THIS IS THE ONE TIME DURING THE YEAR THAT WE HAVE BEEN MOVED INTO HALF THE SPACE, SOMETHING ELSE GOING ON NEXT DOOR AND RATHER THAN MOVE TO AN ENTIRELY DIFFERENT BUILDING IT SEEMED BETTER THAT WE ALL BE MORE COZY. I WOULD ASK ONE THING. SOMEWHERE ABOUT 200 TO 300 OR MORE PEOPLE WHO WATCH THIS LIVE ON THEIR COMPUTERS. SO IF YOU'RE ASKING A QUESTION EITHER MAKE A LOUD NOISE OR WAVE AND WE'LL GET THE MICROPHONE TO YOU BECAUSE I KEEP GETTING THESE MESSAGES, IT' DISCONCERTING TO HAVE SPEAKERS ANSWER QUESTIONS WHEN THEY DON'T KNOW WHAT THE QUESTIONS ARE. SO TODAY'S TOPIC IS MALARIA, AS YOU KNOW. AND WE'RE -- MY FRIEND HARRY ALTAR TOLD ME THAT TO HIM, MALARIA -- COME ON. I WENT TOO FAR. FOR THOSE IN THE AUDIENCE, I PUT UP A COUPLE OF THINGS THAT STRUCK MY ATTENTION, BECAUSE I'M NOT EITHER ALTHOUGH WE'RE DEEPLY INTERESTED. SOME OF IT, YOU GET INVOLVED IN YOUR OWN WORK AND IMPORTANT THINGS GO BY. SO ONE OF THE IMPORTANT THINGS IS THAT MALARIA IS A MAJOR KILLER, MAYBE THE MAJOR KIMER IN CERTAIN POPULATIONS. SOMEWHERE AROUND 2 MILLION DEATHS A YEAR. 9% OF THE DEATHS IN AFRICA, I FIND. AND WE'LL HEAR, IT'S DUE TO A FAMILY OF PARASITES TRANSMITTED BY A MEDAL OF MOSQUITO, AND IT'S A HUGE PROBLEM THAT THE PARASITE HAS BEEN SMARTER THAN MAN'S EFFORTS HAVE BEEN BY OVERCOMING DRUGS DEVELOPED TO KILL THE PARASITE. THAT'S CHANGED THE WHOLE PICTURE OF THIS AS A GLOBAL DISEASE. THE COMPLEX LIFE CYCLE IN MAN AND VECTOR WILL BE PRESENTED AND THE MAJOR PUBLIC HEALTH MEASURES WILL BE DISCUSSED AS WELL AS THE IMPORTANT AREA OF TRYING TO OVERCOME THIS BY VACCINE. NOW, I DON'T KNOW HOW I GOT THIS SLIDE BUT IT IMPRESSED ME THAT -- JUST TO MAKE THE POINT, THAT MALARIA IS NOT ONLY A DISEASE OF SUBJECT TROP TROPAL -- TROPICAL AFRICA, BUT IN THE SMALL WORLD, PEOPLE TRAVEL, PEOPLE SO PLACES. OUR MILITARY GO PLACES. THIS THEY'RE NOT PROTECTED AGAINST MALARIA AS HAPPENED HERE WITH A GROUP OF MARINES WHO WENT TO LIBERIA, ALMOST A THIRD ME BACK WITH MALARIA. IT WAS NOT AN INNOCUOUS DISEASE IN MANY OF THEM. I DON'T THINK THERE WERE ANY FATALITIES, BUT 2 OR 5 REQUIRED TREATMENT IN THE INTENSIVE CARE UNIT. MALARIA WAS A DISEASE IN THE UNITED STATES FOR A LONG TIME. WASHINGTON WAS A MALARIAL FOCUS. SOMEBODY, THE GOVERNOR OF ILLINOIS SAID ILLINOIS WAS A GRAVE YARD BECAUSE PEOPLE HAD MALARIA, AND OF COURSE THE DEVELOPMENT OF QUESTION NINE CHANGED THE -- QI NINE BAKE BECAME -- BECAME THE PENNSYLVANIA OF ITS DAY. EVERY MAN, IT'S ON DOCTOR. THAT'S PROBABLY SOME OF OUR BIG PROBLEMS IN TREATMENT OF INFECTION TODAY. AT ANY RATE, SO WE'RE VERY, VERY FORTUNATE IN HAVING 2 COLLEAGUES TO HAVE VAST EXPERIENCE WITH THIS DISEASE, NOT ONLY HERE IN MAJOR POSITIONS OF DEVELOPMENT, VACCINATION AND RESEARCH, BUT ALSO OVERSEAS. VERY MUCH IN ACTION WHERE THE MOST NUMBER OF PATIENTS AND THE GREATEST PUBLIC HEALTH HAZARDS RESIDE. SO I'M GOING TO BRIEFLY INTRODUCE BOTH SPEAKERS AT THE BEGINNING, AND THEN WE WILL INTERRUPT AT THAT POINT. I ENCOURAGE YOU TO RAISE YOUR HANDS DURING QUESTIONS, EVEN DURING A PRESENTATION. ONE OF THE WORST THINGS IS TO HAVE SOMEONE USING SOME JARGON, FOR EXAMPLE, WHICH YOU'RE COMPLETELY UNFAMILIAR WITH, MAYBE COMING FROM A CLINICIAN OR A BASIC SCIENTIST. IF YOU DON'T UNDERSTAND IT YOU'RE LOST. SO JUST PUT UP YOUR HAND AN INTERRUPT. AT THE END WE'LL HAVE QUESTIONS AND ANSWERS AND DISCUSSIONS AND TEA AND CRUMBETS AND EVERYTHING ELSE. SO 2 SPEAKERS. OUR FIRST SPEAKER IS GRAY HEPPNER WHO IS THE DEPUTY DIRECTOR OF THE WALTER REED ARMY INSTITUTE OF RESEARCH. RAIR. AND IN CAPACITY, HE WAS TRAINED AS A PHYSICIAN AT THE UNIVERSITY OF VIRGINIA AND TOOK A CLINICAL TRAINING ELSE WHERE. WAS IN -- CAME INTO THE ARMY AT WALTER REED, AND HAS HAD VAST EXPERIENCE HERE AND OVERSEAS IN DIRECTING AND DEVELOPING PROGRAMS OF HIS MAJOR INTEREST, WHICH HAVE FOCUSED ON VACCINATION. NOW, OUR SECOND SPEAKER IS PATRICK DUFFY, WHO IS IN THE AID INSTITUTE HERE AND PATRICK IS THE DIRECTOR OF THE LABORATORY OF MALARIA IMMUNOLOGY AND VACCINOLOGY. HE TOOK HIS MEDICAL DEGREE AT DUKE AND THEN TRAINED AT WALTER REED, WAS ALSO IN THE ARMY FOR A GOOD NUMBER OF YEARS. THEN WENT TO THE WEST COAST WHERE HE HEADED IN A COLLABORATIVE TYPE OF EFFORT, A MAJOR RESEARCH PROGRAM IN MALARIA IN SEATTLE. CAME BACK TO THE NIH A YEAR OR 2 AGO TO HEAD THE LABORATORY OF MALARIAL IMMUNOLOGY AND VACCINOLOGY. SO WE'RE DEEPLY GRATEFUL TO BOTH OF YOU FOR TAKING THE TIME TO BE WITH US. GRAY, IF YOU WOULD BEGIN, PLEASE. >> THANK YOU. IT'S GREAT TO BE HERE AT THE NIH. MY IQ GOES UP 20 POINTS JUST WALK THROWING THE FRONT DOOR. IT'S GREAT TO SEE A LOT OF OLD FACES. OUR DISTINGUISHED LIBRARIAN THAT YOU HIRED AWAY, AND JOE THAT WE -- WHERE IS JOE? WE'VE DONE BOOST WORK ON. I APPRECIATE THE OPPORTUNITY. I'M NO LONGER THE DEPUTY DIRECTOR AT THE WALTER REED, I RETIRED THIS MONTH FROM THE U.S. ARMY BY LIKE PATRICK, WE ALL CONTINUE OUR CAUSE, I JOINED THE ARMY 20 YEARS AGO TO WORK ON MALARIA AND I HAVE BEEN FORTUNATE AND PRIVILEGED ENOUGH TO WORK WITH SOME OF YOU, AND MANY OTHER BRIGHT ANODAL TALENTED -- BRIGHT AND TALENTED Ph.D.s AND DOCTORS. IT'S PARTNERSHIPS WITH PEOPLE LIKE THE NIH CDC, USAID AND INDUSTRY THAT HAS MADE ADVANCES POSSIBLE. I DON'T KNOW YOU ALL AS WELL AS YOU MAY KNOW ME. WHO HAS HAD MALARIA BESIDES PATRICK DUFFY AND ME? JOE? THE GENTLEMAN THERE, LADY THERE. ANYBODY ELSE? YOU'LL BE THE PEOPLE I WILL CALL ONLY. DID ANY HAVE TO TAKE MECCLACLONE. DID ANY OF YOUR HAVE DOXYCYCLINE FOR A MONTH. PHOTO SNITCHED, YEAST INFECTIONS? YES. THAT'S RIGHT. THERE IS A COLLECTIVE WISDOM HERE OF PEOPLE WHO HAVE CONFRONTED THIS GREAT KILLER. WE COME OFF THE WORST FOR IT. WE TAKE DRUGS TO PROTECT US AGAINST WORSER EVILS. I'D LIKE YOU ALL TO ASK QUESTIONS. SOMETIMES I DON'T SPEAK VERY CLEARLY. THIS IS A TAG TEAM TODAY. I'M GOING TO TRY TO TELL YOU HOW BAD IT IS, CONVINCE YOU THAT YOU NEED A VACCINE AND PATRICK WILL TELL YOU HOW TOMAKE THE VACCINE. THE LIFE CYCLE, THE LIFE CYCLE. IS THERE A QUIZ AT THE END OF TODAY? WHEN IS IT? NO QUIZ? SO THIS IS -- DOES THIS HAVE A POINTER? >> IT DOES, THE RED AT THE TOP. >> SO IT'S A FORMIDABLE ADVERSARY. NOT THE LEAST OF WHICH IS HOW STEALTHY IT IS. I KNOW PEOPLE DEBATE WHETHER IT'S 1, 10, 100. BUT THESE ARE VERY ELUSIVE. WITHIN SECONDS OF ENTERING THE HOST THEY ARE IN THE LIVER, WITHIN MINUTES, MAYBE HOURS. BUT THE LIVER IS PRIVILEGED AND PATRICK WILL GO INTO WHAT KIND OF MALARIA VACCINE APPROACHES MIGHT BE USEFUL BUT HERE IS WHERE THE STAGGERING NUMBERS BEGIN. SOOTHER THOSE THAT DIDN'T READ UP ON IT BEFORE TODAY, ONCE MEROZITE AMPLIFIES TO 30,000. IF YOU MISSED YOUR CHANCE TO INTERCEPT THESE 1-100 BEFORE THEY ARRIVE IN THE LIVER, YOU SORT OF MISSED A GREAT OPPORTUNITY. IN THE LIVER, THEREIS NO DISEASE. THAT THE ALLEGATIONS OF ASYMPTOMATIC, INCUBATING. APPROXIMATELY 6 DAYS. DEPENDING ON WHAT KIND WE'RE DEALING WITH. THERE ARE 50 SPECIES. ONCE THEY RELEASE THE HEPATIC MEROZITES, THE WORD THAT'S TOO SMALL TO WORD, THERE IS CYCLIC INVASION OF THE RED BLOOD CELLS. IT'S ASEXUAL, LEADS TO A HORRENDOUS NUMBER. BILLIONS AND TRILLIONS OF PARASITES SO THE PARASITE BURDEN OF A CRITICALLY ILL PERSON IS ENORMOUS. THERE ARE 2 PROPERTIES OF THE RED CELL THAT ARE VERY USEFUL. AN INFECTED RED CELL HAS 2 CHARACTERISTICS. IT'S VERY STICKY, JUST LIKE THE TRAFFIC JAM ON THE BELT WAY. WE ALL SUFFER WITH THE SNOW. YOU'RE NOT GOING TO GET THROUGH. SO IF IT'S IN THE BRAIN, YOU HAVE CEREBRAL. IN THE KIDNEYS, YOU CAN HAVE RENAL SHUT DOWN. IT IRRITATE THE ENDOTHELIAL, SURFACES THE RED CELLS. WE SASS MANIFESTATIONS OF -- SEE MANIFESTATIONS FOR PULMONARY EDDEMA, THE OTHER EFFECTIVE COURSE IS THE RED CELL INVADED IS DOOMED. AND WILL DIE. THAT MEANS THAT YOU CAN HAVE PROFOUND ANEMIAS. SOME OF THE PEOPLE COME INTO A CLINIC IN AFRICA, CAN HAVE HEMATOCITES OF 5-10 PERCENT. AND CAN DIE OF PROFOUND ANEMIA. SO WITH THIS CYCLIC INVASION, DEVELOPMENT, REINVASION, WE THEN HAVE A VERY -- DON'T SKIP NO. 6 HERE. THIS IS THE MOST IMPORTANT. IT'S PROBABLY A REAL VULNERABLE POINT. THIS IS WHERE THE ASEXUAL [INDISCERNIBLE] BECOME [INDISCERNIBLE]. THEY'RE REDUCED IN NUMBER AND REPRESENT A VULNERABLE GROUP OF ANTIGENS AGAINST WHICH A VACCINE COULD BE RAISED, SEEMS NOT TO BE UNDER SUCH STRONG IMMUNE SELECTION. FROM THERE THE MALE AND FEMALES YOU NIGHT IN THE GUT OF THE MOSQUITO, FORM A UKIND NATE. AND THAT'S THE CYCLE. PATRICK WILL COVER THE DIFFERENT STRATEGIES OF DISEASE PREVENTING DISEASES. BLOOD STAGE, WHICH COULD LIMIT INFECTION, OR POSSIBLY LIMIT THE DEVELOPMENT OF [INDISCERNIBLE] AND THEN, OF COURSE, THERE ARE APPROACHES BOTH IMMUNOLOGIC AND DRUGS TO ATTACK THE SEXUAL STAGES. I JUST -- JUST TO GAUGE YOUR BACKGROUNDS, THERE ARE 2 MALARIAS WHICH PERSIST IN THE LIVER. THESE ARE SLEEPING FORMS. SO FOR [INDISCERNIBLE], THE INCUBATION IS NO PERSISTENCE IN THE LIVER. 2 MALARIAS, YOU KNOW WHAT THEY ARE. [INDISCERNIBLE] VALLEY, VERY IMPORTANT. THEY HAVE A PERSISTENT FORM WHICH IS THE SLEEPING FORM. KNOWN AS THE HIP INVOLVEMENT ZOITES. IT'S VERY DIFFICULT TO ERADICATE. THERE ARE NO DRUGS THAT CAN BE APPLIED ON A MASS ACTION BASIS. THIS HAS TREMENDOUS IMPLICATIONS FOR MALARIA CONTROL CAMPAIGNS. THERE IS NO SYMPTOMS OF AN INCUBATING HYPNOZOITE THIS. REPRESENTS A REAL CHALLENGE FOR ELIMINATION CAMPAIGNS. I THINK I'VE COVERED THIS. THIS IS JUST TO IMPRESS YOU AGAIN WITH THE NUMBER OF RED CELLS WHICH ACTUALLY CAN BE INVOLVED. IT IS A USEFUL INDICATION WHEN YOU LOOK AT A PERIPHERAL BLOOD SMEAR. YOU CAN SEE THE NUMBERS OF RED BLOOD CELLS. THE CLINICIANS GENERALLY DO THAT IN TERMS OF PERCENTAGE OF RED CELLS WHICH THEMSELVES ARE DIMINISHED ENUMERATOR OF THE PREVIOUSLY DESTROYED RED CELLS. YOU CAN SEE [INDISCERNIBLE] OF 25 OR EVEN 50%. USUALLY THAT'S NOT COMPATIBLE WITH LIFE BUT THEY HAVE BEEN -- THERE HAVE BEEN SURVIVALS THAT HIGH. WE'VE COVERED THE 2 MAJOR MANIFESTATIONS. I THINK PICTURES ARE WORTH A THOUSAND WORDS, ESPECIALLY WHEN I'M SPEAKING. I WOULD LIKE TO SHOW YOU A PICTURE. THIS IS A MUCH, MUCH SHOWN PICTURE OF A CHILD FROM KENYA WHO HAS THE PROFOUND ANEMIA OF MALARIA. THEY CAN TOLERATE THE HEMOGLOBINS, 1/4 OR EVEN LESS, AND TRANSFUSION CAN PLAY AND IMPORTANT ROLE IN RESUSCITATION. THAT'S THE POWER OF RED BLOOD CELL DESTRUCTION. ON THE LEFT IT'S CHARACTERISTIC OF [INDISCERNIBLE], YOU CAN DISTINGUISH THE DIFFERENT SPECIES BECAUSE OF THE CHARACTERISTICS, ESPECIALLY ON THE THIN SPHERE. HERE YOU HAVE MULTIPLY INFECTED RED CELLS. APPLY KAY OF THE RED BLOOD CELLS. PATRICK DUFFY IN THE FRONT ROW EDITED A SPECIFIC BOOK ON THE SPECIFIC IMMUNOLOGY IN PREGNANCY, AND THEY'RE JUST AT VULNERABLE AS NON IMMUNE TRAVELERS, OR INFANTS, AND HE WILL ADDRESS THAT SHORTLY. WHEN PEOPLE ASK WHY IS MALARIA IMPORTANT, THERE ARE LOTS OF BAD DISEASES OUT THERE, I THINK IT'S ONE FELLOW IN THE FRONT ROAD, WE ALWAYS SEE PART OF IT, THE IMMEDIATE DISEASE IN FRONT OF US, BUT MALARIA HAS A PROFOUND EFFECT ON THE LIFETIME ACHIEVEMENTS AND -- OF THE PEOPLE WHO HAVE HAD SEVERE BOUGHT. WE KNOW IF YOU'VE HAD IT, IT DOES EFFECT YOUR MEMORY AND NEUROLOGIC DEVELOPMENTS. I DON'T THINK IT TAKES MUCH CONTEMPLATION TO REALIZE HOW MANY PEOPLE DON'T REACH THEIR FULL LIFETIME POTENTIAL BECAUSE OF SEVERE MALARIA IN CHILDHOOD. I'D LIKE TO PRESENT A CASE OF MALARIA. THIS IS NOT ONE THAT I SAW. IT'S FROM THE NEW ENGLAND JOURNAL. I BORROWED FREELY FROM THE REFERENCES. I THINK IT'S A PRETTY GOOD CASE. IT ILLUSTRATES THE SITUATION THAT YOU OR I WOULD FACE AS NON IMMUNE TRAVELERS, IF WE WERE TO GO TO AFRICA AND CONTRACT MALARIA AND COME BACK. A 3-YEAR OLD GIRL, BORN IN THE UNITED STATES, WAS OF NIGERIAN FAMILY ORIGIN. SHE PRESENTED WITH A CHIEF COMPLAINT OF 5 DAYS OF FEVERS. A FANCY TERM FOR SHAKING COLD. LETHAT AREGY, NAZI AND VOMITING. -- NAUSEA AND VOMITING. THEY SAW A PHYSICIAN PRIOR TO DEPARTURE. THE PHYSICIAN SAID THE MOTHER SHOULD TAKE PILLS FOR THE PREVENTION OF MALARIA, BUT DID NOT PRESCRIBE ANYTHING FOR THE CHILDREN. THEY STAYED IN A HOTEL. IN A CITY NOT SPECIFIED, DID NOT GO TO THE COUNTRYSIDE. RETURNED TO THE UNITED STATES FIVE DAYS AGO. AND 2 DAYS PRIOR TO ADMISSION TO THE HOSPITAL, SOUGHT PRIVATE PHYSICIAN FOR 3 DAYS OF COMPLAINTS. AND AT THAT TIME NO EXAM WAS RECORDED BUT WE HAD SOME BEGINNING LABORATORY ABNORMALITIES. HEMATOCITE IS NORMAL, NO INCIDENT OF PHILS. PLATELETS ARE DIMINISHED. BLOOD SMEAR WAS DONE BECAUSE OF THE TRAVEL HISTORY AND LABORATORY REPORTED PARASITES. SHE WAS PAST MEDICAL HISTORY, IN GOOD HEALTH. AND HAD NO HISTORY OF SIGNIFICANT ILLNESSES. OR HEMO GLOBIN ABNORMALITIES. SO THE PHYSICIANS HERE IN THE AUDIENCE -- SO DO YOU WANT TO COMMENT ON ANY OF THE MANAGEMENT OF WHAT -- WOULD YOU HAVE PRESCRIBED ANYTHING? I GUESS HYPED SIGHT IS -- HINDSIGHT IS 20/20. ARE THERE ANTI-MALARIALS WE CAN GIVE CHILDREN TO PROTECT THEM FROM MALARIA? THERE ARE. MANY PEOPLE HESITATE TO PRESCRIBE DOXYCYCLINE IN PEOPLE UNDER 8. BUT THERE ARE THINGS THAT CAN BE USED. THE FIRST THING NOT DONE, THE RISK WAS ASSESSED AS BEING PRESENT. THERE WAS NO ACTION TO PROTECT THE CHILD. MALARIA IS A VERY FOCAL DISEASE. YOU HAD BE VERY HARD TO GET IT IN NAIROBI. THERE IS VERY LITTLE TRANSMISSION, BUT IF YOU WERE NEAR LAKE VICTORIA. IT WOULD BE EASY TO GET IT. I THINK PATRICK HAS HAD IT 5 TIMES FROM THAT PT OF THE WORLD. THIS IS A RED HERRING. YOU CAN GET MALARIA IN SMALL TOWNS IN AFRICA. YOU NEED TO CONSULT A MALARIA MAP. IF YOU'RE A PRESCRIBING PHYSICIAN. OKAY. LET'S SEE. EARLY PLATELETS BEING DEPRESSED IS A GOOD SIGN, TYPICALLY AN EARLY INDICATOR. NONE OF THESE HAVE HIGH PREDICTIVE VALUES. IT IS PART OF THE LARGER PICTURE. IF YOU DIDN'T KNOW THE PATIENT DID NOT HAVE PARASITES, THIS IS A CLASSIC PROBLEM THAT EVERY PHYSICIAN FACES, CALLED WHAT DO YOU DO WITH SOMEONE WITH A FEVER? YOU GIVE ATE BIG NAME, YOU CALL IT UNDIFFERENTIATED FEVER. BUT IT'S SOMEONE IS SICK. THEY HAVE NO LOCALIZING OR DIAGNOSTIC SIGNS. SO IN THE INTRODUCTION THAT WE WERE GIVEN WE TALKED ABOUT MARINES THAT WERE IN LIBERIA. THERE IS MORE TO THAT HISTORY. THEY SWEPT OUT A WAREHOUSE WHERE SOME OF THEM HAD SLEPT AND IT WAS FULL OF MOUSE DROPPINGS. PEOPLE WORRIED ABOUT LOSS OF FEVER. THERE IS PLENTY OF OTHER THINGS THEY COULD HAVE HAD. BUT THE PROBLEM IS, YOU CANNOT LOOK AT ANYONE AND SAY THEY HAVE MALARIA. IT'S A LABORATORY DIAGNOSIS. AND IT COMES TO ONE OF THE FUNDAMENTAL PROBLEMS OF CARRYING FOR PEOPLE IF YOU DON'T HAVE A DIAGNOSTIC CAPABILITY, AND MANY PLACES OR MOST PLACES IN AFRICA DON'T. YOU END UP USING VERY GOOD MEDICINES ON PEOPLE THAT DON'T NEED IT AND IT EXHAUSTS YOUR LIMITED SUPPLY OF MEDICINES. ONE IS LEFT IN A POSITION OF WASTING A LOT OF INNOCENCE AND PROMOTING -- MEDICINE AND PROMOTING TREATMENT COURSES NOT NEEDED. TOXICITY IS ASSOCIATED WITH UNNEEDED MEDICINES. ON EXAM, SHE WAS -- SHE RAPIDLY BECAME SLEEPY. HER BLOOD PRESSURE WAS STABLE. LITTLE FAST WITH -- WELL, FOR A WHILE THAT'S OKAY. 1:24. FAST BREATHING. HER OXYGEN SATURATION -- ALL OF US SHOULD HAVE OXYGEN SATURATIONS OF 95-100%. YOU DON'T KNOW, THAT'S A -- FROM THE FINGER, YOU DON'T KNOW HOW HARD THE PATIENT IS WORKING BUT APPARENTLY NOT TOO HARD. NO COMMENT OF LABORED BREATHING. NO ENLARGEMENT OF THE LIVER OR SPLEEN. NEUROLOGIC EXAM IS NON FOCAL. FANCY WAY OF SAYING THERE IS NO EVIDENCE OF SPECIFIC LESION IN THE BRAIN. YOU CAN HAVE THAT WITH A VARIETY OF CONDITIONS, ABSCESSES OR TUMORS, SOMETIMES INYOU'VE HAD A BRAIN INFARCTION YOU CAN HAVE A LOCALIZING SIGN. AT THIS POINT THERE WAS NO FACEBOOKALITY TO THE EXAM. 5% [INDISCERNIBLE] THIS IS A MEDICAL EMERGENCY. THEY CAN DIE WITHOUT PROPER TREATMENT. [INDISCERNIBLE] GENERALLY NORMAL. GLUCOSE IS NORMAL. SHE WAS PRESCRIBED ORAL QUININE. AND ADMITTED TO INTENSIVE CARE. DOES ANYBODY HAVE A QUESTION ABOUT HER PRESENTATION? WE'LL MOVE ALONG. THAT WAS A REASONABLE THING TO DO. SHE DEVELOPED -- SHE WENT DOWNHILL RAPIDLY. TEMPERATURE OF 40.3. ACCEPT TEAMIA INCREASED TO 21%. TREATED WITH QUINN ADEAN. IF YOU GIVE TOO MUCH. YOU CAN GET A TACHYCARDIA, WHICH CAN BE LETHAL. HER BLOOD PRESSURE DROPPED TO 50. PHYSICIANS RAPIDLY PUT HER ON IV INFLUENZA, GAVE HER -- FLUIDS, GAVE HER MEDICINES, AND THIS IS A REPRESENTATIVE PICTURE OF WHAT YOU WOULD HAVE SEEN, THE JOURNAL DIDN'T REPRODUCE. SHE WENT INTO EXPERIMENTAL THERAPY. YOU'D THINK IF ALL YOUR BLOOD CELLS ARE LADEN WITH PARASITES, IT WOULD MAKE SENSE TO EXCHANGE THEM. THIS IS WHAT HAPPENED. BUT AS FAR AS I KNOW, PATRICK, IF YOU KNOW DIFFERENTLY, THERE HASN'T BEEN A RANDOMIZED TRIAL TO SHOW A BENEFIT. A LOT OF TIMES WITH A VERY SICK CHILD, PEOPLE WANT TO DO SOMETHING, THIS WAS DONE. HERE IT BEGS THE QUESTION, DID IT EFFECT OUTCOME OR NOT, WE DON'T KNOW. THIS WAS A TIME COURSE, AFTER HER EXCHANGE TRANSFUSION, HER HEMOGLOBIN ROSE BACK TO THE NORMAL RANGE. HER PARASITE COUNT REDUCED. ESSENTIALLY FILTERED OUT BLOOD CELLS TWICE. THIS IS CALLED EXCHANGE TRANSFUSION. SHE MADE A FULL RECOVERY. THIS IS A TRICK QUESTION. SHE HAD REQUIRE [INDISCERNIBLE]. THIS YOUNG GIRL MADE A FULL RECOVERY. SHE ILLUSTRATED -- THERE IS NO QUIZ. I WANTED TO LIST SO YOU COULD UNDERSTAND THE HORROR OF THIS DISEASE FROM YOUNG CHILDREN, FROM THE RED BLOOD CELL DESTRUCTION, THE STICKINESS, CAPILLARY OBSTRUCTION AND ENDOTHELIAL DAMAGE, COMMON PATHWAYS OF COMA, SEIZURES, SHOCK, PROFOUNDAMINIA AND DEATH. NOW, FIRST QUESTION FOR THE AUDIENCE, WAS THIS GIRL'S CASE PREVENTABLE? SHE COULD HAVE -- WHAT COULD SHE HAVE DONE? SHE COULD HAVE SLEPT UNDER A BED NET. PROPHYLAXIS, AND THE PHYSICIAN DIDN'T REALIZE IT WAS AN EMERGENCY. SHE SHOULD HAVE BEEN ADMITTED 2 DAYS PRIOR. [INDISCERNIBLE] HIGH NUMBER OF RED CELLS. SHE ALMOST DIED. BLOOD PRESSURE, 40 OR 50 IS NOT COMPATIBLE WITH LIFE FOR VERY LONG. NOW, FIRST QUESTION, ASSUMING HER BLOOD INFECTION HAD BEEN CURED, DID SHE REQUIRE TREATMENT TO RATICATE PERSISTENT FORMS IN THE LIVER? THERE IS A MAYBE, THERE IS A YES. LETS AASSUME IT'S [INDISCERNIBLE]. IF IT'S JUST FALCIPARUM SHE DOESN'T NEED IT. BUT WHEN I SHOW YOU THE MALARIA MAP IN A MOMENT, IF YOU'RE TREATING A PATIENT OR RETURNING TRAVELERS, MAKE SURE YOUR PHYSICIAN KNOWS WHERE YOU HAVE BEEN. WHEN WE SAY MALARIA, WE THINK OF THE WORST CASE, FALCIPARUM. IF YOU HAVE VIE VAX MALARIA, MANY REQUIRE TREATMENT OR CAREFUL WATCHING. THIS GIRL DOES NOT NEED TREATMENT FOR [INDISCERNIBLE]. SHE HAD FALCIPARUM. WE COULD SEE SHE HAD AN IMMUNIZING EXPERIENCE. IS SHE AT RISK AGAIN IF SHE GOES NEXT YEAR. DOES SHE SAY I JUST HAD A BAD CASE OF MALEERIA, I DON'T NEED PILLS. I'M IMMUNE. IS THAT GOOD THINKING. IT WOULD BE MALPRACTICE CITY THERE. SHE HAD CIRCULATING [INDISCERNIBLE]. FOR THE POINT OF ARGUMENT SHE LIVED IN ROCK CREEK PARK RIGHT NEXT TO A HOUSE HOUSE ON THE PARK -- NICE HOUSE ON THE PARK. SHOULD WE BE WORRIED? WHY? [INAUDIBLE] >> BECAUSE THE VECTORS IS HERE. UNITED STATES WAS A MALARIA ENDEMIC COUNTRY SINCE ITS INCEPTION. IT WASN'T UNTIL THE 50s IT WAS ERADICATED. SHE WAS IS AT RISK. MALARIA IS KNOWN, THE MOST ANCIENT AND WELL DESCRIBED INFECTION, THE CHINESE DESCRIBED IT, PAPYRUS FROM 1875. ASSOCIATED WITH FEVERS, WELL DESCRIBED. IT REMAINS 5,000 YEARS LATER, THE NUMBER ONE KILLER OF CHILDREN UNDER 5. AT THE STATION WHERE PATRICK WORKED IN AFRICA, JOHN AND OTHERS HAVE DESCRIBED -- THERE ARE MENINO GLOBIN VARIANTS WHICH WE THINK DESCRIBE ADAPTIVE MECHANISM. SICKLE CELL AROSE AND PERSISTED BUT THE [INDISCERNIBLE] AROSE BECAUSE IF YOU HAVE THESE -- THIS ENZYME DEFICIENCY, YOU'RE PROOF AGAINST SEVERE DISEASE. IT'S A VECTOR BOURNE DISEASE. WE JUST HAD A REMINDER THAT 1/5 SPECIES CAN CAUSE A SEVERE INFECTION. IT'S VECTOR BOURNE AND DELAYS IN DIAGNOSIS AND LACK OF MEDICINES LEAD TO DEATH. FOR THE MILITARY, THE REASON PATRICK AND I KNOW EACH OTHER IS FOR 20 YEARS WE TRIED TO ADDRESS WHAT HAS BEEN A MAJOR MILITARY ISSUE. THAT IS MALARIA. AFTER WASHINGTON DEFEATED CORNWALLIS, HE VISITED HIS SOLDIERS IN HOSPITAL, MANY HAD BATTLE INJURIES, MANY WITH FEVER. COMMONLY THOUGHT THIS WAS MALARIA. ONE OF THE ACTS OF CONGRESS WAS TO BUY THE BARK, QUININE BARK. THERE WERE 178 CASUALTIES DURING THE HEIGHT OF COMBAT, 178 CASUALTIES PER MONTH. EVERY ONE GOT SICK. 78 OF THE SECOND HUNDRED REPLACE 789S GOT SICK WITHIN A MONTH. THERE WERE GREAT DIFFICULTYEZ. IT WAS A GREAT SPUR TO DRUG DEVELOPMENT IN THE MILITARY. I'VE ALREADY TOUCHED ON THE -- I'M GLAD YOU BROUGHT THIS UP, THEY INTERVIEWED THESE KIDS. THEY THAT HAD [INDISCERNIBLE]. THEY DIDN'T WANT TO TAKE IT. IT HAS A REALLY BAD REPUTATION IN SOME CIRCLES. SO THEY SAID WE DIDN'T THINK IT WAS BAD AFTER IRAQ. THEY WERE ASKED TO TAKE IT IN A LOW RISK ENVIRONMENT, MADE THEIR OWN ASSESSMENTS. THEY DIDN'T TAKE IT. I WON'T DWELL ON THIS IN THE TIME WE HAVE. SOME 3,000 CHILDREN DIE EVERY DAY FROM MALARIA. SINCE WE STARTED, PROBABLY 2-3 PER MINUTE. WE'RE APPROACHING 100 SINCE THIS DISCUSSION STARTED. IT'S PROBABLY THE TIP OF THE ICEBERG. WE KNOW IT'S A SIGNIFICANT CAUSE OF CO-MORBIDITY WHEN IT'S CONTROLLED, A LOT OF OTHER DEATHS WHICH PROBABLY WERE CO-MORBID CONDITIONS WERE AVERTED. IT'S NICE WORK DONE WHICH SAYS THE INTERACTION OF HIGHER VIREMIA WITH COINFECTION, GOOD MODELING TO SHOW IF HIV DOES OVERLAP WELL WITH MALARIA IN AFRICA, THAT IT DOES -- THESE ARE 2 DISEASES WHICH ARE TOGETHER WORSE THAN EITHER ALONE. SO LIMIT -- IT'S A MAJOR CAUSE OF DISABILITY LIFE YEARS, AS WELL AS ECONOMIC IMPACT FROM THE CAREGIVERS, THE PEOPLE THAT HAVE NON DISCRETIONARY FUNDS THAT HAVE TO BE APPLIED TO CARE. THIS MAP SHOWS THAT SINCE THE TURN OF THE CENTURY, ALMOST HALF THE LAND OF THE WORLD WAS MALARIA, DOWN TO 25% W THE POPULATION GROWTHS, THESE ARE REALLY TOUGH AREAS TO COMBAT. SO UNITED STATES WAS MAR LARIOUS UNTIL HALFWAY THROUGH THE LAST CENTURY, MOST OF RUSSIA AND EUROPE, AND NOW IT'S CONFINED TO THE DARK AREAS. MALARIA IS A DISEASE OFF POVERTY. THIS IS THE WORLD MAP OR SERIES, IF YOU'RE NOT FAMILIAR WITH IT, IT'S MY FAVORITE. THIS IS THE WORLD MAP BY POPULATION. THERE IS AFRICA, WHICH IS ALMOST NOT THERE. IF YOU WERE TO DO IT BY PUBLIC HEALTHCARE EXPENDITURES, A MA LARIA MAN TO COME AND SPRAY OR PROVIDE A NET, IT WOULD LOOK JUST LIKE THAT. LESS THAN A DOLLAR A DAY GETS SPENT. MAYBE THE BOTTOM BILLIONAIRE IN THE WORLD ARE LIVING RIGHT THERE. SO THIS IS THE WORLD, ACCORDING TO MALARIA DEATHS. SO OF THOSE CHILDREN THAT DIE EVERY DAY, MOST ARE IN AFRICA AND MOST ARE FALCIPARUM. SIMILARLY BY CASES. SO AS STRATEGIES ARE UNFOLDED AND WISE HEADS COME TOGETHER TO DEVICE A VACCINE, IT'S IMPORTANT TO REMEMBER THAT THE 2 MAJOR SPECIES ARE PLASMODIUM FALCIPARUM AND VIVAX. THE RED IS PROMINENTLY ALMOST ALL FALCIPARUM. AND IF YOU'RE A CLINICIAN, OUTREAD FOR THE WORST -- OIF YOU'RE A PHYSICIAN YOU TREAT FOR THE WORST POTENTIAL CASE. THE PURPLE IS VIE VAX. THIS HAS HUGE IMPLICATES FOR ELIMINATION AND ERADICATION BECAUSE OF SUSCEPTIBILITIES AND DRUG PROFILES. SO WHAT CAN WE DO? UNTIL WE GET THE VACCINE, WE CAN APPLY BED NETS. BED NETS ARE EFFECTIVE. I'M NOT A BED NETOLOGIST, BUT THIS IS -- IT'S NOT CONTROVERSIAL. IF YOU SLEEP UNDER A TREATED BED NET, IT WILL REDUCE YOUR NUMBER OF ATTACKS. IF YOU REDUCE THE FREQUENCY OF ASSAULTS ON THE IMMUNE SYSTEM, PEOPLE DO BETTER. THEY HAVE LESS SEVERE MALARIA. IT IMPROVES MATERNAL FETAL OUTCOME. YOU HAVE BABIES WITH HIGHER BIRTH WEIGHTS, AND LESS INFANTS BORN WITH MALARIA. I HAVE SLEPT UNDER A BED NET. IF IT'S HOT IN THE JUNGLE IN THAILAND AND THERE IS NO BREEZE, YOU HAVE TO HAVE A PRETTY GOOD SCIENTIFIC RATIONALE, THE NORMAL THING TO DO IS GO OUTSIDE AND DRINK A COLD BEER. SO YOU KNOW THAT MALARIA IS PRIMARILY TRANSMITTED FROM DUSK TO DAWN, WHEN A LOT OF PEOPLE GET TOGETHER AT THE END OF THE WORK DAY IT'S PRIME BITING TIME AND SLEEPING AT NIGHT WHEN IT'S HOT. THERE ARE LOTS OF PROBLEMS YOU HAVE TO HAVE A MASSIVE CAMPAIGN TO TEACH PEOPLE TO USE IT AND YOU HAVE TO MAKE SURE IT'S CHEAP AND AFFORDABLE. THEY HAVE BEEN MISUSED FOR FISHING NETS, THEY HAVE BEEN -- STORIES OF BOOT LEGGERS COMING UP DISTRIBUTION CAMPAIGNS IN AFRICA, BUYING THEM UP AND GIVING PEOPLE READY CASH THAT HAVE ALMOST NO CASH. THE STRATEGY HAS TO BE TO FLOOD AN AREA -- IT'S LIKE A NEWSPAPER. NO ONE TAKES 2 NEWSPAPER. YOU CAN ONLY READ ONE. IF EVERY ONE HAS A BED NET, THAT'S THE ONLY SOLUTION. $6 IS BE A WEEK'S INCOME. SO THAT'S THE BED NEAT. DIAGNOSIS IS DIFFICULT. ONE OF THE KEY THINGS FOR DIAGNOSIS IS WRAPPED UP IN THE TIME TO GETTING EFFECTIVE MEDICINE. THERE IS NOT ENOUGH EFFECTIVE MEDICINE IN THE WORLD. AND IF YOU USE IT ON PEOPLE THAT DON'T NEED IT BECAUSE THEY HAVE A FEVER, IT'S A HORRIBLE WASTE. A LOT OF PEOPLE DON'T GET TREATED, A LOT OF MEDICINE IS WASTED. SO DIAGNOSIS, THE REALLY -- 2 WAYS TO DIAGNOSE MALARIA. YOU CAN LOOK AT A BLOOD SMEAR. WHO HERE HAS LOOKED AT A BLOOD SMEAR FROM MALARIA? QUITE A FEW OF YOU. IT'S VERY DIFFICULT, THOUGH. IT'S LIKE ANY OTHER SKILL. PEOPLE WHO ARE PROFICIENT IN DETECTING MALARIA, IT'S GOOD TO PROTECT IT A LOW [INDISCERNIBLE]. YOU REALLY NEED IT. TO DO THAT, ALL YOU NEED IS GOOD STAIN AND A GOOD TECHNICIAN AND GOOD SCOPE, BUT THAT'S IN VERY SHORT SUPPLY. OR A RAPID DIAGNOSTIC TEST. UNFORTUNATELY, UNTIL EVERY ONE HAS THEM AT THE POINT OF CARE WHERE YOU FIRST BECOME -- WHICH HOPEFULLY IS WHERE YOU FIRST BECOME ILL THEY DON'T DO MUCH GOOD. THE WALTER REED IS NOT ALONE IN TRYING TO HELP BEYOND THE RESEARCH EFFORTS. THIS IS A MICROSCOPE SCHOOL. THE ARMY RUNS THIS, AND IT'S GOT STUDENTS FROM ALL OVER AFRICA. DOESN'T JUST TREAT PEOPLE OR TEACH PEOPLE WHO ARE ENGAGED IN PRESCRIPTION DRUGS OR INTERVENTION STUDIES, BUT TAKES PEOPLE FROM HOSPITALS. IT REALLY IS AN APPROACH WHICH IS PROBABLY DIFFICULT TO SUSTAIN, ALL THOSE PEOPLE GRADUATE FROM DIFFERENT EXAMS AND PRESSURE TRAINING. THEY'RE GOING BACK TO HOSPITALS WHERE THEY HAVE TO REUSE THE GLAD SLIDES. THEY PROBABLY -- GLASS SLIDES. THEY CAN'T USE FRESH STAIN WHICH GOES BY. PRESENCE MALARIA INITIATIVE IS TRYING TO HELP WITH THIS. THE PROBLEM IS SO HUGE IT JUST REALLY UNDERSCORES THE ROLE OF POVERTY. AGAIN, THESE PEOPLE ARE PRACTICING MAKING BLOOD SMEARS, THICK AND THIN. IT'S EASIER TO DIAGNOSE ON THICK SMEAR, YOU CAN COMEN MORE BLOOD AT ONE TIME. THIS IS A DIAGNOSTIC TEST. IT CAN WORK ON BLOOD IN LESS THAN 10 MINUTES. IT'S -- A DROP OF BLOOD IS PLACED AT THE BOTTOM. A TUBE IS BUT THERE. IT WICKS UPWARDS. THERE IS A CAPTURE ASSAY, IT HAS A [INDISCERNIBLE] AND A PLAS MOANIA SPECIFIC -- YEAH. SO YOU CAN -- ANTIGEN, SO THAT YOU CAN DIAGNOSE OR GET A ROUGH IDEA OF WHICH -- YOU CAN DEFINITELY DIAGNOSE FALCIPARUM AND THEN IT CAN DETECT MIXED INFECTION AS WELL AS THE OTHER COMMON 3 SPECIES. RESISTANCE IS HUGE IN THE WORLD. WHEN I WAS BORN, [INDISCERNIBLE]. IN THE LATE 50s RESISTANCE AROSE AND DOES ANYONE NOWHERE IT AROSE FIRST. SOUTHEASTERN ASIA. BUT THE RELENTLESS PROGNOSIS OF PAR ASIDE DRUG RESISTANCE, MORE DRUG IS PUT OUT. MORE PEOPLE ARE SICK. MORE RESISTANCE HAS EVOLVED. I'M NOT GOING TO GO INTO THE DIFFERENT INDICATIONS FOR TREATMENT OR DRUGS THAT WOULD BE USED BUT MAYBE JUST YOU CAN TAKE MEDICINES IN A PREVENTIVE MODE, CAN [INDISCERNIBLE] AGAINST THE LIVER STAGE OR BLOOD STAGE. WE'VE TOUCHED UPON TREATMENT, AND HAVE ALLUDED TO THE FACT THAT FALCIPARUM IS DIFFERENT AND IT'S BEING MUCH MORE RESISTANT THAN THE OTHER FORM LAYERS TO TREATMENT -- FORM ALLAYERS TO TREATMENT. DOES ANYONE KNOW WHAT WE TREAT -- WHAT DO WE TREAT MALARIA WITH THESE DAYS? SEVERE MALARIA WITH? FOR FALCIPARUM, QI NINE OR [INDISCERNIBLE]. IF ANY OF THOSE COME BACK FROM AFRICA, WHERE YOU CAN'T TAKE ORAL MEDICATIONS, INTRAVENICE [INDISCERNIBLE] IS PROBABLY THE BEST YOU CAN TAKE, ON A STOCKPILE AT THE CENTERS FOR DISEASE CONTROL. RADICAL CURES WHO ATTACKED HYPNODECIDE. THE SECOND MOST IMPORTANT MALARIA. I TOUCHED ON DRUG RESISTANCE. I WANT TO TALK ABOUT 2 MAJOR ISSUES IN AFRICA. ONE IS THE WAY TO TREATMENT. MANY TIMES IN THE COUNTRYSIDE, YOU DON'T HAVE EMBASSIES AT HOME. THE -- MEDICINES AT HOME. THE EQUIPMENT NEAR YOUR HOUSE IS OUT OF STOCK. YOU MAY NOT HAVE THE MONEY TO GO TO CATCH THE BUS TO GET INTO A CLINIC. SO THE DISEASE PROGRESSES LIKE THE YOUNG GIRL WE SAW A FEW MINUTES AGO. WIDESPREAD COUNTERFEITING OF DRUGS IS IN THE WORLD. THERE ARE SAD ARTICLES CALLED DEATH BY COUNTERFEITING. JUST LIKE IF ARMORSEN WELLS, THE -- ORSEN WELLS, PEOPLE ARE SELLING ACTs AT GREAT PRICES. IT'S NOTHING IN IT. THIS IS A CLINIC NEAR THE WALTER REED PAGE. PATRICK DUFFY DID A LOT OF HIS WORK ON PREGNANCY AN MALARIA. AND THIS IS ACTUALLY 2 OR 3 YEARS AGO. YOU DON'T NEED A PRESCRIPTION. YOU CAN WALK IN AND BUY YOUR OWN MEDICINE. NOT LIKE RIGHT AIDE HERE. I ASKED THE YOUNG LADY TO PUT UP ALL THE DIFFERENT MEDICINES SHE SOLD. THERE IS NO ACT. NO COMBINATION TABLET OF THE MOST EFFECTIVE MEDICINE. [INDISCERNIBLE] PLUS A SECOND MEDICINE. BUT THIS IS WHAT PEOPLE CAN AFFORD. SO THIS MIGHT FOR PEOPLE THAT HAVE SOME IMMUNITY, MIGHT GET THEM BY BUT WON'T HANDLE A SEVERE CASE. THIS IS A VERY SAD CASE. THIS IS FROM THE SMITHSONIAN MAGAZINE, OCTOBER, 2009. BUT TO SHOW YOU THAT ILLUSTRATES 2 THINGS, THAT CHLOROQUINE [INDISCERNIBLE] ARE NOW WIDESPREAD AROUND THE WORLD. IT HAS TO BE CONSTANT DEVELOPMENT OF NEW DRUGS. AND THIS IS SOMEONE HAS GONE TO GREAT EFFORTS TO MAKE THIS FAKE MEDICINE AND SELL IT SO YOU CAN IMAGINE BEING A PARENT BUYING IT FOR YOUR CHILD WITH YOUR WEEK'S WAGES, ONLY TO FIND OUT THERE IS NOTHING IN IT. THE MOST OMINOUS DEVELOPMENT, THOUGH, IN DRUG TREATMENT AND PREVENTION IS THAT THERE [INDISCERNIBLE] OF APPARENTLY BEEN USED ENOUGH IN SOUTHEAST ASIA ON THE THAI CAMBODIAN BORDER, RESISTANT, YOU FIND MUCH DELAYED RESPONSES TO TREATMENT. THIS HAS GIVEN RISE TO AN EMERGENCY TASK FORCE. THEY PUBLISHED THE PLAN IN JANUARY CALLED THE GLOBAL PLAN FOR RESISTANCE CONTAINMENT. IT'S VERY AMBITIOUS. DR. CHAN WROTE THE FORWARD TO IT. BUT THE IDEA, YOU KNOW, BORDERS ARE VERY TOUGH PLACES, YOU HAVE A LOT OF LAWLESSNESS, A LOT OF SMUGGLING, A LOT OF PEOPLE TAKING THINGS BACK AND FORTH THAT DON'T WANT TO BE TALKING TO HEALTH OFFICIALS OR POLICEMAN. SO IT'S IMPORTANT TO REALIZE THAT THIS IS AN AMBITIOUS PLAN BUT IF IT'S NOT FUNDED, IN OTHER WORDS, IF PEOPLE DON'T GO AND TRY TO TRULY ELIMINATE THIS RESISTANT MALARIA, THAT IT'S SPREAD IS INEVITABLE, A TICKING CLOCK FOR MORE DRUG DISCOVERY, AND ALSO FOR VAST. VACCINE. THIS IS A NURSERY SCHOOL. THE TEACHER JUST ASKED THE PEOPLE THAT SHE KNEW, ACTUALLY, TOLD WHICH ONES TO RAISE THEIR HANDS, THAT HAD MALARIA. THESE ARE CHILDREN, GIVES YOU AN IDEA AND PUT A FACE ON MALARIO, HOW COMMON IT IS. ALL THESE CHILDREN HAVE HAD MULTIPLE EPISODES AND ARE SURVIVORS ALREADY AT THIS POINT. I WANT TO MAKE ONE MORE CASE ABOUT WHY WE NEED A VACCINE. BECAUSE IF YOU'RE GOING FROM MOVING FROM LIMITING DISEASE AND MORTALITY TO REALLY TRYING TO ELIMINATE THE DISEASE, YOU'VE GOT SOME REAL SILENT RESERVOIRS OF INFECTION. IF YOU DON'T ELIMINATE THESE SILENT RESERVOIRS, WE WILL NEVER GET TO THE VISIONOF ERADICATING THE DISEASE. AND BY THAT I MEAN IF MANY PEOPLE IN MUCH OF AFRICA HAVE PARASITES BUT NOT SICK, SO I DIDN'T TELL YOU IN THAT CASE REPORT -- REMEMBER THE GIRL I SHOWED YOU AT THE BEGINNING, HER BROTHER CAME TO EVERY CLINIC VISIT. SOMEWHERE DURING THE COURSE OF THE HOSPITAL STAY, THEY SAID WHY DON'T WE CHECK HIS BLOOD? HE HAD A 1% PARASITE TEENIA, WHICH HE WAS CONTROLLING. THEY TREATED HIM. WHEN YOU GO TO ADULTS IN SABSAHARAN AFRICA, THERE ARE PLACES THAT HALF THE PEOPLE THERE ARE CARRYING PARASITES. IT'S THE FACT THAT THEY HAVE [INDISCERNIBLE]. IF THE MOSQUITO BITES THEM, UNTIL YOU GET THE SILENCE RESERVOIRS YOU NEVER ELIMINATE THE DISEASE. SOME PEOPLE ARE HYPERPRODUCERS, SO IT DOESN'T TAKE MANY INTERACTIONS WHEN A MOSQUITO AND THAT PERSON TO PERPETUATE THE DISEASE. WHEN WE TALK ABOUT REDUCING THE BURDEN TO ELIMINATING THE DISEASE, IT'S GOOD TO BEAR IN MIND. THIS IS REALLY A NICE SERIES OF ARTICLES THAT CAME OUT ON DIFFERENT APPROACHES TO TRY TO REALLY MADE A DENT IN THIS DISEASE. I RECOMMEND IT HIGHLY. SO MANY PEOPLE HAVE NO SYMPTOMS. THEY MAY OR MAY NOT GET TO A CLINIC. THEY MAY OR MAY NOT GET A PROPER TEST, AND MAY OR MAY NOT GET AN EFFECTIVE DRUG. YOU CAN GET A CLEAR IDEA. THIS IS FOR FALCIPARUM. WE ALSO COVERED THE IDEA OF THE RELAPSING MALARIAS THAT HAVE THE HIPNA ZOITES. THERE IS NO DRUG THAT WOULD BE WELL TOLERATED ON A MASS CAMPAIGN BASIS. I WOULD LIKE TO GIVE YOU A POSITIVE, THOUGH, OF WHAT MORE RESOURCES CAN DO. THIS IS SOUTH AFRICA, AND THEY EXPERIENCED AND EPIDEMIC, 10 YEARS, FROM 91-2000. THEY HAD -- THE INTRODUCED -- THIS IS VERY DISCREET INDOOR RESIDUAL SPRAYING,DD T. THIS IS THE TIME COURSE, 93-2003. WITH THE INTRODUCTION OF THE DDT AND THE EFFECTIVE ANTI-MALARIALS. THEY REALLY BROUGHT IT DOWN BACK TO A VERY NICE LEVEL. SO THIS IS WHAT WE'RE UP AGAINST, THE CHARGE TO HAND OFF TO PATRICK AND PEOPLE THAT ARE MAKING VACCINES. THE GREEN AREAS IN THE WORLD ARE MALARIA FREE. THESE AREAS WERE MAR LARIOUS. THE BLUE ARE REDUCING THE INCIDENTS DOWN TO VERY LOW LEVELS. THE RED ARE WHERE IT'S HIGH TRANSMISSION, VERY POOR INFRASTRUCTURE, PEOPLE CANNOT AFFORD THE DRUGS. WHERE IT'S REALLY GOING TO TAKE SOMETHING ELSE, SOMETHING EXTRA TO ELIMINATE THE DISEASE. SO FULL COVERAGE IS NOT ACHIEVABLE. IF INDOOR RESIDABLE SPRAYING IS NOT WIDESPREAD, AND I DIDN'T GO INTO SAFETY OF CHILDREN AND PREGNANT WOMAN FOR MANY OF THE DRUGS. PROPER DRUGS ARE BARELY AT HAND TODAY W THE SPECTER OF -- WITH RESISTANCE IT'S NOT CLEAR HOW LONG THEY WILL BE THERE. WE NEED A VACCINE. WHAT KIND OF VACCINE DO WE NEED? WELL, I THINK THAT'S THE SUBJECT OF THE NEXT HOUR. BUT JUST TO LAY THE GROUNDWORK, I'VE WORKED FOR ABOUT 20 YEARS ON A VACCINE CALLED RTSS. THAT'S A VACCINE WHICH IS INTENDED -- IT'S NOT THERE YET. >> TO REDUCE THE INSTANCE OF INFECTION. THEREFORE DISEASE IN TRAVELERS. IT'S RIGHT AT ABOUT 50%. WE'RE WORKING ON IDEAS TO MAKE IT BETTER. BUT IT MAY HAVE LITTLE OR NO EFFECT ON REDUCING THE INFECTIOUSNESS OF THE PEOPLE IN A COMMUNITY. AND SO THE BIG PUSH FROM THE AREA, CONSULTATIVE GROUP ON VACCINES, IS TO DEVISE VACCINES THAT WILL ACTUALLY REDUCE THE INFECTIOUSNESS OF PEOPLE IN THE COMMUNITY SO WE CAN REALLY BEGIN TO ELIMINATE AND ERADICATE THIS DISEASE. SO UNLESS THERE ARE QUESTIONS I'LL TURN IT OVER TO PATRICK. >> THANK YOU VERY, VERY MUCH. [APPLAUSE] >> [INAUDIBLE] I THINK THE ARTICLE WAS COMPRESSED AS MANY ARTICLES ARE IN THE NEW ENGLAND. THE SILENT SERVOIR IN THE WORLD ARE PEOPLE THAT HAVE [INAUDIBLE] LIVE SAVING INFECTION TO THESE PEOPLE WHO COME [INDISCERNIBLE] AND CHRONIC CARRIERS. SO THAT'S ONE USE OF THE TERM, THE SILENT RESERVOIR, THE MEN AND WOMEN WHO GO TO WORK, SICK BUT NOT SICK ENOUGH TO SEEK CARE. THAT'S THE STATE OF MANY ADULTS OF PEOPLE THAT HAVE HAD CURRENT BOUTS AND SURVIVED. THAT'S ONE USE OF THE TERM SILENT RESERVOIR. THE SECOND, FOR THESE PEOPLE NOT PROMPTED TO SEEK TREATMENT. THE SECOND INCIDENCE IS MUCH OF THE WORLD SUFFERS FROM VIE VAX MALARIA. AND THAT IS PARTICULARLY DIFFICULT BECAUSE VIE VAX IS VERY ADAPT AT PERSISTING AS THE SLEEPING FORM CALLED THE HIP IN A ZOITES. PROBABLY OVER WINTER IS CAN GO A VERY LONG TIME. WE'VE HAD PEOPLE BECOME ILL AS LONG AS 5 YEARS LATER FROM VIE VAX. SO THESE PEOPLE HAVE NO PARASITES IN THEIR BLOOD. THERE IS NO DIAGNOSTIC MARKER. SO IF A CAMPAIGN WAS TO ELIMINATE THIS DISEASE, IT WOULD HAVE TO EITHER FIND A DRUG THAT WAS SAFE ENOUGH FOR MASSIVE RADICATION AND ADMINISTRATION, AROUND WE DON'T HAVE THAT DRUG TODAY. [INDISCERNIBLE] DID A GOOD JOB, MANY PEOPLE CAN'T TAKE IT AND THERE IS RESISTANCE, WHICH I DIDN'T GO INTO. SO I THINK THAT'S THE CHALLENGE. >> AT WHAT STAGE DOES PSYCHO HEMOGLOBIN INTERFERE WITH THE PRACTICES MODIUM -- PLAZ YESTERDAYIUM CYCLE? >> WELL, THEY SEEM TO HAVE A LIMITATION ON THE ABSOLUTE [INDISCERNIBLE] COUNTS AND THE SEVERE FORMS. BUT I CAN'T GIVE YOU A DETAILED BACKGROUND ON THE PHYSIOLOGY. MAYBE PATRICK -- >> I THINK ALLEGATIONS OF ABUSE UNKNOWN -- I THINK IT'S UNKNOWN, BUT THERE HAVE BEEN A NUMBER OF HYPOTHESIS. SOME OF THE INTERESTING ONES ARE AT RICK'S LAB RIGHT HERE AT NIH WHERE HE'S SHOWN THAT PEOPLE THAT HAVE DIFFERENT HEMO GLOBINS, LIKE C AND S, THE DISPLAY OF THE SURFACE PROTEINS ON THE INFECTED RED CELLS SEEMED TO BE ALTERED. THERE IS SPECULATION THAT THAT COULD REDUCE THE SEVERITY OF THE DISEASE. AS GRAY SAID, MANY STUDENTS HAVE SHOWN THAT FOR SOME REASON IT KEEPS THE PARASITE COUNT LOWER AND THAT COULD CONTRIBUTE TO REDUCING DISEASE. >> OKAY. IS THAT ALSO HOW THAL SEEMIA WORKS. IF THEY HAVE THAT, OR THE THEORY IS THAT IT HAS SOME EFFECT ON IT. >> YES. >> I POSTED ON THE WEBSITE AN ARTICLE THAT DESCRIBES HEMO GLOBIN S AND THALSEMIA IN RELATIONSHIP. IT WAS A CONJECTURAL TOPIC. YES? >> GRAY, WHAT WERE THOSE MEDICINES IN FRONT OF THE WOMAN IN THE CLINIC IN KENYA? >> I THINK THERE WAS [INDISCERNIBLE], CHLOROQUINE, THERE WAS FANSIDAR. IT'S A COMBINATION OF [INAUDIBLE] NOT IN THAT DISPLAY. BUT IN THE DISTRICT HOSPITAL, NOT THE NEW [INDISCERNIBLE]. THERE ARE POSTERS UP EVERYWHERE SAYING THIS IS THE TREATMENT. >> THANK YOU VERY MUCH. AND WE'LL HAVE MORE QUESTIONS LATER. SO PLEASE. [APPLAUSE] IT'S A GREAT PRIVILEGE TO FOLLOW GRAY HEPPNER. HE IS A VERY HUMBLE PERSON, BUT AN AMAZING LEADER OF THE MALARIA OVER SEVERAL YEARS. HE PLAYED A GREAT ROLE IN THE VACCINE AND BIG MOTIVATOR TO TRY TO DO STUDIES TO TRY TO ENHANCE THE EFFICACY OF THAT VACCINE. I THINK THE WHOLE COMMUNITY IS HOPING THAT GRAY WILL CONTINUE TO WORK ON THAT AREA BECAUSE IT'S A KEY ONE TO GET TO THE THE NEXT PHASE OF VACCINE DEVELOPMENT. I AGREE WITH EVERYTHING GRAY SAID. NOT BECAUSE HE WAS MY BOSS AT WALTER REED, BUT BECAUSE I AGREE WITH EVERYTHING HE SAID. AND I AGREE SO MUCH I'M GOING TO REITERATE A NUMBER OF THE POINTS HE MADE. REITERATION IS THE HEART OF DECISION. PART OF THIS IS TO TRY TO TEACH THIS COMMUNITY ABOUT THE DISEASE. THIS IS ANOTHER LIFE SICKLE. MALARIA PEOPLE LOVE TO PUT THE LIFE CYCLE UP. MAKES THEM LOOK REALLY SMART. IT'S BROKEN DOWN INTO 3 MAJOR AREAS. THIS IS WHEN THE PARASITE ENTERS THE HUMAN HOST AND DIFFERS IN THE LIVER. THIS IS WHEN IT GETS INTO THE BLOOD STREAM THAT FOLLOWS THE LIVER STAGE. THIS IS A REPEATING RECURRENT CYCLE OF GROWTH IS SOME PROPORTIONATE OF THE PARASITES BREAKING OUT THAT EFFECTS THE MOSQUITO WHEN IT TAKES UP A BLOOD MEAL, AND HAS A COMPLEX LIFE CYCLE. THIS INFORMS HOW WE CAN ATTACK THE PROBLEM, AND THE SUBSTANCE OF WHAT I WILL TALK ABOUT, TALKING ABOUT HOW OUR EFFORTS TO DEVELOP INTERVENTIONS PRIMARILY STRIKES ARE INFORMED BY THE PARASIGHT BIOLOGY, THE LIFE CYCLE OF THE PARASITE AND HOW THE HOST INTERFACES WITH THE PARASITE. AT THE POINT AT WHICH THE PARASITE IS ENTERING THE HOST, YOU COULD IMAGINE INTERVENTIONS THAT WOULD PROBABLY BLOCK AN INFECTION BEFORE IT WAS ABLE TO GROW 10,000 FOLD, 30,000 FOLD AS GRAY MENTIONED IN THE LIVER. THERE HAVE BEEN A NUMBER OF EFFORTS HERE AT NIH AS WELL AS WALTER REED AND OTHER GROUPS TO ATTACK THE PARASITE AS IT'S TRYING TO INVADE THE RED CELL. AND BY LIMITING PARASITE TEAMIA TO LIMIT THE DISEASE. I'LL TALK SPECIFICALLY ABOUT HOW YOU MIGHT ATTACK THE SURFACE OF THE INFECTED RED CELL TO LIMIT DISEASE, WHY WE THINK THAT'S FEASIBLE. AND THEN GRAY ALLUDED TO THIS IDEA OF INTERRUPTING TRANSMISSION, SO I'LL TALK ABOUT HOW WE MIGHT PROTECT MOSQUITOES FROM MALARIA. IF WE CAN DO THAT, WE CAN PROTECT OUR COMMUNITIES FROM MALARIA. ANOTHER LIFE CYCLE STAGE IN JUST -- ANOTHER LIFE CYCLE IMAGE, TO REITERATE, WHAT WE'RE GOING TO TALK ABOUT ARE VACCINES THAT BLACK TRANSMISSION TO THE MOSQUITO, BLOCK INFECTION TO THE HOST AND BLOCK DISEASE BY TARGETING THE RED CELL STAGE. AND ALTHOUGH MOST OF IT IS [INDISCERNIBLE] I'LL REITERATE, WE HAVE 5 DIFFERENT PARASITES THAT INFECT HUMANS. THE MOST RECENT KNOWN, LONG KNOWN TO EFFECT [INDISCERNIBLE] BUT IT'S RECENTLY BEEN RECOGNIZED THAT THERE IS HUMAN CASES OF THESE. I DON'T KNOW IF THERE ARE ESTABLISHED CASES BEING TRANSMITTED ONE PERSON TO ANOTHER. BUT PEOPLE CAN DIE OF THAT PARASITE. MOST OF OUR ATTENTION IS ON [INDISCERNIBLE] BECAUSE OF THE HUGE BURDEN OF DISEASE. FOR OURSELVES AT THE LABORATORY, IF WE HAD UNLIMITED RESOURCES, WE WOULD HAVE AN EQUAL PROGRAM TO FOCUS ON PLASMODIUM VIE VAX, BUT DEVELOPMENT OF -- IT OFTEN IS LET'S LEARN WHAT WE CAN FROM FALCIPARUM AND SEE IF WE CAN REPRODUCE THAT IN PLASMODIUM VIE VAM. THAT WASN'T A PLUG FOR RESOURCES, BUT I THOUGHT I'D MENTION THAT WE'D WORK ON THAT. IF WE HAD MORE RESOURCES. LAWYER WHAT WE DO -- [LAUGHTER] WHAT WE DO WORK ON, WE'RE FOCUSED ON 2 AREAS. ONE OF THEM IS WHAT GRAY HIGHLIGHTED, A VACCINE TO INTERRUPT MALARIA TRANSMISSION MUCH AND ONE OF THE AREAS WE WORK ON IS A VACCINE TO PROTECT PREGNANT WOMEN. PREGNANCY MALARIA VACCINE. WE WOULD IMMUNIZE WOMEN AND HAVE RESPONSES THAT WE THINK WOULD PROTECT THEM. HERE IS THE LIFE CYCLE IN THE MOSQUITO. THE PARASITE GETS INTO THE HOST AND GOES TO THE LIVER. THEN GOES TO THE BLOOD STAGE. THESE 3 MAJOR AREAS. MALARIA TRANSMISSION WOULD BE SOMEWHERE, WHERE THE MOSQUITO INTERPHASES WITH THE HOST. THIS IS HOW WE WILL PRESENT MALARIO TRANSMISSION. FOR PREGNANCY MALARIA VACCINE, THAT'S IN THE OTHER AREA, THE BLOOD STAGE PARASITE. THIS IS WHAT WE'LL SPEAK IN SOME DETAIL ABOUT. SO INTERPRETING TRANSMISSION, LOOKING AT HOST ENTRY POINTS. THE MOSQUITO OR THE HUMAN HOST. HERE ARE THE SEXUAL FORMS OF THE PARASITE AND THE INFECTION IS INITIATED IN THE MOSQUITO. AT THE LABORATORY OF LMIV. WE HAVE A LEAD CANDIDATE THAT IS ENTERING CURRICULUM DEVELOPMENT. -- CLINICAL DEVELOPMENT. THIS IS THE MAJOR SURFACE PROTEIN OF THESE EARLY PARASITE FORMS THAT DEVELOP IN THE MOSQUITO CALLED ZYGOTES. ANOTHER PROTOTYPE PROTEIN THAT WOULD BLOCK THE PARASITE FROM GETTING INTO THE HOST IS ONE THAT IS ON THE SURFACE OF THE SPORO DOWETS, THE FORM THAT IS IN THE MOSQUITOSAL VARY GLAND. WHEN IT TAKES A BLOOD MEAL THEY ARE INJECTED INTO THE SKIN AND FIND THEIR WAY INTO THE BLOOD STREAM, THEN INTO THE LIVER. WE HAVE PRECLINICAL DEVELOPMENT EFFORTS NOW AND A PLAN TO COMBINE THESE VACCINES WHEN THE BLOOD TRANSMISSION -- ONE THAT BLOCKS TRANSMISSION, ONE THAT BLOCKS INFECTION. WHY ARE HOST ENTRY POINTS GOOD PLASS TO WORK ON. THEY'RE BOTTLENECKS FOR THE PARASITE A TYPICAL PERSON NOT FEELING SICK BUT CARRYING PARASITES COULD CARRY UP TO 10 OF 11 PARASITES. THIS IS WHERE PEOPLE START TO FEEL SICK. SO IT TAKES VERY -- IT'S INTERESTING, TO THINK WHAT A HUGE BURDEN PAR SITES CAN BE HARBORED WITHOUT FEELING TOO BAD. WHEN A MOSQUITO TAKES A BLOOD MEAL, THAT HUGE NUMBER TO INFECT A MOSQUITO IS REDUCED BY MANY, MANY LOGS. SO OUT IN THE FIELD WHEN YOU LOOK AT HOW MANY PARASITES ARE INFECTING MOSQUITO, WE CALL THOSE [INDISCERNIBLE], USUALLY 1 OR 2, 3, 4 ON THE SURFACE OF THE MID GUT. SO YOU'VE GONE DOWN FROM THIS HUGE NUMBER OF PARASITES TO A PLACE WHERE THERE IS A VERY FEW NUMBER. THIS IS A GOOD PLACE TO TARGET THE PARASITE, ALTHOUGH THE PARASITE USUALLY KNOWS BETTER. OVER THE COURSE. INFECTION, YOU'LL END UP WITH THOUSANDS OF SPORO ZOITES. BUT WHEN THE NEXT BLOOD MEAL IS TAKEN, WHEN THE MOSQUITO INOCULATES INTO THE HOST, YOU HAVE A GREAT REDUCTION OF PARASITES, A FEW DOZEN TO A FEW HUNDRED INOCULATED TO AN INFECTED MOSQUITO TO START THE LIVER INFECTION, TENS OF THOUSANDS OF [INDISCERNIBLE] DEVELOP FROM EACH INOCULATED SPORE OUZO ITOVER THE COURSE OF A WEEK IN A HUMAN HOST W THE NEXT INFECTION, IT COULD BE HIGHER, IT COULD LEAD TO DEATH. THERE IS THIS MASSIVE GROWTH OF THE PARASITE, 2 BOTTOM NECKS TO FOCUS ON. AND THE FIRST ASPECT I'LL TALK ABOUT, HOW WE BLOCK -- HOW WE'RE TRYING TO BLOCK TRANSMISSION TO THE MOSQUITO. A VERY GOOD REASON FOR A TRANSMISSION BLOCKING VACCINE, IN OCTOBER, 2007, BILL AND MELINDA GATES DECIDED THEY WANTED TO ERADICATE MALARIA. THAT WAS A WORD THAT MALAROLOGISTS DID NOT USE BILL AND MELINDA GATES DECIDED THEY WANTED TO ERADICATE MAR LAIA. THERE WAS A LARGE PROGRAM TO TRY TO ERADICATE MALARIA AND MANY THOUGHT IT GAVE IT A BAD NAME. IT DIDN'T SUCCEED. IT DIDN'T ERADICATE MALARIA. IT DIDN'T MUCH A LOT OF BENEFITS. IT ACTUALLY ELIMINATED MALARIA, AND THERE ARE COUNTRIES THAT CONTINUE TO ELIMINATE MALARIA FROM THEIR AREAS. IT WAS VERY UNFASHIONABLABLE TO TALK ABOUT COULD BE IMAGINE GETTING RID OF THIS PARASITE. SINCE BILL AND LINDA ANNOUNCED THEY WANTED TO ERADICATE MALARIA, PART OF THE STRATEGIC VISION OF NIH IS HOW WE CAN CONTRIBUTE AND ELIMINATE AND ERADICATE MALARIA FROM THE FACE OF THE EARTH. IT'S A GREAT DREAM BUT I THINK IN EVERYBODY'S MIND WE'RE LOOKING AT DECADES FROM NOW OF TRYING TO ACHIEVE THIS GOAL. THE TOOLS WE HAVE ARE NOT ADEQUATE FOR THIS PURPOSE. BUT ONE OF THE TOOLS THAT WOULD BE VERY BENEFICIAL WOULD BE TO HAVE A TRANSMISSION BLOCKING VACCINE. THIS IS OUR ESSAY FOR A TRANSMISSION BLOCKING VACCINE. NO A VERY FANCY LOOKING ESSAY. IF ONLY WE HAD SOMETHING THAT COULD MEASURE THIS EFFECT. BUT THIS IS WHAT WE ACTUALLY WANT A VACCINE TO DO. HERE ARE THE PARTS OF THIS FANCY TEST. THIS IS A BLOOD MEAL FOR MOSQUITOES, INSIDE OF THIS GLASS CONTAINER. AND THIS WOULD HAVE MALARIA PARASITES IN IT, THE SEXUAL FORMS THAT INFECT THE MOSQUITO. IT HAS A THIN MEMBRANE THAT THE MOSQUITO CAN STICK ITS [INDISCERNIBLE] THROUGH TO TAKE THE BLOOD MEAL. IT HAS HOT WATER RUNNING THROUGH IT. WHICH ATTRACTS THE MOSQUITO. THEY LIKE THE WARMTH OF THE HOT WATER TO ATTRACT THEM. AFTER THE MOSQUITOES HAVE TAKEN IT, 6 DAYS LATER THE PARASITES WOULD HAVE DEVELOPED, PASSED THROUGH THE WALL OF THE MID GUT, LODGED AND FORMED. OUT IN THE WILD, TYPICAL MOSQUITOES HAVE 1, 2, OR 3. THIS IS NOT TYPICAL, YOU'LL SEE A COUPLE HUNDRED. WE HAVE QUESTIONS HOW IROUR ESSAY IS FOR TELLING US, PREDICTING WHAT'S GOING TO HAPPEN IN PEOPLE WHEN WE GIVE THEM VACCINES IN THE FIELD. HERE IS HOW WE WOULD OPERATE THIS ESSAY. THIS IS ONE TEST SERUM WITH BLOOD IN THIS VIAL. THIS MIGHT BE A CONTROL SERUM. EACH OF THESE FEEDS IS A DIFFERENT TEST SERUM WE WOULD USE, IF WE WERE DOING A VACCINE STUDY. SO I THINK YOU CAN ALREADY ANTICIPATE SOME OF THE PROBLEMS WITH THIS ASSAY. IT'S COMPLICATED BIOLOGICAL, TIME CONSUMING ASSAY. GROWING THE PARASITES IN OUR LABORATORY IS DIFFICULT. I GROWS GREAT IN THE FIELD. LOTS OF PEOPLE WALK AROUND WITH [INDISCERNIBLE] BUT THEY'RE VERY DIFFICULT TO GROW IN THE LABORATORY. NIH HAS THE CAPABILITY TO GROW THESE AND I COULDN'T THEM FOR THESE ASSAYS. -- USE THEM. IT'S INCONSISTENT REPRODUCIBILITY WHICH IS TYPICAL, AND A LOT HAS TO DO WITH THE NUMBER OF [INDISCERNIBLE] WITH ANY PARTICULAR FEED BECAUSE THAT VARIES FROM FEED TO FEED. AND AS I MENTIONED IT'S NOT CLINICALLY VALIDATED. ONE OF THE BIG EFFORTS THAT OUR GROUP IS MAKING, I SEE [INDISCERNIBLE] AND RUTH IN THE ROOM, IS TO TRY TO FIGURE OUT HOW WELL THIS ASSAY REFLECTS WHAT ACTUALLY IS HAPPENING WITH PEOPLE IN ENDEMIC AREAS. I WON'T GO INTO DETAIL. THAT'S A MAJOR EFFORT THAT WE'RE GOING TO TRY TO UNDERTAKE OVER THE NEXT YEAR OR 2. HOST ENTRY WOULD WE ATTACK -- HOW WOULD WE ATTACK THESE PARASITES? WE'RE INTERESTED IN THE PROTEINS THAT ARE ON THE SURFACE. THIS IS A VACCINE THAT WOULD RELY ON ANTIBODIES TO HAVE ITS EFFECT. THERE ARE SEXUAL FORMS OF THE PARASITE IN THE BLOOD STREAM THAT CIRCULATE, SO SOME OF THE PROTEINS ACTUALLY ARE BEING EXPRESSED WHILE THE SEXUAL FORMS ARE IN THE HUMAN HOST. SOME OF THE PROTEINS ARE ONLY EXPRESSED AT LATER STAGES. AS THE PARASITE DEVELOPS IN THE MOSQUITO. THESE HAVE THE ADVANTAGE THAT IMMUNE RESPONSE MIGHT BE BOOSTED. THERE IS A LOT OF SEQUENCE POLYMORPHISM IN THEM. THESE WOULD HAVE THE ADVANTAGE THAT THERE IS VERY LIMITED POLY MORISM IN THESE PROTEINS. THEY HAVEN'T BEEN UNDER IMMUNE PRESSURE. THEY HAVE THE DISADVANTAGE THERE IS NOT GOING TO BE ANY BOOSTING WHEN A PERSON GETS NATURALLY INFECTED. I WILL FOCUS ON ONE OF THESE LATER PROTEINS, A FAMILY OF PROTEINS CALLED P.25, A 25 [INDISCERNIBLE] PROTEIN PRESENT IN THE DIFFERENT SPECIES SUCH AS [INDISCERNIBLE]. SO WE WOULD CALL IT PFS25. IT APPEARS AS A MAJOR SURFACE PROTEIN OF THESE EARLY FORMS OF THE PARASITE AND IT DEVELOPS CALLED DIZZIGATES. WHY ARE WE FOCUSED ON THIS THIS WORKS HERE AT NIH AND WAS PIONEERED BY DAVID, A LEADING VACCINOLOGIST AND MERCK BUT CLONES THE GENE FOR PSS25. AND SINCE HIS WORK, MANY GROUPS HAVE USED THIS IN MANY FORMULATIONS TO IMMUNIZE ANIMALS. IT HAS CONSISTENTLY BEEN ABLE TO INDUCE FUNCTIONAL ANTI-SIERRA. AGAINST THE P [INDISCERNIBLE] FORUM. WHEN WE HAD THE ANIMAL IN THAT NEEDING ASSAY, MOSQUITOES HAVE LOWER INFECTIONS OR DON'T GET INFECTED AT ALL, WHEN WE COUNT THE NUMBER. THERE HAVE BEEN HUMAN TRIALS. BOTH OF THESE WERE PERFORMED HERE AT NIH. ONE WAS ADJUVANTED. THERE WAS FUNCTIONAL ACTIVITY IN THE HUMAN SERA. THERE WAS A HUMAN TRIAL WITH BOTH THE P. VIE VAX VERSION AND THE P. FALCIPARUM [INDISCERNIBLE]. SO THE GOOD NEWS WAS STRONGER IMMUNE RESPONSES WAS INDUCED. MORE FUNCTIONAL ACTIVITY. BUT THE TRIAL HAD TO BE STOPPED EARLY. WE HAVE TO FIND A WAY TO INDUCE BETTER IMMUNE RESPONSES THAT IS TOLERABLE FOR HUMAN VOLUNTEERS. SO THAT IS OUR GOAL. TO ENHANCE IMMUNOGENICITY OF THE IMMUNE RESPONSE, USING DIFFERENT STRATEGIES. USING CONGOGATION TO TRY TO [INDISCERNIBLE]. SO TO GIVE YOU AN EXAMPLE OF CONJUGATION, THIS IS WORK THAT DAVE IN OUR GROUP LEADS. HE HAS BEEN LOOKING AT DIFFERENT PLATFORMS, DIFFERENT CONJUGATION PLATFORMS TO ATTACK THE PFS PROTEIN TO TO ENHANCE THE IMMUNE RESPONSE. THIS IS ACTUALLY A PLATFORM THAT WAS DEVELOPED HERE AT NIH. AND HAS BEEN USED FOR OTHER VACCINES IN THOUSANDS OF CHILDREN. BUT THIS SIMPLE STORY IS TO TRY TO -- IN THIS CASE, WHAT YOU WOULD END UP WITH IS AN AGREEVATE AS WELL AS IS THE ANTIGEN OF INTEREST. THIS IS AN EXAMPLE OF THE RESULTS YOU CAN SEE WHEN YOU COMPARE THE IMMUNE RESPONSE IN ANIMALS, THE ANTIBODY LEVELS AGAINST PFS25 AT DIFFERENT DAYS AFTER AN IMMUNIZATION DESIRES WHERE THE GREEN BOXES ARE THE SALABLE PROTEIN. AND THESE OTHER FIGURES ARE THE CONJUGATED FORM OF THE PROTEIN. CONJUGATED TO THE PROTEIN A, A PROTEIN PRODUCED BY [INDISCERNIBLE]. AND SO WHAT YOU CAN SEE IS A GREATLY ENHANCED ON THE ORDER AFTER COUPLE OF LOGS OF INCREASED RESPONSE THAT IS SUSTAINED AT LEAST OVER TIME IN THIS ANIMAL DESIRES THAT WOULD HAVE COME OUT OF SMALL ANIMALS. THESE WERE CD1 [INDISCERNIBLE] MICE. IT INCREASES THE ANTIBODY LEVEL. ALSO INCREASES THE FUNCTIONAL ACTIVITY, THE FUNCTIONAL LEVEL IN THE SIERRA. THIS SHOWS THE -- SERA. THIS SHOWS THE DEGREE IN OUR MEMBRANE FEEDING ASSAY, IN THIS COMPARISON, WOULD REDUCE THE NUMBER OF [INDISCERNIBLE] ON AVERAGE IN THE MOSQUITOES. AND THE PROPORTION OF MOSQUITOES THAT IT WOULD REDUCE THAT WERE UNINFECTED. IT WOULD REDUCE BY 12% THE PROPORTION OF MOSQUITOES THAT WERE INFECTED. IF YOU COMPARE THAT TO THE CONJUGATED FORM OF THE PROTEIN IT REDUCES THE COUNT BY ALMOST 100% AND REDUCES THE PREVALENCE OF INFECTED MOSQUITOES BY 90%. OF COURSE ULTIMATELY WHAT WE'RE LOOKING FOR IS 0. WE WANT TO KNOW THE NUMBER OF MOSQUITOES NO LONGER INFECTED BUT DON'T KNOW WHICH OF THESE MEASURES TRANSLATES INTO WHAT HAPPENS IN PEOPLE. SO WE'RE LOOKING AT BOTH OF THESE MEASURES. AS TOOLS TO FIGURE OUT IF WE'RE IMPROVING ON OUR VACCINES. THIS IS ANOTHER CONJUGATE STUDY THAT WAS DONE, A COLLABORATION WITH MERCK. THE THING I WANT TO HIGHLIGHT, THIS WAS DONE IN RHESUS MONKEYS, THE STUDIES WAS CARRIED ABOUT OVER ABOUT 2 1/2 YEARS TO HIGHLIGHT THAT CONJUGATED VACCINES CAN PROVIDE A VERY SUSTAINED ANTIBODY RESPONSE. SO IS THE UPPER LINE HERE IS THE CONJUGATE OF PFS25. THE LOWER LINE HERE IS PFS25 IN ONE OF THESE POWERFUL -- IT'S SUSTAINED FOR A LONG PERIOD OF TIME AFTER THE CONJUGATE VACCINE. THOSE ARE THE 2 ISSUES, 2 LEVEL OF ANTIBODY AND DURATION AND TO REMIND YOU, THIS PROTEIN IS NOT EXPRESSED IN THE HUMAN HOST. THERE IS NO BOOSTING. THE ONLY BENEFIT THE PERSON GETS FROM THE VACCINE, HOWEVER, LONG THOUGH ANTIBODIES PERSIST. A PLAN, THEN, HOW TO TAKE SUCH A VACCINE FORWARD INTO THE FIELD. WE DO ALL OF OUR STUDIES FIRST IN HUMAN VOLUNTEERS HERE IN THE U.S. FOR SAFETY AND IMMUNOGENICITY. WE WOULD MAKE SURE THE VACCINE IS SAFE AND LOOKING AT THE FUNCTIONAL ANTIBODIES INDUCED HERE IN THE UNITED STATES WHEN WE IMMUNIZE PEOPLE. IF THEY ACHIEVE -- IF THEY FAIL TO ACHIEVE THE LEVEL THAT WE WOULD LIKE TO SEE IN TERMS OF FUNCTIONAL ACTIVITY, WE WOULD BE LOOKING AT WAYS TO IMPROVE ON THE VACCINE. IF WE ACHIEVE THAT LEVEL OF EFFICACY, WE HOPE TO GO TO AN ENDEMIC AREA. NIH HAS WORKING TO TEST VACCINES, SO WE WOULD GO, AGAIN, ADULTS IN AN ENDEMIC AREA TO SEE WHAT LEVEL OF ACTIVITY OF VACCINE, TRANSMISSION BLOCKING VACCINE WOULD INDUCE. IT HAS BEEN THE OBSERVATION SOME VACCINES VERY WORK WELL IN PLACES LIKE THE U.S. OR EUROPE FAIL TO WORK VERY WELL WHEN YOU GET TO AN ENDEMIC AREA. THAT'S NOT JUST TRUE FOR MALARIA VACCINES. THIS IS A KEY ASPECT OF DEVELOPING THE VACCINES. LOOKING AT THEIR EFFICACY IN THE PEOPLE THAT ARE EFFECTED BY NOT ONLY MALARIA BUT ANY OTHER DISEASES. IF IT DOESN'T MEET THE CRITERIA FOR THE GO NO GO CRITERIA TO MOVE ON, WE WOULD BE EXAMINING HOW TO ENHANCE THE EFFICACY. IF IT MET OUR ACTIVITY CRITERIA, WE WOULD TAKE IT INTO CHILDREN. BECAUSE A VACCINE THAT'S SUPPOSED TO INTERRUPT TRANSMISSION TO MOSQUITOES, YOU CAN'T FOCUS ON ONE PART OF THE POPULATION. THIS HAS TO BE A COMMUNITY EFFORT WHERE EVERYBODY NEEDS TO GET VACCINATED. FINALLY, IF IT MEETS THE LEVEL OF EFFICACY IN CHILDREN, THEN WE WOULD BE INTERESTED IN TAKING SUCH A VACCINE TO THE ENTIRE COMMUNITY. BUT THE MANNER IN WHICH YOU TEST A VACCINE IS NOT SIMPLE. YOU'RE LOOKING AT EFFICACY BY DEFINING IT IN THE COMMUNITY. THIS IS NOT INDIVIDUAL LEVEL. YOU'RE LOOKING TO SEE WHAT HAPPENED IN THE COMMUNITY. THERE HAS BEEN A LOT OF DISCUSSION HOW TO TEST A VACCINE LIKE THIS. THE EVACUATION R. THE SS -- RTSS THAT GRAY WORKED ON IS UNDER GOING A PHRASE 3 TRIAL LOOKING AT INDIVIDUAL EFFICACY. THAT VACCINE TRIAL IS COSTING ABOUT $250 MILLION. SOMEBODY MAY HAVE A MORE ACCURATE FIGURE. I THINK IT'S AROUND THERE. THIS IS A MORE COMPLEX ENDPOINT THAN THAT VACCINE IS. IT'S SOMETHING WE NEED TO SET OUR MINDS TO. SO IN SUMMARY ABOUT TRANSMISSION BLOCKING VACCINES, WE'RE INTERESTED IN PREVENTING THE MOSQUITO FROM GETTING INFECTED. PARASITE IS EXPRESSING DIFFERENT PROTEINS. VACCINE TARGETS WITH DIFFERENT IN ORDER TO PROTECT THE MOSQUITO. THE MODE OF ACTION IS PROBABLY ANTIBODY ALONE, HOW WE'RE DEVELOPING THE VACCINE. ANTIBODIES ARE TAKEN UP WITH THE PARP ASITE IN A BLOOD MEAL, AND HAS THEIR ACTIVITY AS THE PARASIDE EXPRESSES THESE PROTEINS. SOME OF THE DOWN STREAM ANTJEBS HAVE LIMITED POLYMORPHISM. WE HAVE AN ASSAYS AVAILABLE THAT WE NEED TO GET A BETTER UNDERSTANDING OF WHAT IT MEANS. BUT THIS VACCINE WILL REQUIRE SUSTAINED HIGH LEVELS OF ANTIBODY. SO I WANT TO ASK A QUESTION. IF WE HAD SUCH A VACCINE, A VERY EFFECTIVE TRANSMISSION BLOCKING VACCINE, WHO WOULD WE TARGETING WITH THIS TAX. WHO WOULD -- VACCINE. THERE IS A LARGER QUESTION, HOW DID THAT COMPLICATE WHAT WE'RE GOING TO DO. WHO IN THE COMMUNITY WOULD GET A VACCINE, A TRAPS MISSION BLOCKING VACCINE IF WE WANTED TO DELIVER IT? EVERYBODY. OKAY? EVERYBODY WOULD HAVE TO GET THE VACCINE. CONVINCE EVERYBODY TO TAKE A VACCINE? OKAY. AND WHAT DO YOU -- WHAT DO YOU THINK MIGHT BE ASKED ABOUT THAT VACCINE? WHAT IS IT GOING TO DO FOR ME? HOW IS THIS VACCINE GOING TO BENEFIT ME? WHEN I TAKE THIS VACCINE. THAT'S A VERY AMERICAN WAY TO VIEW IT. SOME OTHER COMMUNITIES ARE MORE HOLISTIC ABOUT IT. SO IT MIGHT BE EASIER. SO FORTUNATELY WE DON'T TO HAVE DELIVER THIS HERE IN THE U.S. YOU'D NEVER GET EVERYBODY TO DO SOMETHING HERE. THIS IS AN IDEA OF DELAYED BENEFIT WHERE YOU GET A VACCINE. IT DOESN'T IMMEDIATELY PROTECT YOU. PROTECTS THE MOSQUITOES. IT'S GOING TO PROTECT THE NEXT PERSON FROM GETTING INFECTED. IT'S A DELAYED BENEFIT. THIS COMPLICATES THE REGULATORY PATH. IF YOU'RE NOT GETTING A VACCINE THAT IMMEDIATELY BENEFITS YOU, THAT MEANS THAT THAT SAFETY RISK RATIO IS REALLY HAS TO BE VERY PURE. THE REGULATORS ARE NOT GOING TO ACCEPT ANYTHING THAT HAS ANY FLAVOR OF SAFETY RISK HERE. OKAY. SO LET ME GET ON TO THE NEXT -- YES, GRAY. >> EXPLAIN, IF YOU WOULD, DO YOU AGREE WITH THAT? I MEAN WHEN YOU LOOK AT DISEASE THAT'S PLIGHTING THE CHILDREN, NEUROLOGIC, IS THAT THE RIGHT RISK BENEFIT PARADIGM TO SAY CAN'T CAUSE A RED ARM OR RED SHOULDER. WHAT WOULD YOUENT PEOPLE TO -- >> I THINK THE REGULATORY ENVIRONMENT IS CHANGING. OTHER COMPANIES ARE BECOMING EMPOWERED. I THINK IT'S HARD FOR US TO IMAGINE A DISEASE THAT YOU DESCRIBED WHERE HALF OF SCHOOL KIDS RAISE THEIR HANDS BECAUSE THEY RECENTLY HAD A MALARIA CASE. THE PARENTS ARE GOING TO HAVE A DIFFERENT VIEW. SO I THINK THAT WHAT'S GOING TO HAPPEN IS IMPAIRMENT WILL BE A BETTER DETERRENT. THE WAY WE VIEW THINGS IS INFORMED HOW BE LIVE. THIS IS BETTER INFORMED BY PEOPLE SUFFERING FROM THE DISEASE. I THINK THAT'S PART OF IT. THE OTHER ELEMENT, I THINK WE'RE LOOKING AT A MULTICOMPONENT VACCINE. TO ININDICATE THIS WHERE THERE ARE DIRECT BENEFITS OF SOME OF THE COMPONENTS. I DON'T THINK IT'S GOING TO BE SIMPLE. SO LET'S TALK ABOUT BLOCKING, ESPECIALLY WHEN THE PARASITE GETS INTO THE HUMAN. AND THESE ARE THE SPOROZOITE FORMS. THEY INVADE HEPATOSITES. IT ENTERS, IT FORMS A [INDISCERNIBLE] AROUND ITSELF. ENLARGES, DIVIDES, THEN YOU HAVE 20-40000 MEROZITES THAT A WEEK LATER, THESE ARE RELEASED. INTO THE BLOODTREME TO START THE -- STREAM TO START THE BLOOD STAGE. THAT'S THE SIMPLE DIAGRAM. HERE IS THE SPORE ZOITE PASSING THROUGH. THE VOYAGE IT TAKES, IT PASSES THROUGH THE CELL. YOU'D THINK THAT'S THE LAST PLACE IT WOULD WANT TO GO. IT ENTERS THE -- IT GOES THROUGH ONE OR TWO OR THREE OR FOUR HE PAPO VITAMINS BEFORE -- HEPATOSITES THAT IT WANTS TO STAY IN. THIS IS AN AMAZING CREATURE THAT CAN SWIM, BOROUGH, FORMS -- IT'S AMAZING. THAT'S WHY PEOPLE LIKE GRAY AND I ARE SO PASSIONATE ABOUT THIS, PARTLY BECAUSE OF THE BURDEN OF DISEASE, AND PARTLY BECAUSE IT'S SO AMAZING. IT ROUNDS UP AND GROWS AND FORMS THESE MANY THOUSANDS OF PARO SITES. THIS IS AN IMAGINE OF A [INDISCERNIBLE], MANY MEROZITES. INSIDE A MOUSE HEPATOSITE. WHAT'S HIGHLIGHTED IN RED, THIS IS AN IMAGE FROM STEPHEN, MY COLLEAGUE IN SEATTLE. THIS IS THE FORM THAT WE'RE TARGETING. AND THIS IS THAT PATHWAY WHERE IT COMES IN, DOES ALL THE DEVELOPMENT AND COMES OUT INTO THE BLOOD STAGE. BUT MANY DECADES AGO, THERE WAS A SEMINAL OBSERVATION MADE BY [INDISCERNIBLE] WHERE SHY TENULATED -- SHE ATTENUATED PARASITES BY RADIATING THE MOSQUITOES THAT WERE HARBORING THEM. MORE RECENTLY [INDISCERNIBLE] PIONEERED USING GENETIC REMOVING GENES. BUT IN EITHER CASE THE EFFECT IS TO CAUSE THE MAR ASITE TO A-- PARASITE TO ARREST DURING LIVER STAGE DEVELOPMENT. IF YOU PROVIDE A SUFFICIENT NUMBER OF THESE, THOSE INDUCED STERILE IMMUNITY IN MICE AND MONKEYS AND PEOPLE. SUFFICIENT NUMBER IS GIVEN. IN OTHER WORDS, AFTER EXPOSING PEOPLE TO THESE PARASITES THAT ARREST IN THE LIVER. IF YOU CHALLENGE THEM WITH WILDTYPE, THEY WILL NOT BECOME INFECTED. THIS IS THE -- THE EXPERIENCE REPORTED OUT OF THE WALTER READ AND NAVY CENTERS FOR PROTECTION WITH RADIATION ATTENUATED SPORO DECIDES. YOU MIGHT ASK WHY IT DID IT TAKE MANY YEARS? YOU NEED MORE THAN 1,000 MOSQUITOES TO BITE YOU TO GET IMMUNIZED. TO GET THIS VACCINE, YOU NEEDED MORE THAN 1,000 INFECTED MESQUITOS TO BITE YOU. FER THOSE INDIVIDUALS THAT GOT GREATER 1,000 BITES FROM INFECTED MOSQUITO, THAT HAD BEEN RADIATED, 13 OUT OF 14 PEOPLE WERE COMPLETELY PROTECTED FROM MALARIA. WHEN RECHALLENGED LESS THAN 10 WEEKS LATER. WHEN THEY WERE RECHALLENGED LATER, 5 OUT OF 6 INDIVIDUALS WERE PROTECTED. FOR THOSE INDIVIDUALS THAT GOT LESS THAN 1,000 IMMUNIZING BITES, ONLY 5 OUT OF 15 PEOPLE WERE PROTECTED. BUT HERE IS THE HUMAN DATA. IT FOLLOWED THE DATA THATED HAS BEEN ALREADY ESTABLISHED IN MICE AND MONKEYS. SO VERY EXCITING. THIS IS DRIVEN, MALARIA VACCINE DEVELOPMENT AND THE RESULT OF IT IS THE RTSS VACCINE THAT I DESCRIBED TO YOU, THE MAJOR SURFACE PROTEIN OF THESE SPORO ZOO ITS. THIS IS NICE WORK THAT WAS DONE HERE AT NIH WHICH IS SHOWING THE STRUCTURE OF CSP, A ROD LIKE STRUCTURE, ON THE SURFACE THAT APPEARS AS AN ELONGATED ROD. THIS IS THE PROTEIN THAT'S IN THIS VACCINE. RTSS. THESE WERE THE SEMINOLE STUDIES DONE AT WALTER READ. A REPORT BY KENT, BUT WHAT'S INTERESTING, WE CAN TEST THE EFFICACY RIGHT HERE IN WASHINGTON D.C. BECAUSE WE CAN EXPERIMENTALLY EFFECT PEOPLE WITH MALARIA. THIS IS SOMETHING WALTER REED HAS BEEN DOING FOR A COUPLE OF DECADES, AND HAS A SAFETY EXPERIENCE WITH MANY HUNDREDS OF INDIVIDUALS, SOUNDS STRANGE THAT WE'RE GIVING PEOPLE HERE IN WASHINGTON D.C. MALARIA BUT IT'S ACTUALLY HAPPENING. AND THIS IS THE RESULTS OF THOSE STUDIES. THESE ARE THE 41 INDIVIDUALS THAT GOT THE VACCINE, 23 INDIVIDUALS WHO GOT A CONTROL VACCINE. SO YOU CAN GET VOLUNTEERS THAT KNOW THEY'RE NOT PROTECTED AT ALL. AND GETTING EXPERIMENTALLY INFECTED WITH MALARIA. AND WHAT YOU SEE IS IS THE SURVIVORAL WITH PAR A[INDISCERNIBLE], SO AROUND DAY 9 YOU'LL SEE THE CONTROL GROUP START TO COME DOWN WITH MALARIA. ALL BUT MAYBE ONE INDIVIDUAL BECAME INFECTED. IF YOU LOOK AT THE RTSS GROUP THEY START COMING DOWN LATER. A PROPORTION OF THEM, ABOUT 40%, DID NOT GET INFECTED. THE CHALLENGES ARE DONE ABOUT A MONTH OR 2 AFTER COMPLETING THE IMMUNIZATION SERIES. THIS WAS ONORMISLY EXCITING. WE COULD SEE A SINGLE PROTEIN COULD INDUCE THAT LEVEL OF PROTECTION IN PEOPLE. BUT THEN YOU GO TO THE FIELD. THE FIELD IS A MORE DIFFICULT ENVIRONMENT. PARTLY BECAUSE THE PARASITE HAS THE SAME FORMING. DOESN'T HAVE SEQUENCE DIFFERENCES FROM THE VACCINE THAT'S GIVEN TO THEM. AND PARTLY BECAUSE POTENTIALLY THERE IS AN EFFECT WHEN YOU TAKE THE VACCINE, THERE CAN BE OTHER FACTORS THAT INFLUENCE THE EFFICACY. WHEN YOU START THE TRIALS YOU'RE STARTING IN ADULT IN THESE AREAS. THEIR OWN MALARIA IMMUNITY CONFOUND THE RESULTS YOU'LL SEE. NEVERTHELESS, THIS WAS THE FIRST DEMONSTRATION IN A FIELD ENVIRONMENT THAT A VACCINE COULD ALSO CONFER PROTECTION AGAINST MALARIA TO PEOPLE. THIS IS THE PROBABILITY OF REMAINING FREE. VERY SIMILAR TO THE FIGURE THAT I JUST SHOWED YOU WHERE WE DID THE EXPERIMENT FOR INFECTIONS. THIS WAS A TRIAL THAT WAS A COLLABORATION BETWEEN WALTER REED, GSK AND [INDISCERNIBLE] AND SHOWED THAT AMONG THE INDIVIDUALS THAT GOT THE RTSS THERE WAS SIGNIFICANT DELAY IN THEIR TIME AND THAT PERSISTED OVER ABOUT 3 MONTHS AND THEN THE CURVES CONVERGED. SO IT WAS ABOUT 3 MONTHS OF REDUCED RISK OF HAVING PARASITE EMIA AFTER SERVING THIS VACCINE. THAT DIFFERENCE PROMPTED ME SEE INDIVIDUALS, A LESS HEARTY SOUL MIGHT NOT HAVE GONE FORWARD WITH SUCH A VACCINE. BUT THESE PEOPLE WISELY WENT FORWARD. THESE WERE RESULTS OF STUDIES IN CHILDREN IN MOZAMBIQUE. THIS WAS REPORTED IN 2004. AND ON THE LEFT WHAT YOU'RE LOOKING AT IS THE REVERSE OF THOSE FIGURES, HOW LONG DO YOU SURVIVE WITH PARASITE EMIA. THIS IS SHOWING YOUR CUMULATIVE FIRST EPISODES. YOU HAVE PARASITES THEN YOU FEEL SICK. OR TIME TO PARASITE EMIA. THIS HIGHLIGHTS WHAT GRAY TOLD YOU. KIDS HAVE IT, LOOK HOW MANY WERE SICK WITH MALARIA. THIS ISN'T JUST ADULTS WALKING AROUND WITH PARASITE EMIA. THERE ARE A LOT OF KIDS WALKING AROUND WITH IT. THE GROUP IN RED, THE GROUP THAT GOT THE RTSS, YOU CAN SEE THAT OVER AN EXTENDED PERIOD OF TIME, AND THIS STUDY WAS EXTENDED FOR MORE THAN A YEAR AND THEY CONTINUED TO SEE BENEFITS, THERE IS A REDUCED RISK OF CLINICAL MALARIA AND REDUCED RISK OF PAR ASEAT EMIA, BUT OVER 6 MONTHS YOU'LL SEE ALMOST ALL THE KIDS GOT MALARIA. ANOTHER THING TO DIGEST, ALL THE KIDS ARE GETTING INFECTED LIKE GRAY ALLUDED TO. THIS VACCINE IS NOW UNDER GOING THE HUGE MULTICENTER TRIAL TO SEE HOW MUCH DISEASE -- HOW MUCH WE CAN REDUCE CLINICAL DISEASE IN KIDS. SO IT'S STOPPED REALLY BEING A VACCINE TO PREVENT INFECTION. THE ENDPOINT, EVEN THOUGH IT WAS INTENDED TO BLOCK INFECTION, WAS TO PREVENT CLINICAL DISEASE. I THINK A REFLECTION OF OUR POOR REFLECTION OF MALARIA IMMUNOLOGY. AND STARTING A FOCUS ON THIS AT THE NIH. ONE THING YOU MIGHT TRY TO DO IS ENHANCE THE EFFICACY OF YOUR CSP ANTIGEN. THIS SHOWS RESULTS FROM [INDISCERNIBLE] TO CREM197, ANOTHER PLATFORM AND OR ADDING ADJUVANT TO THE PROTEIN. THESE ARE THE ANTIBODY LEVELS ACHIEVED WITH CPS ALONE. THESE IS 2 DIFFERENT DAYS OF COLLECTING THE SERA. THIS IS WHEN YOU IMMUNIZE THE ANIMALS WITH A CONJUGATED FORM, WHERE IT'S COUPLED TO THE CARRIER AND INCREASED RESPONSE. THIS IS THE RESPONSE WITH JUST THE ADJUVANT ADDED, NOT ANY ENHANCED RESPONSE IN THIS ANIMAL. PUTTING THEM TOGETHER, WE SEE THE HIGHEST LEVELS OF ANTIBODY. IS THIS IS ONE STRATEGY. CAN WE IMPROVE ON CSP. THE OTHER STRATEGY WE CAN TAKE IS WHAT ELSE IS THE PARASITE EXPRESSING THAT CAN BE USED AS A VACCINE? AND SO THAT'S WHAT I'LL TALK ABOUT FOR THE NEXT FEW MINUTES. IS ARE THERE OTHER ANTIGENS THAT MAY BE USEFUL TO ENHANCE THIS VACCINE TO BLOCK INFECTION AND CONTRIBUTE TO INTERRUPTION OF TRANSMISSION. I'M SHOWING IMAGES OF SPORE ZOO TS STAYED WITH CSP, THE BASIS FOR THE VACCINE. AND ALSO HSP70, ANOTHER PROTEIN EXPRESSED BY THE PARASITE. THIS IS TO SHOW WE CAN GROW THESE WITHOUT THE BENEFIT OF THE HEPATOCYTES. WE CAN GROW LIMITED NUMBERS OF THESE THROUGH EARLY LIVER STAGE DEVELOPMENT. AND SO THAT HAS BEEN THE BASIS OF A PROGRAM, WE'VE BEEN PARTNERED WITH WALTER REED FOR DEFINE THE TRANSCRIPT OHM. WHAT ARE ALL THE GENES BEING EXPRESSED WHAT, ARE THE PROTEINS. WE HAVE BEEN USING RNA SEQUENCING, AND WITHOUT GOING INTO A LOT OF DETAILS WE HAVE DEFINED A TRANSCRIPT OHM OF PARASOUTHEAST OF 1500 GENES -- PAR A SITES. THESE ARE ALL DIFFERENT GENES, I'M SORRY I DIDN'T LABEL THEM. AND THE RED, THIS HEAT MAP, MEANS THERE IS GOOD EXPRESSION. THIS IS EXPRESSION IN [INDISCERNIBLE]. SOME OF THESE ARE EXPRESSED IN SPORE AZIDE, MANY ARE NOTICED. MANY ARE EXPRESSED AT 24-78 HOURS OF DEVELOPMENT. SOMER EXPRESSED IN [INDISCERNIBLE]. BUT THE MAJOR FOCUS WAS -- ONE OF THE TOOLS WE HAVE BEEN USING TO DETERMINE WHICH THINGS COULD GO FORWARD TO HUMAN TESTING ARE THE ANIMAL MODELS. SO WE HAVE 5 PARASITES THAT INFECT HUMANS. THERE IS OVER 100 DIFFERENT PLASMODIUM SPECIES, 5 INFECT HUMANS. THERE ARE PARASITES THAT INFECT BIRDS, PENGUINS, MICE, OR RODENTS. THEY ACTUALLY ORIGINATE FROM RATS. WE USE OUR LABORATORY ANIMALS TO STUDY THEM. SO WHAT WE HAVE BEEN DOING TO ASSESS OUR CANDIDATE ANTIGENS, IDENTIFY THE PLASMODIUM IS TO LOOK FOR THE GENE IN THE RODENT PARASITES, MAKE DNA VACCINES OUT OF THEM AND USE DIFFERENT DELIVERY SYSTEMS IMMUNIZE ANIMALS SUCCESSFULLY, THEN TO INFECT THEM BY MOSQUITOES AND DETERMINE WHETHER THE VACCINE WILL REDUCE THE NUMBER OF LIVER STAGE PARASITES GROWING IN THE LIVER. THAT'S THE SIMPLE FORMAT FOR THIS. THIS IS A TYPICAL KIND OF EXPERIMENT THAT WE DO. THIS IS THAT GRAY PROTEIN CSP, THE BASIS OF THAT HUGE VACCINE EFFORT. THIS IS THE DEGREE TO WHICH CSP VACCINE WILL REDUCE THE BURDEN OF LIVER STAGE PARASITES. THESE ARE OUR NOVEL ANTIGENS, TO A DEGREE SIMILAR. SOME OF THE. ANTIGENS HAVE NO EFFICACY FOR REDUCING THE LIVER STAGE BURDEN IN THIS MODEL. AND THIS IS SORT OF A SUMMARY TABLE OF ALL OF THE DIFFERENT GENES THAT WE HAVE BEEN TESTING, ABOUT 24. AND WE HAVE BEEN DOING THAT IN 2 DIFFERENT PARASITE SPECIES THAT INFECT RODENTS, [INDISCERNIBLE] USING THESE DIFFERENT IMMUNIZATION STRATEGIES. WHAT WE HAVE DETERMINED IS THAT -- IT'S NOT SHOWN, THERE ARE 4 GENES WE HAVE IDENTIFIED THAT PROTECT MICE FROM PLASMODIUM [INDISCERNIBLE] AND THESE ARE THE ONES THAT WE'RE FOCUSED ON FURTHER STUDIES. BUT THESE INITIAL STUDIES HAVE TRIED TO TEACH US WHAT ARE THE TYPICAL FEATURES OF THE GENES OR PROTEINS THAT PARASITES EXPRESS THAT MIGHT INDICATE THEY'RE GOOD VACCINE CANDIDATES? AND WHAT WE HAVE OBSERVED SHOWS THE LEVEL OF TRANSCRIPTION THROUGH THE LIVER STAGE INTO BLOOD STAGE. AND THE GENES THAT HAVE CONFERRED NO PROTECTION ACTUALLY PROGRESSIVELY GO DOWN IN THEIR EXPRESSION DURING LIVER STAGE. THOSE THAT ARE PROTECTIVE IN ONE MODEL, NOT THE OTHER, THEY HAVE AN INDIFFERENT PATTERN IN TRANSCRIPTION. THINGS THAT INCREASE IN ABUNDANCE MIGHT BE THE BEST TARGETS SO NOW WE'LL USE THIS INFORMATION TO SELECT A NEW POOL OF CANDIDATES TO EXAMINE AS POTENTIAL VACCINES. THE OTHER THING WE'VE NOTED ABOUT THE ANTIGENS THAT WE FINE PROTECTIVE IS THAT THEY DON'T APPEAR TO BE EXPRESSED VERY MUCH IN BLOOD STAGE PARASITES. THESE ARE THE RESULTS OF STUDIES WE'RE USING ANTIBODIES AGAINST THE PROTEIN TO LOOK AT PROTEIN EXPRESSION AND WE FIND THAT THE PROTEINS ARE IN PLASMODIUM [INDISCERNIBLE] BUT NOT YOU CAN BLOOD STAGE. -- NOT IN BLOOD STAGE. THE DATA IS JUST BEING COLLECTED NOW IN [INDISCERNIBLE]. WE'RE SEEING COMMON FEATURES OF THESE PROTEINS WE THINK ARE PROTECTIVE. IN THIS CASE, THE PATTERN EMERGING IS THE PROTEINS APPEARING TO BE PROTECTIVE MAY NOT BE DURING BLOOD STAGE MALARIA. SO IN SUMMARY, WHERE WE ARE IN TERMS OF VACCINE DEVELOPMENT, THERE IS A VACCINE THAT WE KNOW OVER MANY CLINICAL TRIALS PROVIDES CLINICAL BENEFITS. THERE IS AN EFFECTIVE MALARIA VACCINE. THIS VACCINE IS CALLED RTSS, ENTERED PHASE 3 TRIALS TO REDUCE CLINICAL MALARIA EPISODES, ALTHOUGH IT WAS INTENDED TO PREVENT INFECTION. THE TIMEFRAME FOR FINISHING THIS, LOOKING FOR LISTEN SURE IN 2016 ONCE THE RESULTS OF THIS TRIAL ARE IN. I RELY ON GRAY TO CORRECT ME. WE HAVE FOUND OVER LIVER STAGE GENES CAN GIVE PROTECTION TO RODENTS. THEY HAVE SIMILAR FEATURES, SUCH AS EXPRESSION. SO WE NEED A NEW EFFORT TO TAKE THESE ANTIGENS FORWARD TO FOLLOW THE SAME PATH AND SEE IF WE CAN ENHANCE THIS. AND MOST IMPORTANTLY, TO INCREASE THE EFFICACY TO BLOOD INFECTION. SO THE QUESTIONS I'D ASK ABOUT YOU ABOUT THESE VACCINES ARE WHAT IS THE BENEFIT OF THE RTSS VACCINE IN PHASE 3 TRIALS? YOU'RE LIVING IN THE MALARIA COMMUNITY AND PEOPLE ARE COMING TO TELL YOU THEY'RE GOING TO GIVE YOU THE RTSS VACCINE, WHAT IS THE BENEFIT YOU'RE GOING TO SEE? FROM WHAT I'VE DESCRIBED TO YOU? REDUCE CLINICAL DISEASE. [INAUDIBLE] SO THAT'S -- ONE OF THE BENEFITS OF THISUNAL TRIAL WILL BE HOPEFULLY THERE WILL BE BIG ENOUGH NUMBERS FOR SEVERE DISEASE. OVER TIME, IT'S NOT CLEAR THAT IT ACTUALLY REDUCES THE OVERALL BURDEN. SO AS GRAY MENTIONED, IT'S EFFECT TO BLOCK TRANSMISSION OR BLOCK INFECTION DOESN'T APPEAR TO BE GREAT. CERTAINLY NOT ADEQUATE FOR WHAT WE NEED FOR A VACCINE THAT'S GOING TO ERADICATE THE PARASITE. SO I'VE ANSWERED MY OWN QUESTION. WILL THE RTSS INTERPRET MALARIA TRANSMISSION? THE REASON WE NEED TO IMPROVE CSP, WE DO WANT TO BLOCK INFECTION. RTSS HAS BENEFITS BUT PROBABLY WON'T PLAY A ROLE IN A VACCINE TO INTERRUPT MALARIA TRANSMISSION. SO FINALLY, LET ME GET TO BLOCKING DISEASE. GRAY MENTIONED THE TERRIBLE BURDEN OF DISEASE. HE ALSO HIGHLIGHTED THE DIFFERENT PRESENTATIONS OF DISEASE IN A COMMUNITY. THIS IS JUST TO EMPHASIZE A FEW KEY FEATURES. THIS IS SEVERE MALARIA IN AFRICAN CHILDREN, DIFFERENT IN ADULTS. IN ADULTS IT'S MULTIORGAN DISEASE. THIS IS A VIN DIAGRAM SHOWING WITH IMPAIRED CONSCIOUSNESS, RESPIRATORY DISTRESS, AND MORE THAN ONE FEATURE. THE KIDS THAT HAVE MORE THAN ONE FEATURE ARE MOST LIKELY TO DIE. BUT THE SINGLE PRESENTATION -- IT'S USUALLY A SINGLE PRESENTATION. WE DON'T KNOW WHY THAT IS. GRAY DESCRIBED THIS STICKINESS, THESE ARE 3 INFECTED RED CELLS, AND UNINFECTED. THESE ARE LODGED IN THE BRAIN OF A PERSON IN VIETNAM WHO DIED OF CEREBRAL MALARIA. THIS ALLOWED THE PARASITE TO ATTACH TO THE ENDOTHELIAL. IT STOBS IN THE CIRCULATION. IT DOESN'T TO HAVE PASS THROUGH THE SLEEP. IT LODGES IN POST CAPILLARY WHERE THE OXYGEN IS LOW AND ONE OF THE MAJOR ADVANCES IS WHEN BILL DECIDED TO GROW THE PARASITE IN LOW OXYGEN CONDITIONS AND FIGURED OUT THAT'S HOW WE GROW THIS PARASITE. SO WE THINK THIS IS REALLY THE SOURCE OF THE PROBLEM. NOW, THIS IS EPIDEMIOLOGICAL SIGNAL. THIS IS SHOWING THIS IS THE POPULATION AGE 1, 10, 20. AND THIS IS THE INCIDENCE OF DIFFERENT ASPECT OF MALARIA, THINGS YOU CAN VISIBLY SEE. NORMALIZED TO THE PEEK OF THE INCIDENCES. SO THIS IS PARASITE TEAMIA. THIS IS -- THERE IS A WINDOW OF TIME. COUPLE MONTHS WHERE KIDS ARE PROTECTED, THEN THEY HAVE HIGH DENSITY INFECTIONS THAT LASTS FOR SEVERAL YEARS, THEN STARTS TO BE CONTROLLED AT DIFFERENT AGES, BUT LASTS FOR SOME NUMBER OF YEARS, AND THEN GETS DOWN TO AN ADULT LEVEL WHERE PEOPLE CONTINUE TO BE PARASITIZED BUT LESS FREQUENTLY SICK AND ALMOST NEVER HAVE SEVERE MALARIA, WHICH IS A VERY DIFFERENT EPIDEMIOLOGY FROM SEVERE. SO IT'S VERY IMPORTANT TO UNDERSTAND THE BURDEN OF SEVERE DISEASE DOES NOT TRACK THE BURDEN OF PARASITE EMIA. IT'S MUCH BRIEFER. THERE HAS BEEN POPULATION STUDIES THAT HAVE SUGGESTED THAT KIDS MY ONLY HAVE ONE OFFER 2 EPISODES OF SEVERE MALARIA, AND OUR DATA HAS CONVINCED US, THE KIDS HAVE ONLY ONE OR TWO EPSIDES OF SEVERE. THAT MAKES YOU THINK A VACCINE IS FEASIBLE, BECAUSE WE WANT TO BELIEVE THAT'S IMMUNITY INDUCED BY THAT EPISODE. THIS IS WHAT'S KILLING ALL THESE KIDS. I'M GOING TO TALK ABOUT SOMETHING ELSE BECAUSE I UNDERSTAND IT. WE DON'T UNDERSTAND THIS. SO I HAVE TO TALK ABOUT SOMETHING I UNDERSTAND, WHICH IS PREGNANCY MALARIA. WHEN MOTHERS FIRST BECOME PREGNANT, EVEN THOUGH BEFORE THAT THEY HAD A LEVEL OF IMMUNITY, THEY BECOME VERY DISCUSS SENSIBLE TO MALARIA. THIS IS PARTICULARLY TRUE FOR EFFICIENT TIME MOTHERS, AND WOMEN GOVERNMENT RESISTANT, EVEN WHEN THE MOTHERS ARE INFECTED, LOTS OF TIMES THEY DON'T FEEL THAT SICK AND THEY'RE CARRYING PARASITES ALSO VERY HARMFUL FOR THE DEVELOPING FEEING. BACK TO PREGNANCY IN A MINUTE BUT FIRST, PIVOTAL STUDIES. THIS WAS DONE IN THE EARLY 1960s. WHAT WAS DONE WAS TO PURIFY IMMUNE IGG FROM ADULTS, AND USE THAT FOR TRANSFER THERAPY IN KIDS SICK. THIS WAS FIRST DONE ON GAM BEAN KIDS, THEN TANS NEON KIDS. THIS IS GAM BEAN, IGG PURIFIED FROM HYPERIMMUNE ADULTS, AND IT RESTUDIES THE RESULTS WERE THE SAME. IF YOU PASSIVELY TRANSFER IGG INTO PEOPLE SICK WITH MALARIA. PARASITES COUNTS COME DOWN. THESE ARE DAYS HERE. SYMPTOMS WILL RESOLVE ALSO. VERY STRONG EVIDENCE THAT WE OUGHT TO BE ABLE TO MAKE AN ANTIBODY BASED VACCINE THAT HAS A SIMILAR EFFECT. THIS PARTICULAR CASE, THIS INDIVIDUAL IS INTERESTING. PARASITES CAME DOWN, 2 WEEKS LATER THEY CAME UP. THIS WAS AN ESPECIALLY CAME MUTANT, SO IT'S NOT ESCAPE, YOU JUST NEED ENOUGH ANTIBODY TO PROTECT YOURSELF. THAT WORK PROMPTED A LOT OF ACTIVITY ON THIS PROCESS. THIS IS THE PARASIGHT COMING IN CONTACT WITH THE RED CELL. REORIENTING AND INVADING. A LOT OF THE SEMINAL WORK WAS DONE RIGHT HERE AT NIH, A VERY ATTRACTIVE CANDIDATE FOR A VACCINE. AND THERE IS LOT OF POTENTIAL ANTIGENS THAT ARE ON THE SURFACE OF THESE PARASITE FORMS, THAT'S THE GOOD NEWS. THE BAD NEWS IS, THERE IS A LOT OF ANTIGENS INVOLVED. THERE MIGHT BE A LOT OF REDUNDANCY INVOLVED. AFTER A NUMBER OF TRIALS THAT WERE IMPORTANT TO DO, WE DON'T HAVE A CLEAR PATH TO HOW TO USE THIS PROCESS, TARGET THIS PROCESS FOR AN EFFECTIVE VACCINE. THAT'S MY BRIEF STORY ABOUT THAT BEFORE GETTING BACK TO THIS, THE INFECTED RED CELL. THESE ARE THE NOBODY PROTRUSIONS -- KNOBBY PRODUCES COMMON OFF THE SURE FASHION, THE IS THE PARASITE INSIDE THE RED CELL. THIS IS A PARASITE FROM A PREGNANT WOMAN. THIS IS FROM A CHILD. PARASITES FROM A CHILD FROM A PROGRESS WOMAN. WE ADAPTED THESE TO IN VITRO CULTURE. THESE ARE DIFFERENT KINDS OF PARASITES. SO I WANT TO TELL YOU ABOUT PREGNANCY MALARIA. THESE ARE SEQUESTERED IN THE BRAIN. THIS IS IN A WOMAN'S PLAS SENTA. SO ONE OF THE HALLMARKS OF PREGNANCY IS FIRST TIME MOTHERS BECOME VERY SUS ACCEPTABLE. THE OTHER HALLMARK, THE PARASITES SEEM TO LIKE TO SEQUESTER IN THE PLAS SENA. THESE ARE MANY INFECTED RED CELLS IN THE MATERNAL BLOOD. THE PARASITES DON'T GET INTO THE FETAL BLOOD. WE CAN TALK ABOUT THAT MORE. THAT'S A PET INTEREST -- THAT'S A PET INTEREST. FOLLOWING THE PARASITES ALLEGATIONS OF AACCUMULATED, YOU SEE THESE MARK PAGES, THIS BROWN SPOT STUFF PIGMENT, BREAK DOWN PRODUCT OF HEMO GLOBIN. THEY START EATING EVERYTHING. AND THEY'RE ABOUT 6 TIMES THE SIZE OF A MARK PHAGE. THESE ARE -- MARKCO PHAGE. AND THIS PROCESS ENSUES. THIS IS THE INFLAMMATORY ASSOCIATED WITH THE POOR OUTCOMES OF PREGNANCY MALARIA LEADING TO FETAL DEATH. SO THIS IS SEMINOLE WORK THAT [INDISCERNIBLE], JUST JOINED NIH DID WHEN WE WERE WORKING TOGETHER IN KENYA. OUR HYPOTHESIS WAS THAT THE REASON THAT WOMEN BECOME SUSCEPTIBLE TO MALARIA DURING PREGNANCY IS BECAUSE THOSE PARASITES ARE PHONO TYPICALLY -- FINOTOPCALLY DIFFERENT THAN OTHER PEOPLE. SO THIS IS AN ASSAY, TOOK A SECTION OF PLAS SENTAL TISSUE, FETAL. THE MOTHER, JUST HER BLOOD PASSES THROUGH THE PLEASANTA. AND WE A LOUED THEM TO SETTLE ON THIS PLATFORM AND WASHED AWAY BUT DIDN'T BIND. THE RED CELLS BIND ALONG THE SURFACE OF THE PLAY SENTAL LINING THAT COVERS THE FETAL TISSUE. THROUGH A NUMBER OF DIFFERENT STUDIES, SHOWED THAT THE PARASIGHTS BIND A RECEPTOR CALLED [INDISCERNIBLE] A. EVERY PARASITE WE EVER COLLECTED FROM A PLACENTA, AND THAT DISTINGUISHES PARASITES FROM WE GO WOMEN THAN OTHER PEOPLE. WE HAVE DONE HUNDREDS OF THESE, THEY ALWAYS BIND TO [INDISCERNIBLE] SULFATE A. CONVERSELY, THE PARASITES DON'T BIND TO RECEPTORS LIKE CD36. SO THE PARASITES INFECTING PREGNANT WOMAN HAVE A DIFFERENT PHENOTYPE THAN THE PARASITES IF HE CANNING OTHER PEOPLE. -- AFFECTING OTHER PEOPLE. HE SHOWED THAT WOMEN ACQUIRE ANTIBODIES AGAINST THIS DISTINCT PARASITE FORM OVER SUCCESSIVE PREGNANCIES AS THEY BECOME RESISTANT TO MALARIA. THESE ARE LEVELS OF ANTIBODIES IN FIRST TIME MOTHER. SECOND TIME MOTHERS, SO THESE ARE UNIFORMLY ABSENT IN FIRST TIME MOTHERS, PRESENT IN MULTIGRAFTA WOMEN IN WESTERN KENYA WHERE ALL THESE WOMEN. IN SECOND TIME MOTHERS, THEY HAD HIGHER LEVELS OF ANTIBODIES THAN WOMAN INFECTED. THESE STUDIES HAVE BEEN REPRODUCED ADD MANY OTHER CENTERS SINCE THIS WORK WAS FIRST DONE. WE'VE LEARNED THEY EXPRESS A SUBJECT SET OF GENES THAT -- SUBSET OF GENES THAT DISTINGUISHES THEM FROM PARASITES THAT EFFECT OTHER PEOPLE. THIS SHOWS A GROUP OF GENES. THIS IS COMPARING THE RNA OF MATERNAL PARASITES, ANY GREEN SIGNAL WOULD BE SIGNAL FROM THE CHILDREN, RED IS FROM THE MOTHERS. YOU CAN SEE ACROSS THESE ISOLATES AND MANY REPLICAS, THESE ARE UPREGULATED IN THE MATERM PARASITES. THIS IS A FOCUS OF INTEREST FOR VACCINE DEVELOPMENT. THIS SHOWS 4 OF THOSE. THIS IS VAR2CSA, A VERY LARGE MULTIDOMAIN COMPLEX ANTIGEN THAT HAS BEEN CONSISTENTLY ASSOCIATED WITH THESE PARASITES INFECTING PREGNANT WOMEN. AND HAS BEEN BECOME THE MAJOR FOCUS OF A VACCINE EFFORT. WHAT'S INTERESTING ABOUT THIS IS THAT THIS PROTEIN, WHICH IS INDICATED HERE, FIRST DESCRIBED BY [INDISCERNIBLE] SO I'VE SHOP YOU OUR MICROARRAY RESULTS PERFORMED BY 5 YEARS AGO. BEFORE THAT, THERE WAS A FOCUSED EFFORT TOIFYING OUT WHICH -- FIGURE OUT WHICH GENE IN THIS FAMILY OF GENES, MIGHT BE ASSOCIATED WITH PREGNANCY PARASITES. THIS GROUP DEVELOPS TOOLS AND SHOWED THAT THIS GENE, THIS VARIOUS SURFACE AIN'T GEN, FAMILY HAD ONLY 1 MEMBER THAT WAS CONSISTENTLY UPREGULATED. VAR2CSA. WE HAVE PARTICIPATED WITH OUR COLLEAGUES FROM COPENHAGEN, NIH IN SEATTLE, TO FIGURE OUT WHO MAKE A VACCINE OUT OF THIS. WE CAN'T EXPRESS THIS BIG PROTEIN SO WE FOCUSED ON INDIVIDUAL DOMAINS. WE FOUND THAT 2 DOMAINS CONSISTENTLY ELICIT ANTIBODIES THAT HAVE FUNCTIONAL ACTIVITY TO BLOCK PARASITES FROM BINDING TO CONTRITANT SULFATE A. THIS IS SOME OF THAT DATA. WHAT YOU SEE ARE 5 DIFFERENT IMMUNE GENS. WE'RE TESTING THEIR ACTIVITY, A DEGREE TO WHICH THEY INHIBIT THE BINDING OF 4 DIFFERENT MATERNAL ISOLATES. SO THESE ARE HETERO-- YOU CAN SEES INSIGHT SOME FUNCTIONAL OF ACTIVITY, HOWEVER, IT VARIES. SO OUR CHALLENGE IS TO GET THE ANTIBODY LEVELS HIGHER AND DETERMINE WHETHER IT'S SIMPLY A MATTER OF ANTIBODY LEVELS HIGHER OR WHETHER THERE MAY BE ANOTHER PROTEIN THAT'S REQUIRED. THIS IS WHAT MATERNAL WOMEN'S IGG, USING PURIFIED IGG BY THE WAY. THAT'S OUR GOAL IS TO ACHIEVE THAT LEVEL. SO I SAID THERE MIGHT BE -- THE PROTEINS OF INTEREST. WE HAVE BEEN PURSUING THESE OTHER PROTEINS ALSO UPREGULATED. AND THIS IS FANTASTIC WORK THAT [INDISCERNIBLE] IN OUR GROUP HAS DONE. SHE TOOK THESE MULTIPLE OTHER GENES, UP REGULATED IN PREGNANCY, AND THIS SHOWS THE DEGREE TO WHICH THIS CONTROYEDANT WILL BIND. SO ONE AMONG THESE SUPPORTS BINDING AT A VERY HIGH LEVEL COMPARED TO ANY OF THE OTHER PROTEINS. OKAY? SO WE STARTED CALLING THIS ANOTHER LIGAND FOR CSA EXPRESSED. THIS IS DIFFERENT FROM VAR2CSA, THAT OTHER PROTEIN THAT I WAS TELLING YOU ABOUT. THAT PROTEIN IS ON THESE KNOBS ON THE SURE NASE OF INFECTED RED CELLS WITH MATERNAL PARASITES, BUT CHILDREN'S WERE TREATED SIMILARLY AND THERE IS NO EVIDENCE OF THE PROTEIN ON THE CHILDREN. THIS IS SURFACE SPECIFIC TO PREGNANCY PARASITES. INCREASING LEVELS OF THIS PROTEIN, THIS IS THE OPEN COTS, IT -- DOTS, IT DECREASES IN THE PRESENCE, THE BINDING OF MATERNAL PARASITES IS LAYINGLY NEARLY TOTALLY INHIBITED. THIS IS A CONTROL PROTEIN THAT HAS NO EFFECT TO BLOCK THE BINDING. THIS SHOWS WHEN WE RAISE ANTIBODIES AGAINST THIS PROTEIN, WE'RE ABLE TO INHIBIT THE BINDING OF MATERNAL PARASITES. THESE ARE ALL DIFFERENT MATERNAL PARASITES TO DIFFERENT DEGREES. THIS IS 50% INHIBITION. 100% WOULD BE A HIGH LEVEL OF BINDING INHIBITION. WHAT IS MOST IMPORTANT ABOUT THIS PROTEIN AND MOST SURPRISING, IT IS 100% CONSERVED. WE HAVE BEEN UNABLE TO IDENTIFY ANY SEQUENCE VARIATION THAT'S ON THE SURFACE OF THE INFECTED RED CELL, COMPLETELY NEW. WE HAVE BEEN NEVER DESCRIBED AN INVARIANT ANTIGEN. THIS IS AN EXCITING NEW ADVANCE WHICH OPENS THE POSSIBILITY THAT THERE MAY BE OTHER CONSERVED PROTEINS ON THE SURFACE OF INFECTED RED CELLS. I WILL QUICKLY GO TO THE SUMMARY HERE WHICH IS THE PREGNANCY MALARIA SUMMARY. THESE PARASITES EXPRESSED DISTINCT LIGANDS. FIRST TIME MOTHERS ARE SUSCEPTIBLE BECAUSE THEY LACK IMMUNITY WHICH IS REQUIRED OVER SUCCESSIVE PREGNANCIES, WHICH IS HOW THEY ACQUIRE ANTIBODIES. ALL THIS MAKES US THINK A MALARIA VACCINE IS FEASIBLE THAT WOULD PROTECT PREGNANT WOMEN. WE WANT TO VACCINE YOUNG WOMEN PRIOR TO THEIR FIRST PREGNANCY, AND IN THIS CASE, NATURAL INCIDENT OR INCURRING IMMUNITY. BACK TO THESE PICTURE, WHAT ARE THESE, HAS BEEN A KEY FOCUS OF ATTENTION EVERY SINCE THE DISCOVERY THAT THE PARASITES IN THE PLASTA ARE DIFFERENT. THERE HAS BEEN TANTALIZING EVIDENCE, BUT NOTHING CONCLUSIVE IN THAT REGARD. SO THE QUESTIONS IN THIS SECTION MIGHT BE CAN A VARIANT SURFACE ANTIGEN BE TARGETED TO DEVELOP A MALARIA VACCINE. CAN IT? KATHY HOPES SO. I HOPE SO. >> BUT NOT LIKELY. >> IT WILL BE A CHALLENGE. THE QUESTION IS, WHEN WE SAY VARIANT SURFACE ANTIGENS, THERE IS LARGE ELEMENTS THAT ARE CONSERVED. THE QUESTION IS WHETHER WE CAN MAKE A VACCINE OUT OF CONSERVED ELEMENTS THAT WOULD HAVE THAT HETEROGOUS ACTIVITY. SECONDLY, CAN A BLOOD STAGE VACCINE PREVENT SEVERE DISEASE WITHOUT CONTROLLING INFECTION? CAN A BLOOD STAGE VACCINE PREVENT SEVERE DISEASE WITHOUT CONTROLLING INFECTION? SOMEBODY FROM MY LAB SHOULD ANSWER. THEY'LL GET CALLED ON IN A SECOND. [LAUGHTER] [INAUDIBLE] >> WELL WE KNOW THAT -- I SHOWED YOU THAT EPIDEMIOLOGY. THERE IS A BRIEF TIME WHERE KIDS GET SEVERE MALARIA. THERE IS A TIME WHEN THEY'RE VERY SUSCEPTIBLE. SO IT DOES SUGGEST THERE IS AN IMMUNITY THAT PREVENT DISEASE WITHOUT CONTROLLING PARASITE EMIA. AND IT MIGHT CONTROL A PARTICULAR FORM, AND OTHER PARASITES ARE ALLOWED TO GROW. I THINK THAT POSSIBILITY IS THERE. I THANK YOU FOR YOUR ATTENTION. I WANT TO HIGHLIGHT THE PEOPLE WHO -- THAT HAVE DRAWN FROM THEIR WORK. RUTH ELLIS IS LEADING THE CLINICAL DEVELOPMENT. [LIST OF NAMES] PAGE THE PRODUCTS -- MAKE THE PRODUCTS. KELLY DOES THE FORMULATION WORK, AND OUR HE IS AS ARE PERFORMED BY [INDISCERNIBLE] WHO HANDING THIS SINCE I TRAINED HERE. SHE WAS MY COLLEAGUE IN THE LABORATORY. AND JOAN. FOR THE LIVER STAGE WORK, THIS WAS A PARTNERSHIP THAT STARTED WITH HOWARD HOGAN WHEN I WAS IN -- GRAY HEPPNER AND OUR PARTNERS THERE. THIS COLLABORATION CONTINUES. FOR THE BLOOD STAGE WORK, MY LONG TIME PARTNER IN THIS WORK FOR PREGNANCY MALARIA HAS BEEN [INDISCERNIBLE]. I MENTIONED THE GREAT WORK THAT [LIST OF NAMES] DID. I WANTED TO HIGHLIGHT THEIR CONTRIBUTION. THANKS FOR YOUR ATTENTION. [APPLAUSE] >> THANK YOU VERY MUCH. [INAUDIBLE] DOES ANYBODY HAVE ANY QUESTIONS? >> YEAH. PATRICK, MAYBE YOU CAN COMMENT, YOU KNOW WITH THE RTSS THAT'S BEING DEVELOPED, IF IT HAS 50% EFFECTIVE CLINICAL DISEASE, AND THEN WE LOOK AT MAYBE MORE IMMUNOGENIC OR DIFFERENT FORM OF CSP, THE CLINICAL TRIAL TO SHOW SUPERIORITY OR EVEN EQUIVLENCY OF THAT IS GOING TO HAVE TO BE QUITE LARGE UNLESS YOU CAN HAVE A SURROGATE OF PROTECTION. AND MAYBE YOU OR GRAY CAN COMMENT ON WHAT'S BEING DONE WITH RESPECT TO THE RTSS STUDY TO LOOK FOR SURROGATES OF PROTECTION SO THAT NEW AND IMPROVED VACCINES MIGHT BE -- OFFER AN OPPORTUNITY TO BE DEVELOPED WITHOUT HAVING REALLY TO EXPAND. >> GRAY IS A BETTER PERSON TO TALK ABOUT THAT. >> I THINK THAT THERE IS A STORY UNFOLDING WITH RTSS. THAT IS THAT DESPITE [INDISCERNIBLE] TO THE CONTRARY, I THINK THE PUBLISHED PAPER IN JID THAT COMPARED THE ASO1 TO ASO2 SHOWED 2 THINGS. IT WAS A TIGHT CORRELATION INDEPENDENT OF ANY OTHER CELLULAR RESPONSE. BEJOHN DID AN ANALYSIS THAT MATCHED OUT. WE OFFERED OUR DATA BUT HE EXTRAPOLATED FROM A GRAPH. HE WAS CORRECT IN HIS FIRST 2 ASSERTIONS. THE INTRIGUING THING, FOR PROTEIN WITH ADJUVANT, TO HAVE AN INDEPENDENT ASSOCIATION WITH CD4T. CELLS. THESE ARE -- STILL PRIMITIVE, BASED ON [INDISCERNIBLE] AND IF THEY SHOWED ONE OF 3 CYTOKINES, TNF, ALPHA, CD40 LIGANDS [INDISCERNIBLE] 10 FOLD INCREASE WAS ASSOCIATED INDEPENDENTLY. THAT WILL BE PUT TO THE TEST WITH AN APPROACH WHICH IS GOING FORWARD WITH A COMPANY CALLED -- NOT TO MAKE A DISCLAIMER. [INDISCERNIBLE] BUT I THINK THE FACTS SPEAK FOR THEMSELVES. ANN STEWART DID A TRIAL SHOWING THAT A COMBINATION OF ADENOVIRUS VECTOR, AND JOE WORKED ON IT, TOO, AUGMENTED THE CD4 RESPONSES, SO THAT WOULD BE PUT TO THE CLINICAL TRIAL TEST TO SEE JUST WHAT YOU ASKED. CAN WE USE THESE CORILATED OF PROTECTION TO OP AT THISIMIZE VACCINE. HERE IN THE CHALLENGE TRIAL, I THINK IT'S A VERY MUCH LARGER OPEN -- THE OTHER EXCITING IS A PAPER BY [INDISCERNIBLE] WHICH WAS PUBLISHED IN JID, SHOWS THERE WERE 4 -- USING GENE ANALYSIS, SHOWED RETROSPECTIVELY THE 4 RESPONSES HAVING TO DO WITHYMINO PROTEOME, STRONGLY PREDICTIVE OF PROTECTION. THAT NEEDS TO BE PROSPECTIVE VALIDATED. WILL BE DONE IN THE TRIAL COMING IN A ARMY INSTITUTE NEAR YOU SOON [LAUGHTER] I WOULD LIKE TO ADD SINCE I HAVE THE MIC, ONE OTHER THING. I THINK IT BEGS THE QUESTION OF WHY ARE PEOPLE PROTECTED IN THE FIELD. CLEAR LAY, ANYBODY IN THE FIELD, THERE IS MORE EVIDENCE THAT INITIAL IMPORTANCE AGAINST PROTECTION. THERE ARE EFFORTS UNDER WAY. I'M NOT PART OF THAT WORKING GROUP. PEOPLE HAVE LIKENED RTSS TO PHYSIOLOGIC BED NET. IF YOU REDUCE THE INTENSITY OF EXPOSURE, THE DISEASE IS LEST SEVERE. FOR WHATEVER REASON IT LOOKS THUS FAR, I THINK IN THE STUDY THAT PAT SHOWED, THAT THE [INDISCERNIBLE] DID NOT CONVERGE IN TERMS OF PROTECTION AGAINST CLINICAL DISEASE, AS FAR AS WE KNOW AGAINST SEVERE DISEASE. SO THERE IS SOME EVIDENCE OF ACQUIRED BLOOD STAGE PROTECTIVE EFFECT, I THINK, THAT IS NOT REALLY DIRECTLY TO THE VACCINE BUT AN EFFECT OF THE VACCINE. >> I WONDER IF MAYBE SOME OF THE MON MALAROLOGISTS IN THE AUDIENCE HAVE A QUESTION THAT YOU'D LIKE TO ASK? NON. >> OVER HERE ON THE LEFT. >> I WAS WONDERING WHAT INNATE RECEPTORS THE BODY HAS SPECIFICALLY IN HEPATOSITES. USUALLY THERE ARE DOUBLE STRANDED RNA. ARE THERE THINGS FOR MALARIA SPECIFICALLY THAT GO OFF TO ENHANCE THE IMMUNE RESPONSE IN. >> THAT'S A GOOD QUESTION. THERE IS -- THERE ARE HOST RESPONSES DURING THE LIVER STAGE. THERE HAS BEEN, YOU KNOW, DATA GOING BACK SHOWING [INDISCERNIBLE] SYNTHASE, UP REGULATION SHOWS HEMO OXIDASE EXPRESSION. THESE INFLUENCE OUTCOMES. THERE IS A RESPONSE OF THE HOST TIGHT. IT'S ALSO TRUE THAT YOU CAN INDUCE AN IMMUNE RESPONSE. THAT'S EFFECTIVE AGAINST THE INFECTED HEPATOSITE. ONE OF THE PROBLEMS WE HAVE IS THERE IS NO WAY TO KNOW, IN A MORE GLOBAL PRACTICAL LEVEL. THOSE ARE THINGS YOU CAN EXAMINE WHEN YOU GET A PIECE OF LIVER WHEN SOMEBODY IS INFECTED. WE DON'T HAVE ANY MARKERS THAT TELL US WHEN A PERSON IS INFECTED, OR A SIGNAL THAT TELLS US SOMEBODY IS INFECTED. ONE OF THE COMMON QUESTIONS THAT'S ASKED IS WHY DO PEOPLE KEEP GETTING INFECTED? HOW MUCH DOES IT TAKE. I SHOWED YOU ONE THOUSAND INFECTED MOSQUITO BITES WILL -- PEOPLE LIVE THEIR ENTIRE LIFE IN A COMMUNITY AN NEVER STOP HAVING MALARIA. IT'S TAKING YOUR QUESTION FURTHER AND ASKING ANOTHER QUESTION WHICH IS WHY DON'T PEOPLE COME IMMUNE. >> WHY WE'RE ASKING WHY, WHAT HAPPENS WHEN A PATIENT WHO SEEMS IS TO SAY IN NEW NORTH AMERICA, ISN'T AWARE OF THE FACT THEY MAY HAVE MALARIA, THEY COME TO THE HOSPITAL, AND THEY'RE TREATED WITH CORTICOSTEROIDS FOR, SAY, ACTIVE RHEUMATOID ARTHRITIS OR MAYBE THEY HAVE SURGERY FOR SOMETHING. AND EVEN A LAPPER OSESCOPY. 2, 3 DAYS LATER, THEY'VE GOT ACUTE MALARIA. HOE DOES THAT HAPPEN? >> GRAY MENTIONED THE ONES THAT STAY SILENT, [INDISCERNIBLE]. BUT FAMOUS ONES ARE PLASMODIUM MAR LAIA. THOSE WHO GOT MALARIA 50 YEARS AGO, AND [INDISCERNIBLE], WHICH ACTUALLY PERSISTED IN BLOOD STAGE FORM FOR MANY DECADES. THERE IS NO EVIDENCE. SO THESE PARASITES ARE AMAZING. IN A WAY THE SUCCESSFUL PARASITE, THAT'S WHAT IT DOES. THE LONGER IT HANGS AROUND, IT INFECTS MORE MOSQUITOES. IT DOESN'T WANT TO MAKE YOU SICK. IT WANTS TO INFECT THE NEXT MOSQUITO. THE REASON WHY IT DIFFERS, AND WHETHER IT'S VIE VEX OR [INDISCERNIBLE]. FALCIPARUM DOESN'T PERSIST THAT LONG. I'VE SEEN REPORTS BUT IT'S PROBABLY A COUPLE OF YEARS IN ITS DURATION THAT YOU CAN GET [INDISCERNIBLE] AND THAT WOULD BE FROM THE BLOOD STAGE. [INDISCERNIBLE] WANTS TO DEVELOP EQUILIBRIUM WITH ITS HOST SO IT CONTINUE TO EFFECT MOSQUITOES. >> ANOTHER QUESTION. WHAT IS THAT ORGANELLE IN THE LIVER OR WHAT YOU CALL THE [INDISCERNIBLE]. IT HAS TO BE SEPARATED FROM THE REST OF THE HEPATOSITE, DOES IT HAVE A DIFFERENT PH? HAS IT GOT A PUMP? WHAT SUDDENLY ACTIVATES THESE PARASITES TO GO CRAZY WITHIN THIS CONFINED ENVIRONMENT? >> THE POINT OF ATTACK. THAT'S -- IT IS A GOOD QUESTION. SO -- SOME OF THIS WORK IS FROM [INDISCERNIBLE]. AND THERE ARE ENORMOUS GROWTH REQUIREMENTS, SOME OF THE REQUIREMENTS IS FOR LIPIDS FROM THE HOST. THAT. * FACE IS IMPORTANT TO ACCESS SOME OF THE HOST IN YOU TREE WANTS AND MATERIAL. I THINK THIS IS AN EMERGING AREA THAT I THINK IT CONTINUES TO BE DEFINED. >> THERE IS A DOCTOR [INDISCERNIBLE] GOING TO GIVE A LECTURE HERE NEXT MONTH, DEVELOPED A MARVELOUS SYSTEM FOR LONG TERM -- ARE YOU AWARE OF HER WORK. >> THE NANOTECHNOLOGY AND MAKES THESE LIVER LIKE ENTITIES, WORKING WITH A GROUP TO LOOK AT MAR LAIA -- >> SO THEY HAVE BEEN STUDYING MAR LARIA. >> SHE HAS BEEN DOING GREAT STUFF. >> I JUST BRING IT TO EVERYBODY'S ATTENTION. THERE WAS A QUESTION BACK HERE? [INAUDIBLE]? >> DURING THE PREGNANCY? DOES IT MEAN THAT THIS SPECIAL [INDISCERNIBLE] INHIBITS REPLICATION OF THE NORMAL PARASITE. COULD IT BE A WAY TO COMBAT NORMAL PARASITES USING SOMETHING FROM THESE SPECIAL PREGNANCY PARASITES? >> A VERY GOOD QUESTION SHOULD BE MORE CLEAR ON. THE PARASITES ARE ALL THE SAME. IT HAS TO DO WITH WHICH GENES ARE BEING TRANSCRIBED AND EXPRESSED. IF I SHOWED YOU THE HOTEL TRANSCRIPT OHM OF THE CHILDREN'S VERSES MATERNAL, IT'S EXACTLY THE SAME FOR 5,000 JEANS. IT'S ONLY A HANDFUL THAT -- WHETHER SOME THINGS ARE SPECIFICALLY SUPPRESSED -- [INAUDIBLE] >> I THINK THAT THE NORMAL PARASITE PUTS DIFFERENT THINGS ON ITS SURFACES AND GETS SELECTED BY ITS ENVIRONMENT. WE CAN TAKE A NORMAL PARASITE AND IMMOBILIZE AND BY PANNING IT, WE CAN MAKE A PARASITE THAT BINDS. IT MIGHT BE AS SIMPLE AS ONCE YOU HAVE A PLACENTA THAT DISPLAYS THIS, THE FEW PARASITES THAT PUT THE PROPER LIGAND ON THE SURFACE OF THE RED CELL WILL BE SELECTED AND OVERGROW. MAYBE PREGNANCY HORMONES INDUCE THE PARASITE BUT WE DON'T HAVE EVIDENCE THAT THAT OCCURS. [INAUDIBLE] TO BE FULLY CLEAR, WHEN WE TAKE BLOOD FROM A PREGNANT WOMAN'S ARM, PARASITES THAT COME FROM THE HOME, SOMETIMES THEY BIND TO [INDISCERNIBLE]. CD36. LIKE OTHER PARASITES. THE SAME PARASITES IN PREGNANT WOMAN [INDISCERNIBLE] THAT THE OTHER ADULT GET, SHE HAS THIS NEW BREW. IT'S A HUMAN BURDEN OF JOE GROWN PARASITES IN THE PLACENTA. I WANT TO THANK YOU FOR A VERY, VERY EXCITING -- THANK YOU ALL. VERY EXCITING -- THANK YOU ALL.