720 --> 01:02:30,200 PLATFORM, LET'S SAY IF YOU ARE 1492 01:02:30,200 --> 01:02:31,760 INITIALLY PLANNED WITH MRNA, DO 1493 01:02:31,760 --> 01:02:35,160 YOU GET A BETTER BOOSTER WITH 1494 01:02:35,160 --> 01:02:35,520 PROTEIN-BASED? 1495 01:02:35,520 --> 01:02:36,880 >>UNFORTUNATELY, WE DON'T HAVE 1496 01:02:36,880 --> 01:02:37,080 THAT. 1497 01:02:37,080 --> 01:02:40,200 I MEAN IT WILL BE VERY -- I'M 1498 01:02:40,200 --> 01:02:42,600 VERY CURIOUS TO DO THESE STUDIES 1499 01:02:42,600 --> 01:02:44,280 BECAUSE IT WILL BE GREAT TO SEE 1500 01:02:44,280 --> 01:02:48,920 HOW THE EARLY DYNAMICS AND 1501 01:02:48,920 --> 01:02:49,840 ANTIGEN CLEARANCE WILL BE 1502 01:02:49,840 --> 01:02:52,840 DIFFERENCE BETWEEN THE COMMON 1503 01:02:52,840 --> 01:02:53,880 PROTEIN OR MRNA. 1504 01:02:53,880 --> 01:02:56,680 HOW THAT AFFECTS THE OVERALL 1505 01:02:56,680 --> 01:02:57,000 RESPONSE. 1506 01:02:57,000 --> 01:02:58,480 UNFORTUNATELY, WE DON'T HAVE 1507 01:02:58,480 --> 01:02:59,600 ACCESS TO THESE VACCINES. 1508 01:02:59,600 --> 01:03:01,760 I WOULD LOVE TO DO THESE 1509 01:03:01,760 --> 01:03:02,120 STUDIES. 1510 01:03:02,120 --> 01:03:03,760 IT IS AN IMPORTANT QUESTION FOR 1511 01:03:03,760 --> 01:03:04,960 ALL OF US TO LEARN. 1512 01:03:04,960 --> 01:03:07,000 >>THANK YOU SO MUCH, ALI. 1513 01:03:07,000 --> 01:03:09,360 IT WAS A FASCINATING TALK. 1514 01:03:09,360 --> 01:03:11,440 WE HAVE GONE OVER THE TIME, WE 1515 01:03:11,440 --> 01:03:13,400 LOOK FORWARD TO DISCUSSING MORE. 1516 01:03:13,400 --> 01:03:13,960 THANK YOU VERY MUCH. 1517 01:03:13,960 --> 01:03:14,040 >>THANK YOU FOR HAVING ME. 1518 01:03:14,040 --> 01:03:15,000 I ENJOYED ALL THE QUESTIONS. 1519 01:03:15,000 --> 00:00:00,000 THANK YOU SO MUCH.