Demystifying Medicine 2015 – Dengue: Breakbone Fever: a Major Unpublicized Killer Disease


>>GOOD AFTERNOON, THE REASON WHY WE CIRCULATE THIS ATTENDANCE THING IS FOR 2 REASONS, 1, ANYBODY WHO COMES TO MORE THAN HALF OF THESE SESSIONS AND AT THE END TAKES AN EXTREMELY DIFFICULT ELECTRONIC EXAM, YOU’LL REIVE CERTIFICATE TO THE NIH THAT YOU TOOK PART OF THE DEMYSTIFYING MEDICINE PROGRAM WHICH SOME PEOPLE FIND TO THEIR ADVANTAGE, THE OTHER IT GIVES US A CLUE AS TO WHAT THE AUDIENCE IS, THAT WE WERE GETTING TO. SO THERE ARE MANY WATCHING THIS LIVE AND I MENTION THIS BECAUSE I ENCOURAGE TO YOU ASK QUESTIONS DURING THE TA, IF YOU DON’T FOLLOW WHAT’S GOING ON SAY SO, AND DON’T HESITATE TO INTERRUPT THIS. BUT ALSO IN ANY QUESTION AND DISCUSSION PERIOD, SO WE’LL PASS A MICROPHONE AROUND SO PLEASE DON’T JUST TALK QUIETLY, TALK TO THE MICROPHONE BECAUSE PEOPLE OUT THERE SEND ME E-MAILS SAYING WHAT WAS THE QUESTION? WE KNOW THE ANSWER. BUT IT’S LIKE A TELEVISION PROGRAM HERE’S THE ANSWER, WHAT WAS THE QUESTION. SO IN THINKING ABOUT THIS, IT’S SUDDENLY DAWNED ON ME YESTERDAY, THAT THE FIRST PATIENT WITH DENGUE I EVER SAW WAS A LONG, LONG TIME AGO. I WAS AT THE ALBERT EINSTEIN COLLEGE OF MEDICINE AND THERE WAS A MIDDLE AGED GENTLEMAN WHO CAME IN WITH SOMETHING THAT EVERYBODY THOUGHT WAS THE FLU AND HE BEGAN TO COMPLAIN OF TERRIBLE PAIN IN HIS BONES AND IN HIS JOINTS. IT WAS MORE THAN FLU, SO ABOUT THAT TIME AN INFECT YOWS DISEASE COULT WAS CALLED AND THAT WAS KIND OF INTERESTING BECAUSE THE FELLOW WHO WAS THERE, WAS A MAN NAMED SHELLY WOLFE WHO ANYONE WITH GRAY HAIR WHO’S BEEN HERE FOR A WHILE KNOWS SHELLY WAS THE INSTITUTE DIRECTOR OF NIAID IN LATER, LATER YEARS. AT ANY RATE, THIS WAS A GENTLEMAN WHO GOT ON A PLANE FROM SOME CARIBBEAN ISLAND AND HE HAD WHAT HE THOUGHT WAS A COLD OR A TOUCH OF SOMETHING AND HE ALMOST DIED BECAUSE HE EVENTUALLY HAD THIS SEVERE HEMORRHAGIC AND ALMOST TOTAL SYSTEM FAILURE. AT ANY RATE, WE’LL HEAR MORE ABOUT IT. SO IF YOU ASK MOST STUDENTS AND FELLOWS, YOU KNOW WHAT DISEASES KILL PEOPLE, PARTICULARLY IN THE TROPICS, AND YOU LEAVE OUT MALNUTRITION FOR A MOMENT, EVERYBODY SAYS MALARIA AND HIV, BUT DENGUE TO SOME EXTENT IS A BIT OF AN UNKNOWN AND YET IT EFFECTS AS WE’LL LEARN MILLIONS OF PEOPLE, IT HAS A SUBSTANTIAL MORTALITY RATE AND AS THE WORLD GETS SMALLER AND MAYBE GLOBAL WARMING HAS SOMETHING TO DO WITH IT, I DON’T KNOW, THE VECTOR, THE 80S MOSQUITO MAYBE FINDINGS NEW PLACES, AT ANY RATE THERE ARE PATIENTS IN THE UNITED STATES PARTICULARLY IN THE SOUTH, CARIBBEAN, ASIA, THERE HAVE EVEN BEEN A FEW CASES I THINK REPORTED ROM THE ARCTIC, HOW A MOSQUITO DID ITS THING THERE. ANY RATE, I WON’T BELABOR THIS BUT THE BRIDGE IS THAT THE POINT OF THIS SESSION IS THE CONNECT, THINGS THAT WE LEARNING OR SHOULD KNOW ABOUT MAJOR MEDICAL PROBLEMS FROM A CLINICAL THERAPEUTIC STANDPOINT AND A MORE BASIC APPROACH TO MECHANISTIC VIEWS OF WHAT THESE DISEASES ARE AND WHERE DO WE STAND IN UNDERSTANDING HOW THEY OCCUR. SO WE PUT ALL THIS WHEN WE CAN ON THE WEB AND WE TRY TO GET IT UP A FEW DAYS AHEAD OF TIME AND I ENCOURAGE TO YOU COME TO ALL THE SESSIONS AND CAN YOU SEE POWER POINTS AND EVERYTHING, JUST GOOGLE DEMYSTIFYING MEDICINE AND WHEN YOU LOOK AT IT AND READ SOME OF THE ARTICLES THAT ARE SELECTED, YOU COME UP WITH SO, IF I CAN MOVE THIS, I’LL SHOW YOU WHAT MY QUESTIONS WERE–UH-HUH OH. IT TURNS OUT THAT IT’S SOMETHING LIKE OODORROUS OR SOMETHING AND THIS MOSQUITO TRANSMITS THIS DENGUE OR YELLOW FEVER. SO 1 OF THE THINGS I WONDERED ABOUT, WHY IS IT ONLY THE FEMALES WHO TRANSMIT THE DISEASE TO HUMANS? WHY DO THE MALES DEPRIVED? AND HOW DO YOU CAPTURE THE RARE OCCURRENCES THAT TAKE PLACE IN PLACES THAT AREN’T SO NECESSARILY HISTORICALLY LINKED TO THE TROPIC OR SUBTROPIC? DO WE HAVE THIS MOSQUITO IN SOME WATER THAT’S SITTING AROUND NORTH OF THE MASON-DIXON LINE OCCASIONALLY AND WHY DOES SPECTRUM, MOST PEOPLE WITH MANY VIRAL DISEASES, THEY MAY BE ASYMPTOMATIC OR MILDLY SYMPTOMATIC WHERE THEY HAVE SOMETHING LIKE THE FLU OR THEN THEY HAVE THIS REAL TERRIBLE BONE PAIN WHICH IS WHAT GIVES IT A POPULAR FEVER AND THEN OTHERS GO ON AND HAVE THIS SOMETIMES FATAL, WHAT HAPPENS, HOW DETERMINES IT? DO WE HAVE A VACCINE? IS THE VACCINE GOOD AGAINST ALL THE GENOTYPES? IS THAT NECESSARY? ARE THERE ANTIVIRAL DRUGS? CAN YOU TREAT IN DISEASE IN THE PERSON HAS SUCH, WHAT DO YOU DO? AND I GUESS THE BIG QUESTION FROM A PUBLIC HEALTH STANDPOINT IS MILLIONS OF PEOPLE ARE EFFECTED EVERY YEAR. SHOULD YOU VACINATE THEM? EVERYBODY? THE WORLD. IT’S DIFFICULT. SO WE’RE VERY FORTUNATE TO HAVE THE VERY 2 EXPERTS HERE AT NIH AND JOHNS HOPKINS TO DISCUSS THESE PROBLEMS AND MANY OTHERS, THESE ARE JUST OTHER OFF THE TOP OF MY HEAD THOUGHTS. SO AT FIRST THE SPEAKER IS GOING TO BE STEPHEN? NO, OKAY, THE FIRST SPEAKER IS ANNA DURBIN WHO IS AN ASSOCIATE PROFESSOR AT THE HOPKINS SCHOOL OF HEALTH. PRIOR TO THAT SHE WAS HERE AT NIAID FOR 4 OR 5 YEARS WORKING ON DEVELOPMENTAL TESTING OF VACCINES AGAINST DENGUE AND OTHER VIRAL DISEASES AND BEFORE THAT SHE WENT TO MEDICAL SCHOOL AT LANE STATE UNIVERSITY AND TOOK HER RESIDENCE SCHEFELLOWSHIP THERE AND IN–RESIDENCY AND FELLOWSHIP THERE AND INFEBLGHTIOUS DISEASES. SO ANNA WILL BE THE FIRST SPEAKER AND SHOULD BE FOLLOWED BY STEVE WHITE HEAD WHO RECEIVED HIS Ph.D. DEGREE FROM THE UNIVERSITY OF OREGON IN VIROLOGY AND THEN WAS A POST DOC AT ROCKEFELLER AND THEN CAME TO THE NIH, AND NIAID AND HE’S A SENIOR AND ASSOCIATE SCIENTIST IN THE LAB OF INFECTIOUS DISEASES AND HIS MAIN INTEREST IS THE DEVELOPMENT OF AN ATTENUATE LIVE VIRUSES FOR DISEASES LIKE DENGUE AND ALSO WORKED ON ST. LOUIS EQUINE, ENCEPHALITIS, JAPANESE ENCEPHALITIS, THE BIG 1, WHAT’S THE BIG 1? OH WEST NILE VIRUS WHICH WE HAVE DISCUSSED A FEW TIMES HERE. SO WE’RE LIVING IN A CHANGING WORLD WHERE INFECTIONS ARE NOT STRICTLY AS LIMITED AS THEY USED TO BE. THEY ARE TO VECTORS, BUT I THINK WE EVEN ASK QUESTIONS WHERE THE VECTORS ARE MUTATING. AT ANY RATE, WE LOOK FORWARD TO HEARING YOUR DISCUSSIONS. >>THANK YOU. I WILL START BY ASKING DR. MARTY, HE IS A SCIENTIST HERE AT THE NIH WHO TRAVELED TO IBDIA A COUPLE OF YEARS AGO AND I WILL ASK HIM TO RELAY HIS EXPERIENCE UPON HIS RETURN FROM INDIA AND THEN WE’LL GO INTO TO DISCUSS DENGUE. >>THANKS. >>YOU WANT TO HEAR ABOUT WHAT HAPPENED. >>I WANT TO HEAR ABOUT WHAT HAPPENED. >>SO THE STORY GOES BACK TO INDIA WHICH WAS PART WORK AND PART [INDISCERNIBLE] VISITING RELATIVES AND SO ON. AND IT SHOWED AFTER 10 DAYS, IT WAS 4 DAYS IN INDIA AND 5 DAYS IN CHINA AND [INDISCERNIBLE] AND THEN BACK TO INDIA FOR 3 DAYS AND THEN BACK HERE. AND I WAS FINE DURING THE TRIP, THE WHOLE TRIP BUT I DO ADMIT THAT I DID NOT TAKE PROPHYLAXIS FOR THIS VERY QUICK TRIP THERE, AND I WAS STAYING IN THE URBAN AREAS OF DELI AND ON THE TRIP BACK FROM DHELI, I DEVELOPED SUFFERED MILD TO MODERATE HEADACHES, KNOWING THAT NOTHING THAT RAISED ANY CONCERN. I GOT HOME AND WENT TO BED AND I WOKE UP AT ABOUT 2 IN THE MORNING WITH SEVERE SHAKING CHILLS AND [INDISCERNIBLE] AND COMPLETELY OUT OF THE BLUE. I HAD NO–I LITERALLY WOKE UP OUT OF A SLEEP WITH THAT. SO MY FIRST THOUGHT OF COURSE WAS MALARIA, I HADN’T TAKEN PROPHYLAXIS, THE NEXT MORNING I CAME IN AND DID A SMEAR AND I HAPPENED TO WORK IN PATHOLOGY SECTION, SO–AND IT WAS NEGATIVE. SO SO I WENT ABOUT MY WORK AND DID ANOTHER SMEAR LATER IN THE DAY JUST TO BE SURE I HADN’T MISSED SOMETHING, AND BY THAT STATE I STARTED FEELING FEVERISH, AND I DEVELOPED RIGHT UPPER QUADRANT PAIN AND ABDOMINAL PAIN WHICH WAS GETTING MORE AND MORE SEVERE. SECOND SMEAR WAS ALSO NEGATIVE. SO I WENT HOME AND ANOTHER DAY 1, THE DAY 2 OF THEM AS I WOKE UP WAS STARTING TO GET ACHING PAINS, MAINLY AROUND THE SHOULDERS BUT ALSO IN THE KNEE AND THE HIPS. AND THAT HAS SEEN WITH MALARIA BEFORE AND I WAS STILL FOCUSED ON MALARIA AND I CAME BACK AND DID A THIRD SMEAR AND THAT WAS ALSO NEGATIVE SO I HAD TO CONCEDE THAT IT WAS NOT MALARIA. BUT THEN ON DAY 2, THIS IS DAY 2, BY DAY 3 I WAS GETTING A LOT OF ABDOMINAL PAIN AND THE ACHING PAIN HAD BECOME QUITE SEVERE AND I WAS AT THAT STAGE THINKING ABOUT DENGUE. BY DAY 4, I NOTICED I DEVELOPED LITTLE RED SPOTS ON THE LOWER LEGS AND BOTH LEGS AND THEY WERE GRADUALLY APPEARING UP THE LEG AND END OF DAY 4, I THOUGHT I SHOULD GO TO GET MYSELF LOOKED AT AND ENTER G. W. HOSPITAL. I HAD CHECKED MY CBC ON THE DAY–1 OF THE SMEAR DAYS AND MY PLATELET COUNT WAS LOWER THAN NORMAL BUT NOTHING ALLOWED 13,000, NORMAL BEING 15 OR ABOVE, BUT MY WHITE COUNT WAS DOWN. ALL OF THIS CAN BE SEEN IN MALARIA, AND INDUCED HERE AND CONFUSION, BUT AFTER ADMISSION, THE PLATELET COUNT WAS DOWN TO 15,000. BELOW 15,000 THEY REALIZE THIS WAS MORE SEVERE THAN IT APPEARED AND THE ABDOMINAL PAIN WAS WORSE AND WORSE AND WE DID AN ULTRASOUND WHERE THEY FOUND I HAD FLUID IN THE ABDOMEN. AND THEY WERE WORRIED ABOUT BLOODING AS WELL BECAUSE OF THE PLATELETS, SO THEY GAVE ME A PLATELET TRANSFUSION AND THAT’S ANOTHER CONTROVERSIAL AREA WHICH PERHAPS CAN YOU ADDRESS. AND LOTS OF FLUID REPLACEMENT AND I WAS IN THE HOSPITAL FOR 4 DAYS AND I TURNED AROUND QUICKLY AFTER THAT. IT WASN’T LONG SEVERE, AND WHEN I GOT OUT OF HOSPITALS, IT TOOK ME ABOUT 6 WEEKS TO REALLY GET BACK TO MY BASELINE AND MAIN PROBLEMS WERE EXTREME FATIGUE, ACHES AND PAINS AND JOINT PAINS. THE RASH DISAPPEARED AFTER ABOUT 4 DAYS. BUT THE OTHER SYMPTOMS KEPT ME VERY RUNPRODUCTIVE FOR 6–UNPRODUCTIVE FOR 6 WEEKS. >>SO BEFORE I GO ON DOES ANYONE HAVE ANY QUESTIONS THEY WOULD LIKE TO ASK THE DOCTOR ABOUT HIS ILLNESS? >>DID YOU GET AN ACTUAL DIAGNOSIS? [INDISCERNIBLE] >>YES, I AM LUCKY TO BE WORKING AT THE NIH BECAUSE WE HAVE A REAL HE GOOD DENGUE LAB AND THE LAB DREW ON DAY 2 AND I SENT TO STEPHEN HE GREW OUT–[INDISCERNIBLE] >>NOT THAT I REMEMBER. I GREW UP IN INDIA, AND DENGUE OBVIOUSLY TRANSMITS AND IS ENDEMIC IN INDIA, BUT MAYBE I LITTLE– >>YEAH, WELL HE LIKELY DID BASE THE SEROLOGY THAT WAS DONE HERE AT THE NIH. >>THIS IDEA DISAPPEARED BY THE TIME I LEFT THE HOSPITAL, >>THEY DIDN’T GIVE DIURETICS BECAUSE A LOT OF THE FLUID LOSS IS FROM LEAKING CAPILLARIES AND’S ON ITS OWN. >>[INDISCERNIBLE]. >>NO I DID NOT. >>ANY OTHER QUESTIONS FOR DR. MA HANY. >>THANK YOU. >>SO I TRIED TO SUMMARIZE THE DOCTOR’S ILLNESS VERY BRIEFLY AND I THINK HE BROUGHT UP GOOD POINTS. THE FIRST POINT I WANT TO MAKE IS THAT HE BECAME ILL WITHIN 2 WEEKS OF BEING IN AN ENDEMIC AREA AND THAT’S VERY KEY BECAUSE F IT HAD BEEN LONGER THAN 2 WEEKS FROM THE TIME HE LEFT INDIA, TO THE TIME HE DEVELOPED SYMPTOMS, THEN DINGHY WOULD HAVE BEEN UNLIKELY. WHAT YOU CAN SEE ARE VERY CLASSIC SIGNS AND SYMPTOMS OFS
ILLNESS. SO VERSES THE HEADACHE AND WE OFTEN DESCRIBE THAT AS A HEADACHE THAT CAN BE BEHIND THE EYES OR AROUND THE EYES, HEADACHE, CHILLS AND THE ABDOMINAL PAIN ALSO IS VERY KEY BECAUSE THAT RELATED TO THE DIAGNOSE THAT YOU SEE. HIS PLATELET WAS AROUND 140,000. HOWEVER AS HIS ILLNESS PROGRESSED WHAT WE SEE IS THAT HIS PLATELET COUNTS CAME DOWN TO 15,000 WHICH WAS EXTREMELY LOW. HE ALSO HAD A LOW WHITE COUNT ALTHOUGH WE DON’T HAVE THE EXACT ABSOLUTE NUTRIFILL COUNT. HE HAS ABNORMAL LIVER FUNCTIONS, LOW PLATELET COUNTS AND EVIDENCE OF WHAT WE CALL VASCULAR LEAK WHICH IS THE [INDISCERNIBLE] WE SAW ALL CHARACTERISTIC IN TERMS OF DIAGNOSING CLINICALLY DENGUE AND DENGUE IS BY AND LARGE A CLINICAL DIAGNOSIS WHICH IS EXTREMELY DIFFICULT TO CONFIRM AND YOU NEED TO RECOVER THE VIRUS WHICH ONLY SPECIALIZED LABORATORIES CAN DO, OR BY SúROLOGY AND AGAIN ONLY SPECIALIZED LABORATORIES DO THAT, PARTICULARLY HERE IN THE UNITED STATES, IF YOU’RE IN AN ENDEMIC AREA, THERE ARE RAPID DIAGNOSTIC TESTS THAT HAVE BEEN APPROVED FOR YEWS IN ENDEMIC AREAS THAT ARE NOT APPROVED FOR USE BY THE FDA HERE IN THE UNITED STATES. THIS IS A PICTURE OF DR. MAHANTY’S RASH AND WHAT YOU SEE ARE LITTLE RED SPOTS HERE THAT ARE PETRESSABLE TECHY AND THESE ARE EVIDENCE OF MICRO VASCULAR LEAKING INTO THE SKIN. SO YOU’RE ACTUALLY BLEEDING INTO THE SKIN. THIS IS A RASH THAT WON’T BLANCH OR WHITEN WITH PRESSURE THE WAY ANOTHER TYPICAL DENGUE RASH DOES AND YOU WILL SEE A PICTURE OF THAT LATER. SO THIS RASH HERE IS EVIDENCE OF A PLEADING MANIFESTATION OR HEMORRHAGIC MANIFESTATION. SO FOR DR. MAHANTY, WE HAVE CLINICAL SIGNS AND SYMPTOMS OF DENGUE WITH A LOW PLATELET COUNT AS LOW AS 15,000, EVIDENCE OF VASCULAR LEAKAGE BASED ON [INDISCERNIBLE] AND A BLEEDING MANIFESTATION AND WE’LL TALK ABOUT THIS LATER SO I GIVE HIM A DIAGNOSIS BY ALL W. H. O. CRITERIA OF DENGUE HEMORRHAGIC FEVER. SO HE HAD EVIDENCE OF DENGUE FOR WHICH HE WAS HOSPITALIZED. TREATMENT WITH PLATELETS AS DR. MAHANTY IS CONTROVERSIAL IN DENGUE AND TYPICALLY IT’S NOT GIVEN UNLESS THE PLATELET COUNT IS LOW WHICH HIS WAS, WITH THE CONCERN THAT IF SOMEBODY FALLS WITH THAT LOW PLATELET COUNT, THEY COULD HAVE A SEVERE BLEED. SO HE WAS GIVEN THE TRANSFUSION, YOU CAN SEE THAT IT DIDN’T HELP THE PLATELET TRANSFUSION ALL THAT MUCH. IT WENT FROM 15,000-25,000. THE PLATELETS ALTHOUGH THEY’RE LOW, THEY’RE TYPICALLY NORMAL BUT BECAUSE OF THAT LOW PLATELET COUNT, YOU DO NOT WANT TO TREAT SOMEBODY WITH WITH DENGUE WITH DRUGS LIKE MOTE RIN OR ASPIRIN WHICH CAN EFFECT THE WAY THE PLATELETS WORK. SO WE DON’T TREAT FEVERS WITH THE NONSTEROIDAL ANTIINFLUMATORYS, IF YOU ARE GOING TO GIVE SOMETHING TO TREAT THE FEVER, YOU WILL GIVE ACET O MENOFIN AND YOU HAVE TO BE CONCERNED OF THE ABNORMALITIES WHILE YOU’RE GIVING ASEAT O MENOFIN. SO I WILL TOUCH BRIEFLYOT HISTORY AND THIS HAS BEEN AROUND CLINICALLY FOR QUITE A LONG TIME AND DR. BENJAMIN RUSH WHO WAS THE SIGNER OF THE DECLARATION OF INDEPENDENCE AND FOUNDER OF THE AMERICAN SOCIETY FOR TROPICAL MEDICINE AND HYGIENE AND DESCRIBES THIS AND WHEN YOU READ THE DESCRIPTION, CAN YOU THINK OF THE DOCTOR AS HE RETURNED FROM INDIA. BUT THE FEVER CAME ON WITH REGULAR, AND THE PAIN IN THE HEAD WERE SOMETIMES IN THE BACK PARTS OF IT AND AT OTHER TIMES THEY OCCUPIED ONLY THE EYEBALLS AND THAT’S A CLASSIC DESCRINGZ OF DENGUE. —DESCRIPTION OF DENGUE. THERE ARE 4 GENOTYPES, DENGUE 1, TWORKS 3, 4. AND THIS DOES COMPLICATE NOT ONLY VACCINE DEVELOPMENT BUT ALSO THE REASON WHY WE SEE SOME PEOPLE WITH MORE SEVERE DISEASE AND SOME PEOPLE WITH LESS SEVERE DISEASE AND WE’LL TALK MORE ABOUT IT. I’LL GO INTO THE IMMUNITY BRIEFLY AGAINST DENGUE, IT’S AN RNA VIRUS AND WE THINK THAT IF YOU DEVELOP ANTIBODY AGAINST THE ENVELOPE PROTEINS, THAT IS PROTECTED. SO THE E-PROTEIN IS THE PROTECTIVE ANTIGEN. FOUR GROUPS OF DENGUE WHEN WE LOOK AT YELLOW FEVER, THERE’S ONLY 1 SEROGROUPS, THERE ARE SEROGROUPS OF JAPANESE ENCEPHALITIS, THESE ARE TICK BORN AND MOSQUITO BORN. I PUT THIS UP SO CAN YOU SEE THE STRUCTURALLYAURAL PROTEINS OF WHICH THE ENVELOPE IS WON AND WE THINK THAT IS THE PROTECTIVE ANTIGEN. THESE ARE NONSTRUCTURAL PROTEINS AND DR. WHITE HEAD’S GOING TO GO INTO DETAIL WHEN WE TALK ABOUT THE VACCINE. WE DO BELIEVE THAT THE NONSTRUCTURAL PROTEINS ARE PROTECTIVE AND ARE IMPORTANT FOR PROTECTION AGAINST REINFECTION WITH DENGUE OR AT LEAST IN TERMS OF VIRAL CLEARANCE IF YOU DON’T BECOME AS ILL IF YOU’RE GETTING A SECOND SECTION. SO THIS IS THE ANNUAL BURDEN OF DISEASE FOR MORE RECENT DATA. WE THINK THAT THERE ARE ABOUT 400 MILLION INFECTIONS WITH DENGUE EVERY YEAR. OF THOSE ABOUT A HUNDRED MILLION ARE SYMPTOMATIC, PRESENTING FOR HONDURAS CARE AND ABOUT 5% OF INFEBLGHTS, WE DECIDE THE SEVERE INFECTIONS IN THE OLD TERMINOLOGY, DENGUE FEVER, OR RORSHACK’S SYNDROME. WHEN YOU HAVE AN OUTBREAK, WHAT HAPPENS IS HEALTHCARE SYSTEMS ARE OVERWHELMED. THERE ARE TOO MANY PEOPLE PRESENTING THE HEALTHCARE SYSTEM CAN’T HANDLE THE LOAD AND IT’S DIFFICULT TO GET CARE. WHAT YOU SEE HERE, INTERESTING, WE THINK THAT INDIA IS GOING TO BE THE NEXT REALLY HOT BED OF DENGUE. WE’VE SEEN INTRODUCTION OF DENGUE INTO CENTRAL AND SOUTH MIRK AMERICA AND YOU WILL SEE IN A MINUTE HOW THAT’S EFFECT THE NUMBER OF CASES )5rTHAT
OCCUR ANNUALLY. THIS IS A VERY IMPORTANT POINT. EACH IS PROTECTION AGAINST THAT INDIVIDUAL SEROTYPE BUT IT DOES NOT CONFER LONG-TERM PROTECTION AGAINST THE OTHER 3 SEROTYPES. THAT MEAN FIST YOU HAD 1 DENGUE INFECTION, IF THE DENGUE 1 VIRUSES, YOU CAN STILL GET DENGUE 2, 3, OR 4. AND NOT ONLY DOES IT NOT PROVIDE PROTECTION AGAINST THE OTHER 3 SEROTYPE ITS SETS YOU UP FOR MORE SEVERE DISEASE IF YOU ARE INFECTED WITH THE DIFFERENT SEROTYPE AND WE WILL GO THROUGH WHY THAT IS IN JUST A MINUTE. THIS IS WHERE PEOPLE ARE LIVING CLOSE TOGETHER AND THE MOSQUITO GOES FROM PERSON TO PERSON AND TO GET TO DR. ARIAS’ POINT, REASON THE FEMALE TRANSMITS, IT’S BECAUSE SHE FEEDS THE EGGS SO ONLY FEMALE MOSQUITOES TRANSMIT DENGUE, CAN YOU TRANSMIT IT WITHIN THE MOSQUITO SO THERE IS SOME VERTICAL TRANSMISSION, THERE IS A JUNGLE CYCLE WHERE DIFFERENT MOSQUITOES IN THE JUNGLE TRANSMIT IT TO NONHUMAN PRIMATES. WHAT’S INTERESTING IS THAT NONHUMAN PRIMATES DON’T BECOME ILL WITH DENGUE, THEY’RE ASYMPTOMATIC AND UNLIKE FEVER VIRUS WHICH CAN KILL NONHUMAN PRIMATES. WE DO THINK THERE ARE SOME VIRUSES THAT CAN INFECT PEOPLE. HOWEVER, THE VAST MAJORITY OF THE BURDEN OF ILLNESS IS IN THIS URBAN CYCLE WHERE YOU’RE LOOKING AT CITIES WHERE THERE’S LARGE POPULATIONS OF PEOPLE WHO ARE SUSCEPTIBLE TO DENGUE INFECTION. THE REASON–1 OF THE REASONS WE’VE SEEN SUCH A RESURGENCE OF DENGUE IS THE FACT THAT THE VECTOR ITSELF HAS BEEN ABLE TO REPOPULATE AREAS OF LATIN AMERICA. SO, THERE WAS A LARGE MOSQUITO ERADICATION CAMPAIGN IN LATIN AMERICA TO TRY TO GET RID OF YELLOW FEVER AND MALARIA AND IT WAS QUITE SUCCESSFUL IN ERADICATING THE MOSQUITO FROM CENTRAL AND SOUTH AMERICA FOR THE MOST PART. THOSE PROGRAMS ENDED IN THE LATE 1950, EARLY 1960S AND WHAT WE SEE IS THAT THE VECTOR ITSELF HAS BEEN ABLE TO REINHABIT AREAS WHERE IT WAS ONCE ERADICATED AND WITH THE VECTOR WE HAVE THE MEANS TO TRANSMIT THE VIRUS. SO THAT’S 1 OF THE REASONS WE’VE SEEN A RESURGENCE OF DENGUE. THERE A THE DECLINE IN THE VECTOR RADICATION PROGRAM, IT’S PROBABLY THE LARGEST REASON AND WE THINK THAT GLOBAL WARMING MAY IN FACT PLAY A ROLE IN THIS. UNCONTROLLED URBANIZATION PROVIDES BREEDING GROUNDS FOR MOSQUITOES. THIS REQUIRES EXTREMELY LITTLE WATER IN ORDER TO LAY ITS EGGS. THE AMOUNT OF WATER CAN SELL THE SODA BOTTLE CAP SO YOU DON’T NEED A LOT OF WATER, OLD TIRES, PLANTS THAT ARE HEAVILY WATERED. ALL OF THOSE PROVIDE GOOD MOSQUITO BREEDING AND ONCE THE VECTOR IS THERE ALLOWS TRANSMISSION OF THE VIRUS. WE HAVE INCREASED WORLD TRAVEL BY AIRPLANE. DR. MAHANTY, FELT WELL BY THE TIME HE LEFT, AND BY THE TIME HE GOT TO D. C. HE WAS UNWELL. SO THAT VIRUS CAN BE BROUGHT INTO THE UNITED STATES OR OTHER AREAS OF THE WORLD. IF THE VECTOR IS THERE, AND THE TEMPERATURE’S RIGHT, WHEN YOU BRING DENGUE IN IT CAN SPREAD PRETTY EASILY. THIS IS AN IMPORTANT TERM TO KNOW. THIS IS WHEN MULTIPLE SEROTYPES ARE CIRCULATING AT THE SAME TIME AND THAT’S REALLY THE SET UP FOR CAUSING SEVERE DISEASE IN PEOPLE. YOU NEED MULTIPLE TYPES WITH THE DIFFERENT SEROTYPES. WHEN WE LOOK AT RESURGENCE OF DENGUE THIS IS FROM W. H. O. LOOKING AT NUMBER OF CASES OF HEMORRHAGIC FEVER AND DEATH. YOU CAN SEE A STEADY INCREASE FROM THE 1970S ONWARD. MUCH OF THIS INCREASE THROUGH THE 90S AND THE 2000S IS DUE TO THE RESURGENCE OF CENTRAL AND SOUTH AMERICA. WE’RE SEEING MORE AND MORE CASES AND WE THINK THESE NUMBERS ARE GOING TO INCREASE MORE AND MORE. SO THIS IS A SUMMARY, IN RED IS DENGUE AND BLUE IS HEMORRHAGIC FEVER. ONE, 2002, DEN DENGUE 3 WAS INTRODUCED INTO BRAZIL OR SOUTH AMERICA AND THAT’S WHERE WE SAW AN INCREASE BUT IF YOU LOOK AT THE NUMBER OF CASES OF DENGUE HEMMERRAGE RICK FEVER, TO THE NUMBER CASES OF DENGUE, WHAT WE SEE OVERTIME IS THIS RATIO OF HEMORRHAGIC FEVER INCREASES AND WE SEE DIFFERENT SEROTYPES INTRODUCED OVER THIS PERIOD OF TIME. SO HERE WE HAD IN 2002 WE HAD DENGUE#Nú 3 COME IN, IN 2010 WE HAD DENGUE 4 AND IN HERE WE HAD A DENGUE 2 VIRUS CIRCULATING. AND WITH THIS YOU GET MORE CASES ASSOCIATE WIDE THAT. THERE IS SOME OF THE OUTBREAK, AGAIN A POINT OF THIS SLIDE IS TO SHOW THAT ALTHOUGH IN SOME OF THESE OPERATIONS, IN BRAZIL, WE HAVE SIMILAR NUMBERS OF CASES OF DENGUE, WHAT WE SEE ARE INCREASING NUMBERS OF SEVERE DENGUE OR HEMORRHAGIC FEVER AND DEATH AND THAT’S BECAUSE WE HAVE MULTIPLE SEROTYPE CIRCULATING AT THE SAME TIME. THIS WAS THE OUTBREAK IN INDIA IN 2012, THE DENGUE 2 SEROTYPE I DON’T THINK WAS MENTIONED DENGUE 2 AND THAT WAS THE SEROTYPE THAT WAS RECOVER FRIDAY DR. MAHANTY. SO THIS WAS AN ARTICLE THAT APPEAR INDEED 2008 IN JAMA. –APPEARED IN 2008 IN JAMA IT WAS WRITTEN BY TONY FAUCI AND DR. MORAN, IT’S REPORTED CASES ALONG THE TEXAS-NEW MEXICO BOREDDER AND LOOKING AT THE REEMERGENCE OF THE VECTOR IN THE UNITED STATES. AD THIS UP ALONG THE
WE COAST, THIS IS CAPABLE OF TRANSMITTING DENGUE AND THEN WHAT WE SEE IN 2010 WE SEE LOCALLY APPLIED DENGUE IN THE FLOWER FLOWER KEYS AND CASES OF ACQUIRED DENGUE OUT OF FLORIDA EVERY YEAR SINCE 2010. SO WE CERTAINLY HAVE THE RIGHT ENVIRONMENT IN TERMS OF VECTOR, TEMPERATURE, HUMIDITY FOR TRANSMISSION AND WE’RE STARTING TO SEE THIS IN FLORIDA. SO WHEN WE LOOK AT THE ILLNESS, WE CAN RANGE TO THE MILDLY SYMPTOMATIC TO A SEVERE INCAPACITATING ILLNESS. IT’S EASILY CONFUSED WITH A LOT OF OTHER ILLNESSESS AND MALARIA, INFLUENZA, MEASLES, DIFFERENT RICK EATSIAL DISEASES CAN ALL LOOK THE SAME AND CAN BE CONFUSED WITH DENGUE OR DENGUE CAN BE CONFUSED WITH THEM. THE MORE SEVERE FORMS OF THE DISEASE USED TO BE CALLED DENGUE HEMORRHAGIC FEVER AND THERE’S BEEN A NEW CLASSIFICATION SYSTEM BY W. H. O. AND HEMORRHAGIC FEVER AND INTERCHANGEABLY BECAUSE YOU’LL SEE BOTH TERMS IN THE LITERATURE, AND THE MORTALITY RATES 0.2% AND IF YOU GO INTO HOTCHY MIN CITY AND GET DENGUE AND PRESENT TO HOSPITAL, THEY WILL TAKE VERY GOOD CARE OF YOU. IF YOU GO INTO RURAL MONTANA HAVING FLOWN FROM THAILAND, YOU MAY NOT DO WELL. YOU WANT TO GO TO A PLACE THAT KNOWS DENNING SCHEKNOWS HOW TO TREAT IT BECAUSE FLUID MANAGEMENT IS REALLY KEY TO THE PROPER MANAGEMENT OF DENGUE. THEY SAID EARLIER IT’S ONLY A SMALL PERCENTAGE OF CASES THAT RESULT IN SEVERE DISEASE BUT IT IS A SIGNIFICANT NUMBER AND CAN REALLY OVERWHELM HEALTHCARE SYSTEMS IN EFFECTED AREAS. WE USED TO SAY THAT CLASSIC DENGUE FEVER WAS GENERALLY A DISEASE OF ADULTS, THIS WAS–IT’S A DISEASE REALLY OF YOUR FIRST PRESENTATION, AND SO BEFORE WE HAD ALL 4 SEROTYPES CIRCULING IN MANY DIFFERENT AREAS OF THE WORLD, PEOPLE WOULD PRESENT WITH CLASSIC DENGUE FEVER, IF YOU’RE A TRAVELER FROM THE UNITED STATES ON YOUR FIRST TRIP TO AN ENDEMIC AREA, TO SOUTHEAST ASIA, EXCUSE ME, SOUTH AMERICA, YOU MAY GET CLASSIC DENGUE FEVER WHICH REALLY IS WHAT THE DESCRIPTION BY DR. BENIA MIN RUSH DESCRIBED WELL. HEMORRHAGIC FEVER OCCURS COMMONLY WITH THE INFECTION AND THAT’S KEY AND WE’LL TALK ABOUT WHY THAT IS. WE SEE IT IN HYPER ENDEMIC AREAS IN CHILDREN YOUNGER THAN 15 YEARS OF AGE BECAUSE THEY’VE BEEN EXPOSED TO MULTIPLE SEROTYPES BY THE TIME THEY’RE 15, IT REALLY OCCURS IN AREAS THAT ARE HYPER ENDEMEC FOR DENGUE. SO THIS IS WHAT WE CALL CLASSIC DENGUE FEVER, IT’S AN ACUTE ILLNESS, YOU HAVE A FRONTAL HEADACHE, PAIN BEHIND THE EYES, SEVERE MUSCLE AND JOINT PAIN WHICH IS WHERE IT GETS THE NAME BREAK BONE FEVER, A VERY TYPICAL RASH, LOW WHITE COUNT AND LOW PLATELET COUNT. THOSE ARE ALL VERY CLASSIC. IF YOU LOOK AT THE SLIDE,OT LEFT, WE HAVE DENGUE FEVER GOING DOWN TO HEMORRHAGE ELECTED FEVER, AND THIS IS SEVERITY OF DISEASE GOING DOWN AND THEN WE HAD POST INFECTION GOING ACROSS AND YOU CAN SEE EARLY ON YOU HAVE VIREMIA, IT’S WHERE YOU’RE STARTING TO SEE VIREMIA AND YOU CAN SEE PEAK VIRUS TIGHTERS, THIS CORRELATES WITH SEVERITY OF DISEASE, SO MORE VIRUS, YOU HAVE, THE CHICKER YOU’RE GOING TO BE, WE DON’T REALLY KNOW HOW THAT HIGH VIRUS RELATES TO THE VASCULAR LEAK SYNDROME THOUGH THAT CAUSES SHOCK. AND WE’LL TALK A LITTLE BIT ABOUT THAT. >>HERE YOU HAVE A FEVER, SADDLE BACK FEVER, IT LOOKS LIKE YOU’RE GETTING BETTER, FEVER GOES DOWN AND THEN IT GOES BACK UP AGAIN. YOU HAVE HEADACHE AND PAIN, THE RASH CAN LAST AS LONG AS 2 WEEKS. IT’S INTERESTING IS SHOCKIN CHROME, HEMORRHAGIC FEVER, SYNDROME APPEARS TO OCCUR AT THE POINT OF EVER ESTIMATE THAD ENSEL WHEN YOU’RE FEVER BREAKS. SO YOU THINK YOUR PATIENT IS GETTING BETTER AND THEN THEY GO INTO SHOCK. IT’S A VERY RAPID VASCULAR LEAK SYNDROME AND I’LL SHOW YOU OF HOW THAT MANIFEST AND DENGUE HEMORRHAGIC FEVER CLASSICALLY, THAT WAS AN EPIDEMIOLOGICAL DIAGNOSIS AND IN ORDER TO HAVE HEMORRHAGIC FEVER, YOU HAD TO HAVE A CLINICAL DIAGNOSIS OF DENGUE FEVER, AND YOU HAD TO HAVE HEMORRHAGIC PHENOMENON LIKE THE PE TECHIAE, AND YOU HAVE TO HAVE ORAL DIFFUSION OR SOME EVIDENCE OF VASCULAR LEAK AND YOU HAVE TO HAVE THROMBOW CYTOPENIA, IN ORDER TO HAVE DENGUE SHOCK FEVER, YOU HAD TO HAVE FEVER PLUS SHOCK WHICH TYPICALLY IS MANIFESTED BY NARROWING OF THE PULSE PRESSURE. PEOPLE GO INTO SHOCK NOT BECAUSE THEY’RE BLEEDING OUT. PEOPLE GO INTO SHOCK BECAUSE ALL OF THEIR INTRA VASCULAR FLUID IS LEAKING OUT INTO THE PLURAL CAVITY. INTO THE STOMACH AROUND THE LIVER AND THEY CAN’T MAINTAIN THEIR BLOOD PRESSURE. THIS IS A TYPICAL CLASSIC DENGUE RASH, WHAT YOU CAN SEE IS IT LOOKS LIKE A VERY BAD SUN BURN. IT BLANCHS IF YOU APPLY PRESSURE WITH THE HAND AND RELEASE IT, IT GOES RIGHT–IT’S EXTREMELY UNCOMFORTABLE. PEOPLE DESCRIBE IT AS THEIR SKIN BEING ON FIRE OR VERY, VERY ITCHY OF THE IT’S VERY UNCOMFORTABLE RASH. THIS IS WHAT WE CALL THE CONVALESCENT RASH WHERE YOU SEE LITTLE ISLANDS HERE AND AT THIS STAGE, CAN YOU ACTUALLY HAVE THE SKIN PEELING OFF THE HANDS AND FEET. IT’S A VERY, VERY PRONOUNCED EFFECT. SO THESE WILL BE ALL W. H. O. CRITERION AND I WILL TELL YOU THE CRITERION WERE CHANGED BUT IN ORDER TO HAVE DENGUE HEMORRHAGIC FEVER AND PLUS MINOR-MAJOR PLEADING, A PLATELET COUNT LESS THAN A HUNDRED THOUSAND AND EVIDENCE OF PLASMA LEAKAGE, IN ORDER TO HAVE DENGUE SHOTS SYNDROME, YOU HAD TO HAVE ALL THE SHOTS OF HEMORRHAGIC FEVER PLUS EVIDENCE OF SHOCK, CARDIOVASCULAR COMPROMISE. YOUR PLATELET COUNT WENT INTO HIGHER THAN 20,000, YOU DID NOT HAVE DENGUE FEVER, CAN YOU DID NOT HAVE DENGUE SHOTS SYNDROME. AND FOR THAT REASON, THERE WAS CONCERN ABOUT HOW THESE EXTREMELY ILL PEOPLE WEREN’T MEETING THE CASE DEFINITION SO THE KITERRIA WERE REVIED AND HOWEVER THE NEW ARE TRIAGED AND THEY’RE NOT USEFUL FOR EPIDEMIOLOGICAL PURPOSES SO YOU HAD DIFFERENT GROUPS, YOU COULD BE GROUP A, GROUP B, GROUP C. GROUP A, YOU CAN EAT AND DRINK FLUIDS, YOU DON’T HAVE EVIDENCE OF VASCULAR LEAK OR LOW PLATELET COUNTS. YOU CAN BE SENT HOME. GROUP B IS REFERRED FOR HOSPITAL MANAGEMENT AND THAT IS, YOU HAVE WARNING SIGNS WHICH I’LL GO THROUGH AND YOU’LL SEE THESE WARNING SIGNS ARE QUITE GENERAL OR HAVE YOU A CO-EXISTING MORBID ID OR COMPLEMENT YOUR ILLNESS SUCH AS EVEN DIABETES FOR INSTANCE. THAT’S CO-MORBIDITY THAT WILL BRING YOU INTO GROUP B. GROUP C IS WHAT WE WOULD CALL SEVERE DENGUE, THAT’S WHERE YOU HAVE SEVERE PLASMA LEAKAGE, SEVERE HEMORRHAGE, SEVERE ORGAN IMPAIRMENT AND YOU REQUIRE EMERGENCY TREATMENT. WHAT HAPPEN SYSTEM YOU WILL SEE GROUP B, THIS IS WARNING CIPES. SO IF YOU HAVE ANY OF THESE, OR LABORATORY WARNING SIGN THAT LOOKING LIKE HAVE YOU INCREASING HCT WHICH IS A SIGN OF LEAKAGE OR RAPID DECREASE IN PLATELET COUNT. YOU NEED TO BE HOSPITALIZED SO THE NEW CRITERIA RESULTED IN REALLY A TREMENDOUS AMOUNT OF HOSPITALIZATION. SO AGAIN THIS, IS VERY, VERY DIFFICULT FOR–FOR HEALTHCARE SYSTEMS IN COUNTRY MANAGED THE NUMBER OF PATIENTS THAT ARE REQUIRING HOSPITALIZATION WHICH THEY PRESENT WITH SUSPECT DENGUE. THESE ARE SOME OF THE BLEEDING MANIFESTATIONS OF DENGUE, THESE ARE LITTLE PETCHIAE THIS IS A LARGE AREA OF BLEEDING HERE AND YOU SEE HERE IS A BLISTER, IT’S A FLUID FILLED BLISTER FROM INTRA VASCULAR VOLUME LEAKING INTO THE SKIN THERE. THIS IS CLASSIC, CLASSIC EXAMPLE OF VASCULAR LEAK. WHAT YOU SEE HERE IS AN EXTRA WHERE THE PERSON IS PLACED ON THEIR SIDE AND GRAVITY DOES THIS WORK, THE FLUID AROUND THE LUNG, THE PEARL CAVITY IS ABLE TO GO DOWN WITH GRAVITY ON A CHEST X-RAY, AIR IS BLACK, THINGS OF HIGHER DENSITY ARE WHITE. SO THIS IS WHAT A NORMAL LUNG LOOKS LIKE ON A CHEST EXTRA, HERE, ALL OF THIS HERE IS FLUID THAT HAD SEEPED INTO THE PLURAL CAVITY. YOU CAN SEE HERE THE AMOUNT OF FLUID AND UNDERSTAND NOW WHY PEOPLE GO INTO SHOCK. THIS IS LEADERS AND LITERS OF FLUID. FLUID MANAGEMENT IS KEY TO THE TREATMENT OF SEVERE DENGUE. SO HOW DO YOU MAKE A DIAGNOSIS OF DENGUE, AGAIN IT’S A CLINICAL DIAGNOSE. YOU LOOK AT HOW THE PATIENT IS PRESENTING AND YOU SAY, I THINK THIS IS DENGUE, YOU CAN SEND OFF TESTS FOR ISOLATION OF VIRUS OR SEROLOGY, THESE TESTS TAKE QUITE A WHILE TO COME BACK. THERE ARE RAPID TESTS IN COUNTRIES THAT ARE EFFECTED, YOU CAN DO A RAPID NS1 TEST, DIFFERENT TESTS THAT WILL CONFIRM THE DIAGNOSIS OF DENGUE BUT MUCH OF THESE TESTS TAKE A LONG TIME TO COME BACK AND MANY OF THESE ARE NOT SPECIFIC, SO IN TERMS OF EPIDEMIOLOGY SAYING WE’RE HAVING A DENGUE 2 OUTBREAK OR 1 OUTBREAK, THE RAPID TESTS ARE NOT CAPABLE OF DISTINGUISHING, ALL THEY WILL TELL YOU IS YES, NO, DENGUE. MANAGEMENT OF DENGUE WE TALKED ABOUT, IT’S REALLY CAREFUL FLUID MANAGEMENT AND IT’S NOT ANYTHING THAT’S HIGH-TECH, WHAT YOU WILL SEE ON DENGUE WARS IN THESE COUNTRIES AND THEY WILL BE A SMALL CENTRIFUGE AT THE BEDSIDE, THEY WILL COME AROUND, PRICK A FINGER, PUT THE BLOOD IN A TUBE AND SPIN IT DOWN AND THEY’LL LOOK AT THE RATIO OF PLASMA ON TOP TO RED CELLS ON THE BOTTOM AND THAT’S ESSENTIALLY EYEBALLING WHAT THE HEMATTA KRID IS AND ADD THAT PLASMA TO THE RED CELL RATIO GETS LOW E, THAT’S A BAD SIGN AND THEY’LL GIVE YOU MORE FLUID. CAREFUL FLUID MANAGEMENT IS KEY TO SUCCESSFUL TREATMENT. OFTEN TIMES WITH INEXPERIENCED CAREGIVERS WHAT HAPPENS IS YOU GIVE TOO MUCH FLUID AND YOU FLUID OVERLOAD THE PERSON SO THAT WHEN THE VASCULAR LEAK SYNDROME REVERSES THEY HAVE NO WAY TO GET RID OF ALL THE FLUID YOU’VE GIVEN THEM. YOU WANT TO AVOID NONSTEROIDAL NONANTIINFLAMMATORY AGENTS BECAUSE OF THE PLATELET EFFECT. THERE CURRENTLY IS NO DRUG YOU CAN GIVE SPECIFICALLY FOR DENGUE, YOU CANNOT GIVE AN ANTIVIRAL AGENT THAT WILL STOP THE PROGRESSION AND CLEAR IT IS VIREMIA, THERE ARE SEVERAL AGENTS THAT ARE EVALUATED THAT THERE IS NOTHING THAT HAS BEEN SHOWN TO BE EFFECTIVE AND THEY’VE LOOKED AT STEROIDS FOR THE TREATMENT OF DENGUE AND FOUND THAT STEROIDS DO NOTHING TO HALTER THE COURSE OF DISEASE, SO STEROIDS ARE NOT RECOMMENDED FOR THE TREATMENT OF DENGUE. SO WHY DO SOME PEOPLE GET SEVERE DENGUE AND SOME PEOPLE DON’T AND WHY IS THE SECOND INFECTION AND THAT’S WHAT WE WILL TALK ABOUT RIGHT NOW. IN STUDIES THAT THEY DID LOOKING AT SERIES OF CASES FROM THE CHILDREN’S HOSPITAL, WHAT YOU SEE IN THIS SLIDE IS 2 PEAKS OF ILLNESS, YOU SEE HERE A PEAK OF DHF, AROUND 9 YEARS OF AGE BUT YOU ALSO SEE THIS PEAK AT LESS THAN 1 YEAR OF AGE. VERY YOUNG KIDS AND WHEN HE BROKE THIS DOWN INTO MONTHS WHAT HE SAW HERE IS ABOUT BETWEEN 0 AND 4 MONTHS, VERY LITTLE DENGUE, BETWEEN 4 AND 10 MONTHS, YOU SAW INCREASING NUMBERS OF HEMORRHAGIC FEVER IN INFANTS AND THEN THAT FALL OFF BETWEEN 10 AND 12 MONTHS AND WHEN THEY LOOK AT MATERNAL ANTIBODY, FROM THE MOTHER WHO IS GAVE BIRTH TO THESE BABIES WHAT THEY FOUND IS THAT MATERNAL ANTIBODY IN HIGH TITERS RIGHT AFTER BIRTH APPEARED TO BE PROTECTIVE AND BUT AS THAT MATERNAL ANTIBODY DECAYED OVER TIME, THEY FOUND IT ACTUALLY ENHANCED DISEASE. SO THESE TITERS OF NOCURNAL ANTIBODIES WERE CORRELATE WIDE MORE SEVERE DISEASE THAN THESE INFANTS AND THEN IT’S MATERNAL ANTIBODIES THAT DECLINED FARTHER AND THEY SAW IT HAD NO EFFECT AND IT WAS NEITHER PROTECTIVE NOR WAS IT ENHANCING SO HERE WITH HIGH TITERS OF MATERNAL ANTIBODY, THEY COULD SHOW PROTECTION AGAINST DENGUE BUT IN TITERS BETWEEN ABOUT AS THEY DECAYED BETWEEN 4 AND 10 MONTHS OF AGE, THAT ANTIBODY SEEMED TO CORRELATE WITH MORE SEVERE DISEASE. WHY IS THAT, IT’S WHAT WE CALL ENHANCING ANTES BODY, AND SECONDARY INFECTIONS, WE KNOW YOU’RE ABOUT 15 TIMES MORE LIKELY TO HAVE DHS WITH THE SECOND INFECTION THAN YOU ARE WITH THE FIRST INFECTION AND YOU’RE ABOUT 50-100 TIMES MORE LIKELY TO HAVE SYNDROME WITH YOUR SECOND INFECTION COMPARE WIDE YOUR FIRST INFECTION AND WE THINK THAT ENHANCING ANTIBODY HAS A LOT TO DO WITH THAT. HOW DOES IT WORK, WHILE ENHANCING ANTIBODY WHAT WE THINK IS HAPPENING IS THAT PREEXISTING CROSS REACTIVE ANTIBODY FROM YOUR FIRST DENGUE INFECTION COMBINED TO THE [INDISCERNIBLE] OF YOUR SECOND DIFFERENT DENGUE INFECTION WITHOUT NEUTRALIZING THAT VIRUS AND NOT ONLY DOES IT NOT NEUTRALIZE THE VIRUS BUT ALLOWS THE VIRUS TO ENTER THE MONOCYTES AND MACROPHAGES VIA THE FC RECEPTOR AND WHEN THE VIRUS TRIGGERS, IT’S IN THAT AND THE VIRUS CAN REPLICATE TO HIGHER TITERS. SO IF WE LOOK AT IT HERE, WE WILL SAY THAT YOU HAD A DENGUE 1 INFECTION BEFORE SO HAVE YOU DENGUE 1 ANTIBODIES, CIRCULATING HERE, AND NOW YOU’RE INFECT WIDE DENGUE 2, THAT–DENGUE 1 ANTIBODY COMBINED THE DENGUE 2 VIRUS BUT IT DOESN’T NEUTRALIZE IT. IT ACTS ALMOST AS A CHAPERON AND THEN THAT ANTIBODY VIRUS COMPLEX COMBINED TO THE FC GAMMA RECEPTOR HERE ON MONOCYTES AND MACROPHAGES AND ALLOW AGAIN, ALLOW THE VIRUS TO ENTER THE CELL WITHOUT TRIGGERING THE INNATE IMMUNE RESPONSE IN THE CELL. THAT VIRUS CAN REPLICATE WITHIN THE MONOCYTE AND MACROPHAGES LEADING TO HIRE TITERS OF VIRUS WHICH IS ARE THEN RELEASED AND YOU GET A HIGHER VIRAL LOAD AND WE KNOW FROM DIFFERENT EPIDEMIOLOGICAL STUDIES THAT A HIGHER VIRUS TITER SEEMS TO CORRELATE WITH MORE SEVERE DISEASE. SO HOW DO YOU PREVENT DENGUE, WELL, TODAY JANUARY 13th, 2015, YOU WEAR LONG PANTS, LONG SHIRTS, YOU USE DID HE TELLS, YOU PREVENT–TRY TO PREVENT BEING BITTEN BY MOSQUITOES. THERE IS NO LICENSED VACCINE TO DATE FOR DENGUE. THERE’S DENGUE VACCINE DEVELOPMENT WHICH IS ONGOING WHICH DR. WHITE HEAD WILL GO OVER AND IT’S VERY EXCITING. THE VERY BIG KEY TO DENGUE VACCINE DEVELOPMENT HOWEVER IS THAT ANY VACCINE HAS TO BE PROTECTIVE AGAINST ALL 4 SEROTYPES OTHERWISE WE RUN THE RISK OF PUTTING PEOPLE AT RISK FOR MORE SEVERE DISEASE DOWN THE ROAD IF THEY’RE INFECTED WITH 1 OF THE SEROTYPES OF THE VACCINE DOES NOT PROTECT AGAINST. SO, IT IS A VERY HIGH BAR. THERE ARE A LOT OF HURDLES TO DENGUE VACCINE DEVELOPMENT. DR. WHITE HEAD WILL GO OVER THOSE IN HIS TALK AND WE WILL NOW MOVE ON TO THE DENGUE VACCINE DEVELOPMENT UNLESS YOU HAVE QUESTIONS FOR ME. I AM HAPPY TO ASK–ANSWER WHILE I TURNOVER THE MICROPHONE. >>THERE WAS A SIMILAR DISEASE WITH THE CARIBBEAN WITH A LONG NAME. >>CHICK GUNNIA,–HAVE YOU NO SIN OIVITIS. YOU HAVE NO SINYIVITIS. SO THAT IS A WAY TO DISTINGUISH, THIS IS NOT AS FREQUENT IN DENNING SCHETHAT’S ANOTHER DISTINGUISHING FEATURE. THE VECTOR IS THE SAME. >>CAN IT CAN BE LONG LIVED. IT CAN BE MONTHS TO YEARS. >>[INDISCERNIBLE] >>SO WE’VE USED AND STEVE MAY TOUCH ON THIS IN A LITTLE BIT. WE’VE USED EXTENSIVELY IN VACCINE DEVELOPMENT BECAUSE THEY SUPPORT VIRAL REPLICATION SO WE LOOK FOR–WE LOOK FOR OUR VACCINE TO PREVENT VIRAL REPLICATION AND NONHUMAN PRIMATES BEFORE THE CRITERIA BEFORE WE MOVE INTO HUMANS. >>THE MOSQUITO MULTIPLE SEROTYPES HAVE BEEN RECOVERED FROM DIFFERENT MOSQUITOES, WE KNOW FROM OUR VACCINE STUDIES THAT WHEN WE GIVE A TOUCH OF VALENT VACCINE WE CAN RECOVER MORE THAN 1 FROM OUR VACCINEEES, IT’S UNCOMMON TO RECOVER MORE THAN 1 TYPE IN PEOPLE WHO ARE ILL, THAT’S PROBABLY BECAUSE YOU SEE AN EPIDEMIC IS THAT THERE’S DOMINANT SEROTYPES SO DENGUE 2 WILL DOMINATE SO THE MOSQUITOES MAY NO CARRY MORE THAN 1 SEROTYPE AND THAT SEROTYPE ABLE TO OUTCOMPETE THE OTHER 1. >>[INDISCERNIBLE]. >>YEAH THE PROBLEM IS 1 SEROTYPE MAY DOMINATE SO IT’S A SHORT LIV–VERY SHORT LIVED RESPONSE THAT COULD ACTUALLY BE HARMFUL DOWN THE ROAD. YOU’LL SEE SOME ACROSS THE GRAPHS SEVERAL YEARS. >>SO WHAT DO YOU ANTICIPATE THE EFFECTS OF–CAN 1 PREDICT THE EFFECTS OF GLOBAL WARMING IN TERMS OF DISTRIBUTION OF THE MOSQUITO GIVEN SAY WHAT’S HAPPENED OVER THAT INTERVAL THAT YOU SHOWED, WHAT ARE THE PREDICTIONS AS TO WHAT IS LIKELY TO HAPPEN AND I’M CURIOUS ARE THERE ANY OTHER DISEASE MOSQUITO TRANSMITTED DISEASES WHERE IT’S ONLY THE FEMALE THAT TRANSMITS. >>IT’S MALARIA, MALE MOSQUITOES TEND NOT TO TAKE BLOOD MEALS SO THEY DON’T TRANSMIT WITH MALARIA, CHICK, DENGUE, IT’S THE FEMALE THAT NEEDS THE BLOOD MEAL AND SO IT’S THE FEMALE THAT BITES BUT THE MALE MOSQUITOES CANNOT–ALL THE WOMEN. SO WITH GLOBAL WARMING WE DON’T HAVE FIRM PREDICTIONS. WHAT WE DO KNOW IS THAT NONAPOPTOTIC SWEET OS AND I VIRUSES PREFER CERTAIN TEMPERATURE RANGES AND THEY PREFER DIFFERENT HUMIDITYS SO THERE ARE SOME MODELS THAT TAKE GLOBAL WARMING INTO EFFECT AND THINK THAT THAT’S GOING TO SPREAD THE VECTOR CERTAINLY, SO THE VECTOR WILL INHIBIT NEW AREAS WHERE THE HUMIDITY AND THE TEMPERATURE ARE FAVORABLE FOR THAT VECTOR, THERE ARE MODELS THAT SHOW INCREASING SPREAD OF DIFFERENT MOSQUITO BORN DISEASES. >>I CERTAINLY THINK THAT URBANIZATION OUTPACES THE EFFECT OF GLOBAL WARMING. GLOBAL WARMING WILL BE A LONG-TERM THING. SO IT’S A DROP IN THE BUCKET AT THIS POINT. URBANIZATION IS WHAT’S CAUSING MOST OF THE PROBLEM. >>RIGHT. >>GOOD, THANK YOU. >>WOW WE NEED A VACCINE, RIGHT? YOU KILLED IT ANNA. OKAY, WHEN WE DEVELOP A VACCINE FOR DENGUE THERE ARE CERTAIN CONSIDERATIONS THAT WE NEED TO TAKE INTO ACCOUNT AND THE DOCTOR HIT ON OF COURSE NEEDING A VACCINE FOR DIFFERENT SEROTYPES AND AN EFFECTIVE VACCINE WILL NEED TO PROTECT AGAINST ALL 4 VIRUSES. ONE SEROTYPE IS LIKELY TO PROVIDE LONG LONG PROTECTION WHEREAS YOU ONLY GET THIS, HETEROTYPIC SHORT-TERM FOR THE STRAIN. WE KNOW AT LEAST BROADLY NEUTRALIZING ANTIBODY RESPONSE. SO IF YOU LOOK AT ALL THE PEOPLE HERE ON THE STREET IN VIETNAM, MOST OF THESE ADULTS ARE DENGUE IMMUNE, YOU HAVE TO ASK THE QUESTION, HOW DID THEY GET THAT WAY? AND CAN WE SAFELY INDUCE THIS IMMUNITY IN CHILDREN? AND I LOVE THIS PICTURE BECAUSE VACCINATION RESPONSES CERTAINLY CHANGE OVER TIME, YOU GO BACK IN TIME HERE, DENGUE IS REALLY FUNNY, UNTIL THEY GET CLOSER TO THIS POINT. THIS GUY’S, YOU KNOW TERRIFIED. AND THIS IS NOT A DENGUE VACCINATION BY THE WAY. [LAUGHTER] CAN WE SAFELY INDUCE THIS BROAD NEUTRALIZING ANTIBODY RESPONSE BY VACCINATION. IN INDEMMIC AREAS AS DR. DURBINALLUDED TO, DENGUE IMMUNITY IS MOSTLY ACQUIRED BY SEQUENTIAL EXPOSURE TO DIFFERENT SEROTYPES. WE DEMONSTRATED THIS IN A CLINICAL STUDY WHERE WE TAKE INDIVIDUAL WHO IS RECEIVED JUST THE DENGUE 4 VACCINE AND 2-7 YEARS LATER WOOY CAME BACK AND GAVE THEM DENGUE 1. SO, ON DAY 0 OF THEIR SECOND ADMINISTRATION THIS IS WHAT THE NEUTRALIZING ANTIBODY PROFILE LOOKED LIKE, THEY STILL HAVE DENGUE 4 ANTIBODY, THEY CALL THIS ANTIBODY, BECAUSE THEY HAD BEEN INOCULATED WITH DENGUE 4. AND 1, 2, 3, THEY’VE NEVER SEEN, THEY DON’T HAVE ANY ANTIBODY AND WHEN WE GAVE DENGUE 1, WE SEE A BOOST IN THE DENGUE 4 ANTIBODY, DAY 42, WE ALSO SEE PRIMARY IMMUNIZATION AGAINST DENGUE 1. THIS IS HOMOTYPIC. THEY HAVE 2 HOMOTYPIC RESPONSES. THEY SEE DENGUE 1 AND 4, THEY HAVE ANTIBODIES FOR DENGUE 1 AND 4 AND THEN WE ALSO SEE, THIS HETEROGENEOUS ROW TYPIC ANTIBODY COMING UP. THEY’VE NEVER SEEN DENGUE 2 OR 3, AND THEN WE ARE HAVE ANTIBODIES NEUTRALIZING ANTIBODY WE CAN MEASURE AGAINST THESE VIRUSES BUT WHEN YOU’RE LIVING IN HANOI, DRIVING A MOTORCYCLE, AS AN ADULT YOU PROBABLY ENCOUNTERED 2 DIFFERENT DENGUES IN YOUR LIFE. YOU MAY OR MAY NOT HAVE BEEN SICK. MOST PEOPLE ARE ASYMPTOMATIC, OTHER THAN ADULTS HAVE YOU A PROFILE LIKE THIS, YOU ARE PROTECTED. YOU WON’T GET DENGUE. THEY REMIND US THAT PRIMARY INFECTION IS NOT THE PROBLEM, IT’S DURING INTERVAL OF INFECTION, HAVE YOU THE POSSIBILITY OF ENHANCED DISEASE WHICH I THINK DR. DURBIN EXPLAINED VERY WELL. WE TALKED ABOUT THIS. THERE IS NO ESTABLISHED CORRELATIVE PROTECTION AGAINST DENGUE VIRUS, IS IT NEUTRALIZED ANTIBODIES, WE THINK IT IS. IS IT T-CELL IMMUNITY? PROBABLY. BOTH? MOST LIKELY. NO USEABLE ANIMAL MODEL FOR DENGUE DISEASE. AS WE MENTION SAID YOU CAN USE PRIMARILY REECES MONKEYS, AND WE CAN DETERMINE HOW PATHOGENIC DENGUE VIRUS IS AND HOW ATTENUATE IT IS. AND PREVIOUSLY THERE’S BEEN NO HUMAN CHALLENGE MODEL TO TEST THE EFFICACY. WHY DID WE DEVELOP A LIVE ATTENUATE DENGUE VACCINE OTHER VIRUSES AND YELLOW VIRUS AND THERE ARE LIVE ATTENUATE VIRUSES FOR THESE. THE BIOVACCINES FOR THESE VIRUSES, THEY WORK VERY WELL. A LIVE ATTENUATE VIRUSES BOTH HUMORAL AND CELLULAR RESPONSE, THE RIHAVE YOU SEENS ARE IN THEIR NATIVE FORM, THEY PRESENT EPITOPES IN THEIR NATIVE CONFIRM AGES AND YOU GET LIFE LONG IMMUNITY, ONCE YOU’VE BEEN VACINATED, YOU ESSENTIALLY HAD LIFE LONG IMMUNITY AGAINST YELLOW FEVER. YOU ARE RECOMMENDED TO GET A BOOST EVERY 10 YEARS IF YOU’RE NOT LIVING IN A AN AREA, THEY’RE VERY INEXINSURE MARKETTIVE TO PRODUCE, LIVE ATTENUATE VIRUSES ARE CHEAP. CAN YOU GROW UP A LITER OF VIRUS, IN OUR CASE THAT,’S A MILLION DOSES OF VACCINE. WHERE YOU GIVE MULTIPLE DOSES, THESE ARE ALL ADMINISTER MUCOSALY RATHER THAN INJECTED AND I THINK THE ISSUE HERE IS YOU NEED TO MAKE SURE YOU ARBITRATE AREN’T INFECT THANKSGIVING MUCOSAL SURFACE. WHEN YOU INJECT INTO AN ARM, YOU WILL HAVE ALL THE VIRUSES IS DELIVERED SYSTEMICALLY. THIS IS A CONCEPT, THAT WE’LL TALK ABOUT FURTHER WITH THE DENGUE VACCINE. WHAT’S IN THE CURRENT DENGUE VACCINE PIPELINE? THERE ARE 3 LIVE ATTENUATE VACCINES THAT ARE BEING TESTED. THE LITTER IN THE FIELD IS A VACCINE THAT WAS DEVELOPED AND HAS BEEN LICENSED AND HAS COMPLETED EFFICACY TRIALS INAZZIA AND THE AMERICAS, THIS VACCINE IS A CHIMERIC VACCINE, PART OF IT IS YELLOW FEVER, PART TELEVISION IS DENGUE, SO THIS IS A DIAGRAM GENOME STRUCTURAL PROTEIN ARE DERIVED FROM DENGUE VIRUSES, ALTHOUGH THE LIFE OF THE PROTEINS ARE DERIVED FROM THE YELLOW FEVER VACCINE VIRUS, AND THOSE VACCINE VIRUS AND PART DENGUE. AND YOU MAKE 4 DIFFERENT VARIETIES INTO THIS, 1 HAS DENGUE 1, 3, 4, SUBSTITUTED FOR THE PRE-EMAND E. YOU CAN MAKE CHIMERAS WHERE YOU USE THE DENGUE VIRUS BONE AND THENN YOU JUST EXCHANGE THE DIFFERENT SEROTYPES AND THAT IS THE STRATEGY THAT’S USED FROM A VACCINE THAT WAS ABOUT TO THE CBC, LICENSED INVARMIS RAGEN AND JAPAN AND THEN OUR JACK SEEN WHICH I’LL DESCRIBE A BIT LATER. AND ACTIVATED SUBUNIT VACCINES, 1 OF THEM IS DEVELOPED BY BIOTECH, PURCHASED BY MERCK IN WHICH YOU JUST MADE THE E-PROTEIN ITSELF IS IN THE INSIDE CULTURE, SUBUNIT VACCINE. IT PAYS FOR COMPONENTS, 1 FOR EACH SEROTYPE, THIS IS HAS GONE THROUGH A PHASE 1 TETRAVALENT VACCINE TRIAL USING THE MATRIX ADJUVANT OR SUBUNIT VACCINES, YOU GENERALLY NEED AN ADJUVANT ALONG WITH WITH A VIRUS. THIS IS GIVEN ME 3 DOSES, THE RESULTS ARE PENDING. IT WAS VERY–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’S 4 DIFFERENT COMPONENTS. THEY DID A PHASE 1, THEY ACTUALLY HAD A FAIRLY LOW RATE OF SEROCONVERSION, ABOUT 42% THAT ARE WORKING ON IMPROVEMENTS TO THIS PLATFORM. I’LL SPEND A COUPLE MINUTES TALKING ABOUT THE EFFICACY TRIALS BECAUSE THERE ARE THINGS TO BE LEARNED FROM THESE TRIALS. THERE WAS A TRIAL IN THAILAND, A TRIAL IN SOUTHEASTAZZIA AND A TRIAL IN THE AMERICAS AND YOU CAN SEE THE OVERALL EFFICACY WAS 37%, 57%, OR 61%. IF YOU LOOK AT THE EFFICACY BY SEROTYPE, IT BECOMES VERY APPARENT, THIS IS DENGUE 1, 2, 3, 4. THIS IS EFFICACY, THE EFFICACY IN THAILAND WAS 9% FOR DENGUE 2. IT’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’VE GONE WHEN THEY PUBLISH THIS PAPER. SO THAT’S ALL THE GOOD NEWS. SOME OF THE BAD NEWS IS THE SUPPLEMENT TO THE PAPER WHEN YOU LOOK AT THE VOLUNTEERS YOU DIVIDE BETWEEN THOSE WHO HAVE BEEN EXPOSED TO DENGUE AND SERONEGATIVE, AND THIS WAS DONE IN 9 TO 16 YEAR-OLDS AND SOME OF THEM ENCOUNTERED DENNING SCHESOME HAVE NOT IN THEIR LIFE AND WE NOW SEE THE EFFICACY IF YOU ARE DENGUE, DENGUE PRIMED. YOU HAVE 84% EFFICACY WITH THIS VACCINE THIS IS NOT A STATISTIC LOAMACYY SIGNIFICANT LEVEL OF EFFICACY. WHAT THIS TELLS US IS THAT YOU NEED MOTHER NATURE TO INTERVENE. MOTHER NATURE PROVIDES THE FIRST DONEES AND THE LIVE ATTENUATE VACCINE IS THE SECOND DOSE OR THE THIRD DOSE OR THE FOURTH DOSE AND YOU LOOK AT THAT DATA IN THE SEROPOSITIVE INDIVIDUALS, YOU PROBABLY DON’T NEED ALL 3 DOSES, YOU COULD GET BY WITH 1 OR 2 DOSES SO WITH THE EFFICACY TRIAL THEY WENT WITH 3 DOSES AS THEY HAVE STUDIED IN THEIR PHASE 1 AND 2 STUDIES. SO THE OTHER PIECE IS WHEN YOU LOOK AT EFFICACY IN OTHER COUNTRIES, IT’S DIFFERENT. BUT HERE IN BRAZIL, IT’S 78% BUT IN MEXICO IT’S 31%, WHY IS THIS? >>I’LL TELL YOU, IF YOU LOOK AT THE NUMBER OF CASES BY SEROTYPE, CAN YOU SEE THAT DURING THIS STUDY, MOSTLY DENGUE 4 WERE SEEN, DENGUE WAS REPLICATING IN BRAZIL, HEY THIS VACCINE IS BETTER FOR DENGUE 4 THAN IT IS FOR DENGUE 1 AND DENGUE 2 WHICH WAS CIRCULATING IN MEXICO DURING THE TRIAL. ALSO SO THOSE ARE POSITIVITY AND THEY HAVE HIGHER EFFICACY VERSES THOSE THAT ARE A BIT LOTER AND HAVE THE LOWER EFFICACY, WHY DOES THE CIRCULATING SEROTYPE MATTER IN THESE TRIALS. I NEED TO EXPLAIN THE EARLY SIGNS OF THIS VACCINE, WE GIVE 1 DOSE TO FLAVI-NAIVE PEOPLE, THIS IS 2 DIFFERENT TRIALS 1 WAS DONE IN THE U.S., 1 WAS DONE IN MEXICO, HONDURAS AND PUERTO RICO, DENGUE 4 DOMINATES, THE CYD IS PRINCIPALLY A DENGUE 4 VACCINE, IT WORK FORS POSITIVE INDIVIDUALS BECAUSE THEY’VE BEEN PRIMED TO THE OTHER SEROTYPES LIKE I SAID WHEN YOU GIVE A SEQUENTIAL, SEQUENTIAL INFECTION WITH DENGUE, YOU GET THIS BROAD NEUTRALIZING ANTIBODY RESPONSE. THAT’S PROBABLY WHAT’S GOING ON HERE. BECAUSE IT’S SUPPOSED TO BE A VACCINE. WHEN YOU INDUCE THIS IN INDIVIDUALS YOU SEE THE OTHER 4 COME UP, DENGUE 4 DOESN’T COME UP EARLY EARLY AND IT REMAINS THROUGHOUT THE VACCINATION. THE DENGUE 1, 2, 3, RESPONSES INCREASE AFTER SUBSEQUENT DOSES. HERE’S THE IMPORTANT PART. IN BRAZIL, IN 2012 AND 2013 WHEN THE VACCINE WAS TESTED, IT WAS MOSTLY DENGUE 4 THAT WAS CIRCULATING. PRIOR TO 2011, IT WAS 24, AND DENGUE 3 WAS REPLACE WIDE DENGUE 1 AND 2 AND THEN DENGUE 4 WAS INTRODUCED. YES, SO YOU COULD HAVE A GREAT DENGUE 4 VACCINE FOR A COUPLE OF YEARS IN BRAZIL TO ANSWER YOUR QUESTION. IT WORKED WELL. YOU FORGET EFFICACY. THERE’S NO DENGUE 4 IN MEXICO, AND 1 AND 2 CIRCULATE NOTHING 2012, 2013, THE ZACH SEEN DOES NOT WORK WELL, DENGUE 2 IS THE HILL, IT WORKS A LITTLE BIT AGAINST TENGEY 1. HAVE YOU LOWER EFFICACY IN MEXICO. YOU GO BACK AND WE SEE THE GREAT REPLACEMENT OF DENGUE 1. SO THAT WOULD EXPLAIN WHY THE CIRCULATING SEROTYPE MATTER OR WHY DO YOU SEE DIFFERENT EFFICACYS IN DIFFERENT ENVIRONMENTS? I THINK I COVERED MOST OF THESE POINTS. THAT VACCINE HAS A FAIRLY LOW RATE OF THE CONVERSION IN DENGUE INDIVIDUALS, 3 DOSES PROVIDES A RESPONSE AT 78. SO, YOU HAVE MANY INDIVIDUALS WHICH HAVE A PARTIAL IMMUNITY AFTER 3 DOSES OF THIS VACCINE, ALSO THE CD8-T-CELL RESPONSE IS DIRECTED AGAINST YELLOW FEVER NONSTRUCTURAL PROTEINS BECAUSE THE BACKBONE OF THIS VIRUS, NONSTRUCTURAL PROTEINS WHICH ARE GREAT FOR THE EPITOPES FOR T-CELLS ARE FOUND ARE YELLOW FEVER. THEY GET A GREAT YELLOW FEVER T-CELL RESPONSE BUT WE DON’T THINK IT’S THAT CROSS REACTIVE WITH DENGUE. THAT IS UNDER A LOT OF SCRUTINY AT THIS POINT. THE OTHER VACCINE TECADA I JUST HAVE AWE FEW MINUTES, IS THE DENGUE 2, IN THE TRIALS DESCRIBED HERE THEY GAVE 2 DOSES THERE AND THEY GAVE A LOW DOSE, THIS IS THE LOG OF EACH COMPONENT, THAT’S GIVEN AND THEY GIVE A SUBCUTANEOUS AND INTERDERMALLY, AND WE GET IT SUBCUTANEOUSLY AFTER 2 DOSES, YOU SEE A CONVERSION IS 58 OR 47% IN THE INDIVIDUAL, YOU GIVE AN INTERDERMALLY, USING THIS DEVICE, THIS SINGLE USE DEVICE, YOU SEE ABOUT 70%. I THINK THEY’RE GOING TO SUFFER FROM THE SAME PROBLEM. THAT VACCINE IS RECIPROCAL, THEY HAVE A VERY STRONG DENGUE 2 RESPONSE, VERY MARGINAL DENGUE FULL RESPONSE AFTER A SINGLE DOSE. WHAT ABOUT THE NIH VACCINE, WE ALSO LIVE VACCINE, WE HAVE A COMOPPOSITE BEHAVIORIAL PHENOTYPE THAT HE WENT IS ALL DENGUE 1, ALL DENGUE 3, ALL DENGUE 4 AND WE HAVE A CHIMERIC ON THE BACK BONE FOR DENGUE 2, OR HUNDREDS OF VACCINE CONSTRUCTS, WE TESTED THEM IN MONKEYS THAN WE DID STUDIES IN PHASE 1 STUDIES IN ABOUT 700 SUBJECTS TO TRY TO PICK A GOOD COMPONENT TO GO INTO WHAT WOULD EVENTUALLY BE A TETRAVALENT FORMULATION, THE NAMES WERE THE NECESSARILY IMPORTANT BUT YOU’LL NOTICE EACH OF THEM HAS THIS DELTA 30 DESIGNATION, VACCINE HAS A 30 NUCLEO TIDE DELETION IN THE 3 PRIME UTR, DENGUE 3 HAS MORE OF A DELETION AND THESE ARE THE VACCINE CANDIDATES THAT ARE GROWN INDIVIDUALLY COMBINED INTO A TETRAVALENT VACCINE. THERE’S 2 FORMULATIONS, TB003, TB005, THEY ONLY DIFFER BY THE 2 COMPONENT. WE PERFORMED ALL OF THESE STUDIES IN BALTIMORE, DR. DURBIN, AND IN VERMONT, IN SERUM NEGATIVE INDIVIDUALS THAT’S WHAT WE HAVE IN THE U.S. THESE WERE SAFETY STUDIES. WE HAD CLINICAL–A SINGLE ADMINISTRATION OF THE TETRAVALENT VACCINE OF THE CLINICAL FOLLOW UP FOR 16 DAYS, AND 28, 42, OR WE HAVE AN EXPANDED SCHEDULE, WITH THE 9028, 56, 90. WHY DID WE INCREASE THE DENGUE 2 COMPONENT. WHEN WE GAVE IT INITIALLY, THEY CONVERTED TO DENGUE 1, 2, 3, 4, WE SAW THAT DENGUE 2 WAS A BIT LOW. AND WE THOUGHT IF WE INCREASED THE POTENCY AND THE VACCINE WE MIGHT BE ABLE TO TO INCREASE THAT NUMBER, WE SAW ONLY A MARGINAL INCREASE AND THIS WAS WHEN WE EVALUATED SIM ON DAYS 28 AND 42. WHILE WE DISCOVERED IS WE USE THIS EXPANDED NUMBER OF DAYS OFF THIS, THAT’S WHEN THE E STANDS FOR, EVEN WITH THE 3, WHERE WE GAVE 3 LABS OF EACH VIRUS, WE SAW A PRETTY SIGNIFICANT INCREASE IN DENGUE 2, WHEN WE INCREASE A NUMBER OF MONITORING AND INCREASE POTENCY OF THE DENGUE 2 COMPONENT. WE HAVE WHAT WE THINK IS A VERY EVEN, LOW BALANCED DENGUE VACCINE. IT’S DIFFERENT FROM THE VACCINE BUT IS THAT THEY DON’T HAVE TOO MUCH OF A DOMINATING RESPONSE HERE, AGAIN IT MAY BE HIGHER ML VACCINE. WHEN WE–WHEN WE USE TB003 AND OUR EXPANDED SCHEDULE, WE HAVE 74% TETRAVALENT RESPONSE AFTER 1 DOSE, WE USE TB 005, WE’RE NOT TO YOU 90% SEROCONVERSION FOR ALL 4 TYPES AFTER SINGLE DOSE. I DON’T WANT TO GO OVER ALL THIS, THE CLINICAL SUMMARY IS THE ADVERSE EVENTS OF THE VACCINE, REALLY RASH IS ALL WE SEE. A LOT OF TALK ABOUT THE RASH FROM THE NIH VACCINE. OKAY. A LITTLE MORE THAN HALF OF THE INDIVIDUALS HAVE A RASH AFTER VACCINATION. THIS IS WHAT THE RASH LOOKS LIKE AT THE MACULAR PAP, THIS IS THE CHEST OF A VOLUNTEERS, THE CHEST OF ANOTHER VOLUNTEERS THESE SMALL RED SPOTS, ASYMPTOMATIC, NOT ITCHY, THE VOLUNTEERS DON’T COMPLAIN, THEY DON’T KNOW IT, WE DO A PHYSICAL EXAM WE REMOVE THE SHIRT, SURE ENOUGH DR. DURBIN THE EAGLE EYE:ITION SAYS HAVE YOU A RASH, IT’S MASHED AS A RASH. THIS IS THE RASH WE’RE TALKING ABOUT. IT’S NOT THE TYPICAL DENGUE RASH THIS, IS A VACCINE-ASSOCIATED RASH RATHER THAN A WILD-TYPE DENGUE RASH. IS IT A GOOD THING OR A BAD THING? GO AHEAD? >>YEAH, I’LL SHOW YOU, IT’S ABOUT 10 DAYS. SO IT COMES ON AFTER ABOUT 10 DAYS OF VACCINATION THEN LASTS FOR DEN DAYS IN GENERAL. >>[INDISCERNIBLE] BETWEEN 21 AND 28, THAT’S CREATED [INDISCERNIBLE]. >>YEAH. IT COMES AND GOES KIND OF SILENTLY. OKAY, WHEN WE LOOK AT ALL OF OUR VACCINE SEES AND LOOK AT THOSE WHO HAVE RASH, 61%, THOSE WITH NO RASH, 39%, IF YOU HAVE A RASH, YOU’RE GOING TO HAVE A TETRAVALENT SEROCONVERSION MOST LIKELY. IF YOU DON’T HAVE A RASH, YES, CAN YOU HAVE A TETRAVALENT RESPONSE BUT SOME PEOPLE HAVE A TRIVALENT OR BI VALENT RESPONSE. A VACCINE IS MORE LIKELY TO HAVE THE ANTIBODY RESPONSE IF THEY PRESENT WITH THE VACCINE ASSOCIATED RASH, SIGNIFICANT, I CALL IT THE HAPPY RASH, OKAY? PEOPLE THINK THIS IS–THE TERM, BUT IT REALLY IS, ASSOCIATED WITH A TETRAVALENT SEROCONVERSION. THE OTHER VACCINE FOR THE EFFECT IS NOT NOVEL TO OUR DENGUE VACCINE, THE MMR, ZOSTER, YELLOW FEVER, JAPANESE ENCEPHALITIS, THEY ALL HAVE A MILD RASH AS A SIDE EFFECT, PROBABLY ONLY 1, 2, 3, 4% OF VACCINEES, WE HAVE IN 50%, IT’S NOT UNCOMMON AMONG OTHER LIVE ATTENUATE VIRUS, VACCINES. ONE DOSE OR 2 DOSES, HOW MANY OF THESE DO WE NEED TO GIVE. I PUT IT ALL HERE ON 1 SLIDE. SO HERE’S TB005. OUR BEST FORMULATION GIVEN AS 2 DOSES, 6 MONTHS A PART. SO WE LOOKED TO NEUTRALIZING ANTIBODIES, 90 DAYS POST VACCINATION. SO HERE’S DOSE 1. IN THIS CASE, WE HAVE VERY HIGH SEROCONVERSION TO EACH OF THE [INDISCERNIBLE] SEROTYPES WHERE WE GAVE DOSE 2, WE SAW ABOUT THE SAME. THERE’S NOT MUCH ROOM FOR IMPROVEMENT HERE SO YOU KNOW WE DON’T SEE A LOT OF IMPROVEMENT HERE. WE SEE NEUTRALIZING ANTIBODIES AFTER THE FIRSTWIÑ DOSE. AND THIS IS 90 DAYS AFTER THE FIRST DOSE. BUT WE WAIT 6 MONTHS AFTER THE FIRST DOSE AT THE TIME WE’RE GOING TO GIVE THE SECOND DOSE, THIS IS WHAT THE ANTIBODIES LOOK LIKE. THIS IS THE ANTIBODY LEVEL IT DOES GO DOWN. THIS HAPPENS IN EVERY VACCINE, HAVE YOU A PEEK. YOU COME DOWN TO A BASELINE LEVEL. WHEN WE GET THE SECOND DOSE WE DON’T SEE MUCH OF A BOOST IN THE ANTIBODY TITERS, WE DON’T SEE MORE THAN A 2 FOLD BOOST. THIS IS ALL WE DO SEE, THOUGH. AT THE SECOND DOSE WE SEE NOW VIREMIA, NO RASH. WHEN WE LOOK AT THE FIRST DOSE, WE HAVE THE VIREMIA, REPLICATING WE HAD RASH, NEAR STERILIZING IMMUNITY AND POST MINIMAL ANTIBODY BOOST. THIS IS A LIVE VACCINE, IF YOU GIVE A LIVE VACCINE IN TANDEM, IF YOU HAD A GOOD RESPONSE AT YOUR PRIMARY VACCINATION POINT, YOU SHOULD NEUTRALIZE ALL THE VACCINE VIRUS AT LEAST OKAY, IF YOU’RE NOT NEUTRALIZING THE VACCINE VIRUS, HOW ON EARTH WILL YOU NEUTRALIZE A WILD-TYPE VIRUS. THAT’S WHY MOST LIVE ATTENUATE VACCINES ARE GIVEN AS A SINGLE DOSE BECAUSE A SECOND DOSE DOESN’T DO ANYTHING BECAUSE YOU’RE–BECAUSE YOUR IMMUNE RESPONSE NEUTRALIZES THE VACCINE. IT’S LIVE, IT HAS TO REPLICATE. COULD I BOOST THESE ANTIBODY TITERS. WITH ENACTIVATED VACCINE? PROBABLY, DON’T NEED REPLICATION. THAT’S CALLED A PRIME BOOST STRATEGY, THERE ARE SOME WHO ARE INVESTIGATING THIS IN THE DENGUE VACCINE, STILLED. IF YOU COMPARE THE 3 VACCINES, I FEEL LIKE I USED CAR SALES MAN BUT MY PURPOSE HERE IS I WANTED TO SEE WHAT WAS HAPPENING WITH THE OTHER VACCINES WHERE YOU ENCOUNTER THIS SAME ISSUE, I WANTED TO KNOW THAT BEFORE WE SPEND A LOT OF MONEY OR OTHER COMPANIES SPEND A LOT OF MONEY ON THEIR EFFICACY TRIALS; SO THE WINDOW VACCINE, WE SEE A TETRAVALENT RESPONSE IN THE NAIVE SUBJECTS ABOUT 90%. OUR VACCINE IS DESIGNED TO BE GIVEN TO NAIVE INDIVIDUALS, WE WANT A VACINATE YOUNG CHILDREN. THEY’VE NEVER BEEN EXPOSED TO DENGUE. YOU HAVE TO HAVE SOMETHING THAT’S GOING TO WORK IN NAIVE INDIVIDUALS. IN THAT POPULATION, YOU CAN’T COUNT ON MOTHER NATURE BEING THERE FIRST AND PRIMATE INDIVIDUALS. AND THE VACCINE, WE’LL PROBABLY NOT WORK VERY WELL IN NAIVE INDIVIDUALS, THEY ARE LOOKING AT A VACCINE AGE OF AT LEAST 10 YEARS OLD BEFORE YOU GET VACINATED SO YOU PROBABLY COME INTO–YOUR EXPOSURE TO DENGUE PRIOR TO HAVING THE VACCINE. THE ONLY 1 IN CRITICAL PHASE 3, OVERALL I STATED 30-61%, WE DON’T KNOW WHAT THE EFFICACY WILL BE FOR OUR VACCINE. I’M GOING TO ONLY TAKE 2 MINUTES TO DESCRIBE WHAT WE DO KNOW ABOUT EFFICACY WITH OUR VACCINE AND THAT IS DERIVED FROM OUR DENGUE CHALLENGE STUDIES. REMEMBER WE TOOK ALL THEE VIRUSES AND STUDIED THEM IN MONKEYS, THAT WAS 1 VIRUS WE COULD USE, DELTA THIRD WHICH WAS NOT PARTICULARLY ATTENUATE IN MONKEYS. WE THOUGHT MAYBE WE COULD USE THAT AS A CHALLENGE STRAIN. PREPARE IT AS A CLINICAL TRIAL MATERIAL, UPTOWARD ADMINISTRATION. IT’S A DIFFERENT SEROTYPE, AND THEN OUR VACCINE, IT WAS–IT WAS DERIVED FROM A TONGA OUTBREAK IN 1974, THAT OUTBREAK HAD MUCH MILD DISEASE LOWER LEVELS OF VIREMIA, LIKE I SAID IT WAS LESS ATTENUATE INDEED THE RHESUS MA CABBINGS, SO WE CHECKED THE SAFETY FIRST. SO 10 SUBJECTS RECEIVE A THOUSAND PLATFORM UNITS THAT’S HOW WE MEASURED MEASURED, 8 SUBJECTS HAD A RASH ANDLET RASH OR SOME RETROORBITTAL PAIN. THIS IS WHAT WE SAW COMPARED TO THIS PLACEBO, THERE’S P-VALUES, THE 1S IN BOLD THAT WERE NOTABLE COMPARED TO PLACEBO. AND THIS IS A RASH THAT LOOKS MORE LIKE A DENGUE RASH COMPARED TO WHAT WE SAW OF THE DENGUE VACCINE RASH; HUNDRED% OF INDIVIDUALS RECEIVE 2 DELTA 30 HAD A VIREMIA, IT WAS HIGHER TITER, ALMOST 2 LARGE HIGHER, HUNDRED TIMES HIGHER, CAME ON EARLIER, LASTED LONGER THAN WE SAW WITH OUR VACCINE CANDIDATE. WHAT WE DID IS WE TOOK 48 SUBJECTS, HALF OF THEM RECEIVED OUR TB003 VACCINE AND HALF RECEIVED THE PLACEBO. SIX MONTHS LATER THEY COME BACK TO BE CHALLENGED. OUR PRIMARY EFFICACY END POINT WAS VIREMIA, AGAINST IT IS DENGUE 2, SECONDARY EFFICACY END POINTS WERE PROTECTION AGAINST RASH, AGAIN WE COLLECTED SAMPLES AS WE HAD DONE IN THE PAST, THEN THESE INDIVIDUALS CAME BACK, WE GOT CHALLENGED AND THEN WE FOLLOWED THEM AFTER THE VIRAL CHALLENGE, IF YOU HAVE PLACEBO HAVE YOU VIREMIA, ALL OF THEM HAVE I HAVE REAM YARKS ALL OF THEM HAVE THE RIHAVE YOU SEEN LOAD, THIS IS ON DURATION, IF YOU HAD BEEN VACINATED WITH TB 003, HAVE YOU NO VIREMIA AND OF COURSE, NO RANGE ONSET OR DURATION, HUNDRED% PROTECTION AGAINST THIS I HAVE VIRUS. YOU LOOK AT RASH, 84% OF THE PLACEBO HAD RASH, REAL% OF THE VACCINEES HAVE RASH. THERE PROVIDES 100% EFFICACY AND IT’S A CHALLENGE, THIS GIVES US SOME HOPE THAT WHEN WE INTRODUCE THIS IN AN EFFICACY TRIAL, EARLY ON WE SEE TRUE EFFICACY, WE CHOSE DENGUE 2 BECAUSE IT GAVE US A PROBLEM IN OUR EARLY FORMULATION. I THINK I’VE GONE OVER ALL OF THAT. THE LICENSE IS BY IN THE U.S., THE BUTANTAN SAO PAL O, BIOTECH IN NEW DELHI, IT’S BEING SCALED UP FOR MANUFACTURING THESE AREAS, THESE AREAS WILL HAVE TO DO EFFICACY TRIALS. AND THAT’S IT. [ APPLAUSE ] WE MADE IT. WITH 7 MINUTES TO SPARE SEE! GO AHEAD. >>THANK YOU VERY MUCH. >>SO THIS IS A POSITIVE RNA VIRUS AND YOU ARE USING IT AS YOU’RE MOSTLY WHAT WE’RE–HOW MUCH DRIFT DO YOU SEE IN THOSE OVER THE YEARS? >>THOSE DRIFT. >>OKAY. >>BUT WE DON’T RUN IN–OKAY, FLU PEOPLE, OSE YOUR EARS, YOU DON’T RUN INTO THE PROBLEMS YOU HAVE WITH FLU. IF YOU HAVE BEEN EXPOSED TO 1 DENGUE TERIO TYPE, LET’S SAY YOU HAVE DENGUE 1 AND YOU LATER ENCOUNTER A DIFFERENT GENOTYPE OR DRIFT YOU WILL BE PROTTED. PROTECTED AGAINST WITHIN THAT SEROTYPE IS IT’S GOOD FOR THE ENTIRE SEROTYPE. >>SO, THE DRIFT AND SHIFT IS NOT AS PROBLEM–IS NOT PROBLEMATIC AND THEY WILL NOT UPDATE THE VACCINE AND IT’S MORE CONFIRMATIONAL. >>SECOND QUESTION, REAL QUICK, SORRY IN YOUR RMULATION YOU’RE USING YOU DELETED 30 BASE PAIRS OUT OF THE REGION HOW DOES THAT ATTENUATE THE VIRUS. >>THAT’S A GOOD QUESTION, YEAR STUDYING THAT. –WE’RE STUDYING THAT. NOW THAT WE DEVELOPED THE VACCINE WE CAN LOOK AT THESE ISSUES AND PROBABLY HAS SOMETHING TO DO WITH REPLICATION. ALTHOUGH– >>[INDISCERNIBLE]. >>LINEAR VIRUS. >>[INDISCERNIBLE]. >>YES, BUT IT’S ALL FOLDED UP AND WT WE DID IS HAVE–PROBABLY NOT VIRUS REPLICATION BECAUSE THE VACCINE VIRUSES IN TISSUE CULTURE CELLS, 0, GO VERY WELL, IN FACT GSK IS INTERESTED IN THE VACCINE TO ATTENUATE OR ENACTIVATED VACCINE BECAUSE IT GROWS SO WELL. SO WE THINK THAT THE DELTA 30 MUTATION IS REDUCING REPLICATION IN HUMANS AND THE CELLS THAT THE VIRUS REPLICATES AND IN MONKEYS WHICH ARE PART HUMAN. >>WHAT DO WE KNOW ABOUT THE CELL BIOLOGY OF DENGUE? IN OTHER WORDS HOW DOES IT ENTER AND REPLICATE [NDISCERNIBLE]? >>SO IT’S SO WE THINK THAT TARGET CELLS ARE DENDRITIC CELLS MONOCYTE MACROPHAGES, WE KNOW THAT THE DCC SIGN IS A VERY GOOD RECEPTOR FOR DENGUE, IT’S NOT CLEAR WHAT THIS–THERE’S BEEN DIFFERENT PUTATIVE RECEPTORS AND DC SIGN, IF WE–WE BELIEVE THAT MONOCYTES MACROPHAGES, DENDRITIC CELLS ARE TARGET CELL WHEN PEOPLE HAVE DONE AUTOPSIES STUDIES, THINGS LIKE THAT, IT’S VERY–THAT’S–THEY CAN FIND THE VIRUS IN MANY DIFFERENT TISSUES BUT IT’S THOUGHT TO BE REALLY LOCATED TO THOSE TYPICAL CELL LINES AND THEN WHEN IT ENTERS THROUGH THOSE PARTICULAR RECEPTORS, IT CAN TRIGGER THE INNATE IMMUNE RESPOE WITHIN THE CELL. WE’RE STILL LOOKING FOR OTHER TARGET CELLS AND RECEPTORS FOR DENGUE. >>WE REALLY DON’T KNOW WHAT SELL IS PUMPING OUT ALL THE VIRUS BECAUSE IF YOU LOOK AT SOMEBODY WHO HAS DENGUE HEMORRHAGIC FEVER THEY CAN HAVE A VIRUS LOAD OF 10 TO THE 9, PEOPLE WHO HAVE DENGUE FEVER, SIMPLE DENGUE FEVER, MAYBE 10 TO THE 4, 5, OR 6. WE DON’T KNOW WHAT CELL IS PUMPING OUT ALL THAT VIS AND THAT’S 1 OF THE MYSTERIES OF DENGUE. >>I WAS SURPRISED TO SEE THAT PUERTO RICO, IS THE PROBLEM– >>BIG PROBLEM IN PUERTO RICO, IT IS A PROBLEM THROUGHOUT ALL THE CARIBBEAN. YES. >>SO WHAT DO YOU– >>CDC HAS AN ENTIRE DENGUE BRANCH LOCATED IN PUERTO RICO. >>[INDISCERNIBLE]–HOPELESS WITH ALL THE TRAVELS OR WHAT? >>VECTOR CONTROL WORKS. SO YOU CAN SPRAY AN AREA AND IT WILL WORK, IT’S NOT SUSTAINABLE. SO YOU PRAY, YOU PRAY THE HELL OUT OF THE REGION, DENGUE GOES AWAY, NEXT YEAR THERE’S NO MONEY TO DO THE SPRAYING, DENGUE GOES BACK. >>NOBODY’S TRIED DOING THE STERILE MALES THAT SORT OF THING. >>THERE IS A LOT OF GENETIC MODIFICATION TO MOSQUITOES THAT’S A WHOLE SEPARATE TOPIC AND THAT DOES–THERE’S EVIDENCE THAT THAT MAY WORK, AGAIN, HOW SUSTAINABLE THAT IS, IT’S VERY HARD TO FOOL MOTHER NATURE. IT’S VERY HARD TO GET A REPLACEMENT OF 1 MOSQUITO BECAUSE WHEN YOU DO THE GENETIC MODIFICATION YOU TAKE A HIT IN FITNESS AND EVEN IF IT’S A SMALL HIT OVER TIME, THAT CAN BE A POINT, SOURE LITTLE PROJECT WHERE THEY DON’T SEE SUCH A FITNESS FOR THE MOSQUITO, THOSE MAY WORK. >>DENGUE DENGUE MOSQUITOES AND WERE ERADICATED FROM SOUTH AMERICA THAT,’S WHY IT’S [INDISCERNIBLE]. WHEN YOU TOOK THE ADT A–DDT AWAY, IT ALL ENDED. >>SORTS OF THE–[INDISCERNIBLE] >>THAN OTHERS–[INDISCERNIBLE]–THAT COULD HELP CIRCULATING? >>THAT’S POSSIBLE, IT’S MORE OF A STRAIN ISSUE RATHER THAN A SEROTYPE ISSUE. THERE ARE STRAINS THAT THE-HAVE–VIRULENCE THAT DO NOT TRANSMIT AS WELL, THEY DON’T CAUSE AS MUCH DISEASE IN THE SHORT-TERM AND THEN THEY GET REPLACED WITH A DIFFERENT STRAIN. WHAT MAKE ITS THAT WAY, WE’RE NOT SURE. >>MUCH OF THIS I AN IO-2 PHENOMENON, THE VASCULAR BLEED? >>[INDISCERNIBLE] THEY LOOKED AT DIFFERENT MEDIATORS. THEY THINK IT MAY BE PRODUCT OF THE SYSTEMS, THE TOXINS LIKE C3 A AND 5 A, THEY LOOK AT IL8. THEY LOOK AT TUMOR NECROSIS FACTOR, THEY LOOK AT A LOT OF DIFFERENT CYTOKINES AND THERE’S NOT 1 WE THEY CAN PINPOINT TO SAY THIS, IS WHY WE’RE SEEING THAT, WHAT WE KNOW IS THAT THE CELLS ARE NOT DESTROYED THAT THE JUNCTIONS OF THE CELLS APPEAR TO BE LEAKY BUT THEY DON’T APPEAR TO BE DAMAGED. SO IT DOES LOOK AS THOUGH IT’S A CHEMICAL MEDIATED EFFECT BY CYTOKINES OR AS A SAID AN AMP LOW TOXIN BUT WE DON’T KNOW EXACTLY WHICH 1. >>THEY’RE THE CYTOKINE STORM. >>AND THE STORM IS INCRIMINATED MECHANISM AND THE FORM OF DISEASE, HEPATITIS IS A PRETTY GOOD EXAMPLE OF IT. AND THEN HERE IS SOMETHING THAT IS FULMINATE EFFECTS PRIMARILY THE VASCULAR SYSTEM– >>SUPPOSED TO BE. >>IN ASIA, 90% OF THEM HAD AMOT GOLGI AND THEY DON’T TYPICALLY HAVE HEPATITIS ALTHOUGH IT CAN OCCUR. >>WELL ARE ANY OTHER QUESTIONS? DONE? THANK YOU VERY ISSUE VERY MUCH. >>THANK YOU. YOU DON’T HAVE TO WORRY TONIGHT.

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