>> GOOD AFTERNOON, EVERYONE, AND WELCOME TO THE ANNUAL ADVANCES IN CANCER PREVENTION LECTURE. I'M REALLY PLEASED TO BE HERE AND REALLY PLEASED TO WELCOME OUR ANNUAL SPEAKER, DR. JOHN SCHILLER. BEFORE I INTRODUCE YOU TO HIM, I WANT TO SAY A FEW WORDS ABOUT THE FELLOWSHIP PROGRAM. I'M THE DEPUTY DIRECTOR OF THE CANCER PREVENTION FELLOWSHIP PROGRAM. I'M ALSO THE DIRECTOR OF THE SUMMER CURRICULUM PROGRAM. THE CANCER PREVENTION FELLOWSHIP PROGRAM CELEBRATED ITS 30TH YEAR LAST YEAR. AND IT'S A POSTDOCTORAL TRAINING PROGRAM THAT SEEKS TO TRAIN FUTURE LEADERS IN CANCER PREVENTION. WE DO THIS THROUGH VARYING MECHANISMS, THROUGH MENTORED TRAINING OPPORTUNITIES HERE AT THE NCI, BUT WE ALSO PROVIDE DIDACTIC TRAINING SUCH AS GRANT-WRITING, LEADERSHIP TRAINING, AS WELL AS THE NCI SUMMER CURRICULUM PROGRAM. AND THE ANNUAL ADVANCES LECTURE IS PART OF THE NCI SUMMER CURRICULUM PROGRAM. EVERY YEAR WE INVITE A SPEAKER THAT HAS MADE MAJOR CONTRIBUTIONS TO THE FIELD OF CANCER PREVENTION. WE'VE INVITED DR. DOUG LOWY AND MANY OTHER WELL-KNOWN RESEARCHERS. THIS YEAR I'M REALLY HONORED TO INTRODUCE TO YOU ANOTHER GIANT IN THE FIELD OF CANCER PREVENTION, DR. JOHN SCHILLER. DR. JOHN SCHILLER ASKED ME TO KEEP HIS BIOSHORT BUT I WON'T. [LAUGHTER] HE'S AN AMAZING MAN. SO DISTINGUISHED INVESTIGATOR AND SECTION CHIEF IN THE LABORATORY OF CELLULAR ONCOLOGY HERE AT NIH, AT THE NATIONAL CANCER INSTITUTES. IN HIS 35 YEARS AT NCI, HE HAS STUDIED VARIOUS ASPECTS OF THE PAPILLOMA VIRUS, PLEAK ALREADY BIOLOGY, IMMUNOLOGY AND EPIDEMIOLOGY AND HAS CO-AUTHORED MORE THAN 150 PAPERS. TOGETHER WITH DR. LOWY, DR. SCHILLER LED THE DISCOVERY AND CHARACTERIZATION AND CLINICAL TESTING OF VIRUS-LIKE PARTICLE VACCINES TO PREVENT HPV INFECTIONS THAT CAUSE CERVICAL CANCER AS WELL AS OVER TYPES OTHER TYPES O F CANCERS. HE ALSO HELPED FACILITATE TECHNOLOGY TRANSFER TO POTENTIAL HPV MANUFACTURERS IN DEVELOPING NATIONS. AND HAS WORKED TIRELESSLY ALSO TO TAKE THE LEADERSHIP TO HELP IN THE IMPLEMENTATION OF HPV VACCINE GLOBALLY. HE HAS RECEIVED MANY AWARDS. I WILL JUST CITE A FEW. IN 2007, HE RECEIVED THE GOLD MEDAL AWARD. IN 2014, HE RECEIVED THE NATIONAL MEDAL OF TECHNOLOGY AND INOH OVATION AWARD PRESENTED TO HIM BY PRESIDENT OBAMA. AND IN 2017, HE RECEIVED THE LASKER CLINICAL MEDICAL RESEARCH AWARD. THE COUNTRY'S MOST PRESTIGIOUS AWARD FOR BIOMEDICAL RESEARCH. DR. SCHILLER'S CURRENT INTERESTS INCLUDE BASIC STUDIES OF PAPILLOMA VIRAL ASSEMBLY IN INFECTION, THE DEVELOPMENT OF SECOND GENERATION HPV VACCINES AND VACCINES AND THERAPIES FOR OTHER INFECTIOUS DISEASES AND CANCERS. WHEN I MET WITH DR. JOHN SCHILLER, I WAS NOT ONLY IMPRESSED WITH HIS KNOWLEDGE BUT WITH HIS MODESTY. I FELL IN LOVE WITH HIM, WHAT CAN I SAY, HE'S A WONDERFUL MAN. I ASKED HIM TO TALK NOT ONLY ABOUT HIS RESEARCH BUT IF HE COULD JUST SPEND A FEW MINUTES TO TALK TO YOU ABOUT HOW HE DISCOVERED THE HPV VACCINE WITH THE IDEA THAT HOPEFULLY THIS WILL INSPIRE FUTURE LEADERS IN CANCER PREVENTION. SO THANK YOU VERY MUCH, PLEASE JOIN ME IN WELCOMING DR. JOHN SCHILLER. [APPLAUSE] >> WAIT TO APPLAUSE UNTIL YOU SEE WHAT THE TALK IS ABOUT HERE. WELL, THANKS FOR THE NICE INTRODUCTION. I REALLY APPRECIATE IT. EVEN MORE, I APPRECIATE YOU ALL COMING OUT HERE ON A NASTY DAY TO HEAR ME PONTIFICATE HERE ABOUT HPV VACCINES. SO WHAT I'LL BE TELLING YOU TODAY IS SHOWN ON THIS FIRST SLIDE. THERE REALLY ARE THREE TOPICS. THE FIRST ONE IS TO TELL YOU A LITTLE BIT OF BACKGROUND ABOUT HPV AND ITS ASSOCIATION WITH CANCER. AND THEN TALK TO YOU ABOUT THE DEVELOPMENT OF THE PROPHYLACTIC VACCINES AND SOME OF THE EFFICACY OF THIS VACCINE IN CLINICAL TRIALS. THAT'S REALLY THE SUCCESS PART OF THE TITLE HERE. THEN IN THE END TALK ABOUT THE IMPLEMENTATION ISSUES ASSOCIATED WITH THIS VACCINE, WHICH REALLY PRESENTS THE CHALLENGES AS NOTED ON THIS SLIDE. SO OBVIOUSLY THE REASON WE WANTED TO DEVELOP A VACCINE AGAINST HPV IS BECAUSE IT CAUSES CANCER. A WHOLE LOT OF CANCER. IT'S BEEN ESTIMATED ABOUT 5% OF ALL CANCERS ARE CAUSED AS THEIR INITIAL EVENT IN HPV INFECTION. YOU CAN SEE IN THE WORLDWIDE INCIDENCE, THIS SPECTRUM IS TOM IS DOMINATED BY CERVICAL CANCER. 250,000 SERVE CAN250,000 CERVICAL CANCER D EATHS. ABOUT 70% OF THESE ARE BY ONE OF TWO TYPES, HPV16 AND 18, AND THAT ABOUT 90% OF THE OTHER CANCERS THAT YOU SEE HERE ARE CAUSED BY THESE TWO TYPES. NOW THE DISEASE BURDEN IN THE UNITED STATES IS CONSIDERABLY DIFFERENT THAN WHAT YOU SEE WORLDWIDE. YOU CAN SEE THAT HPV CANCERS IS NOT AS DOMINATED BY CERVICAL CANCER AS IT IS WORLDWIDE, AND THAT'S FOR TWO REASONS. ONE IS WE HAVE A DEFECTIVE CANCER SCREENING PROGRAM FOR CERVICAL CANCER, PAP SCREENING AND MORE RECENTLY HPV DNA-BASED SCREENING WHICH HAS REDUCED THE INCIDENCE OF HPV BY OVER 80%. HPV-CAUSED CERVICAL CANCERS WOULD BE A HORRIBLE BURDEN IN THE UNITED STATES IF IT WEREN'T FOR THESE SCREENING PROGRAMS. THE OTHER REASON IS BECAUSE THERE'S BEEN WHAT'S BEEN CALLED AN EPIDEMIC OF HPV-ASSOCIATED OROPHARYNGEAL CANCERS OVER THE LAST DECADE OR TWO. AND WHAT YOU CAN SEE IS THAT ABOUT TWO THIRDS OF THESE OCCUR IN MEN RATHER THAN WOMEN, AND SO THIS INCREASES THE HPV DISEASE BURDEN ALONG WITH ANAL CANCER IN MEN MORE IN THE EU.D STATES THAN WHAT YOU WOULD FIND INTERNATIONALLY. IT PROVIDES A REASON FOR UPTAKE OF HPV VACCINES IN MEN AS WELL AS WOMEN. NOW JUST TO TELL YOU A LITTLE ABOUT THE VIROLOGISTS, BASICALLY I'M A VIROLOGIST, I'M NOT AN IMMUNOLOGIST OR EPIDEMIOLOGIST. I'LL THROW OUT THESE SORTS OF THINGS, BUT I'M REALLY A VIROLOGIST SO I WANT TO TELL YOU A LITTLE ABOUT THE GENOME AND WHAT THIS VIRUS IS THAT CAUSES THE CANCER. SO IT'S A REALLY SIMPLE SMALL VIRUS, IT'S ONLY GOT ABOUT 10 PROTEIN CODING UNITS, OPEN READING FRAMES, AND ON ONE SIDE, THESE ENCODE THE STRUCTURAL PROTEINS AND THEN THESE OTHER ONES THAT ARE INVOLVED IN REPLICATION AND VARIOUS OTHER ASPECTS, AND TWO GENES, HPV6 AND E7 ARE SELECTIVELY EXPRESS AND RETAINED IN CANCER. WE'VE OVER THE YEARS FOUND OUT THEY DO A WHOLE BUNCH OF STUFF TO POTENTIATE CANCER BUT FOR INSTANCE, TWO MAIN ACTIVITIES IS E6 BINDS INTO GRADES P53, AND E7 BINDS INT O PRB WHICH ARE THESE TWO MAJOR TUMOR SUPPRESSOR GENES THAT ARE OFTENTIMES MUTATED IN NON-HPV-ASSOCIATED CANCERS. NOW THE GENOME IS PACKAGED WITHIN THIS SHELL, AND AGAIN, THE SHELL IS QUITE SIMPLE. IT'S COMPOSED OF ONLY TWO PROTEINS. THE L1 MAJOR CAPSID PROTEIN OF WHICH THERE ARE 70 OF THESE BEULT BEAUTIFUL STAR SHAMED PENTAMERS, AND YOU CAN SEE WHERE IT SORT OF FITS IN IN THIS HOLLOWED OUT SHELL AND THAT SURROUNDS THE CHROME ADVERTISED CHROMA IT TIZED GENOME. THE VIRUS LIFE CYCLE IS QUITE UNIQUE IN THAT THE ONLY PLACE IT CAN REPLICATE IS IN A STRATIFIED SQUAMOUS EPITHELIUM, A MULTI-LAYERED EPITHELIUM, AND IT NEEDS TO GET INTO THE BASAL LAYER, THIS LAYER AT THE BOTTOM, BY BINDING TO THE BASEMENT MEMBRANE IN A PROCESS THAT WE'VE ACTUALLY STUDIED QUITE A BIT BUT I WON'T GO INTO. THEN IT'S TRICKY BECAUSE IT EXPRESSES VERY SMALL LEVELS OF THESE PROTEINS THAT ARE REQUIRED FOR EP SOMOL MAINTENANCE AND REPLICATION, AND THEN THESE VERY IMMUNOGENIC VIRIONS, THEY ONLY MAKE DIFFERENTIATED EPITHELIAL CELLS WHERE THEY AREN'T UNDER CLOSE SURVEILLANCE AND SHARE THEIR VIEWER EU LENS IN THESE SQUAMES. NOW ALTHOUGH IT CAN ONLY MAKE A PRODUCTIVE INFECTION, IT'S ACTUALLY KIND OF INTERESTING THAT MOST OF THE CANCERS ACTUALLY DON'T ARISE IN STRATIFIED SQUAMOUS EPITHELIUM. FOR INSTANCE, HPV INFECTION IS VERY COMMON IN THE VAGINAL TRACT BUT VAGINAL CANCERS ARE RELATIVELY UNCOMMON. WHEREAS CERVICAL CANCERS ARE VERY COMMON. WHY IS THAT? IT'S BECAUSE THERE'S A PREDILECTION FOR THESE INFECTIONS TO GO ON TO CANCER IN AN AREA CALLED THE TRANSFORMATION ZONE, WHERE THERE'S A JUXTAPOSITION OF SIMPLE COLUMNAR EPITHELIAL AND STRATIFIED SQUAMOUS EPITHELIAL. THERE'S VERY SPECIAL SPECIALIZED CELLS, EMBRYO LOGICAL TYPES OF CELLS IN THIS REGION, WE DON'T KNOW EXACTLY WHY THEY'RE HIGHLY SUSCEPTIBLE TO CARCINOGENIC PROGRESSION BUT THE FACT IS THAT MOST CERVICAL AND ALSO ANAL CANCERS ARISE AT THE SCWAI MALL-COLUMNAR JUNCTION. SO THIS IS THE TIMELINE BETWEEN THE HPV INFECTION AND THE DEVELOPMENT OF CERVICAL CANCER. SO INFECTIONS ARE VERY COMMON SOON AFTER SEXUAL ACTIVITY BEGINS, AND LIFETIME INCIDENCE OF GENITAL HPV INFECTION IN THE UNITED STATES IS OVER 80%. SO HAVING A GENITAL HPV INFECTION SOMETIME IN YOUR LIFE IS ALMOST SYNONYMOUS WITH BEING SEXUALLY ACTIVE, BUT FORTUNATELY FOR US, ALMOST ALL THESE INFECTIONS CLEAR AND PRESUMABLY BY IMMUNOLOGICAL MECHANISMS AND THEN THIS ELIMINATES THE RISK OF CANCER. IT'S NOT CLEAR WHETHER YOU CLEAR THEM OR HAVE A LATENT INFECTION BUT IF YOU DO GO TO THE LATENCY, THE CHANCES OF IT GOING TO CANCER SEEM RELATIVELY LOW. BUT PERSISTENT INFECTION BUT AN ONCOGENIC HPV TIME TYPE IS THE CRITICAL RISK FACTOR FOR PROJECTION TO CANCER. PRE-CANCER DEVELOPS -- PEAKS ABOUT A DECADE AFT INITIAL PEAK OF INFECTION AND THEN CANCER REALLY STARTS TO BE MUCH MORE PREVALENT ABOUT TWO DECADES OR THREE DECADES AFTER INITIAL INFECTION. SO IT'S A SLOW PROCESS THAT CAN BE INTERVENED WITH SCREENING. JUST TO SHOW HOW OFTEN AND RAPIDLY ACQUISITION IS ACQUIRED, THIS SHOWS SUPERVISOR POSITION OF TWO DATA, UNITED STATES AND U.K. OF CUMULATIVE RISK OF GETTING AN HPV, GENITAL HPV INFECTION AFTER SEXUAL DEBUT. WHAT YOU CAN SEE, ALMOST 50% OF YOUNG WOMEN GET AN HPV INFECTION WITHIN TWO YEARS OF SEXUAL DEBUT. THIS IS REALLY THE REASON WHY WHEN WE TALK ABOUT VACCINATION, WE TALK ABOUT VACCINATION PRE-ADOLESCENCE BECAUSE ONCE YOU BECOME SEXUALLY ACTIVE, THE CHANCES OF BEING INFECTED GO UP VERY RAPIDLY. NOW IT'S KIND OF IRONIC THAT WE'RE RYING TO DEVELOP THIS HPV VACCINE FOR THE CANCER THAT WE PROBABLY ARGUABLY HAVE THE BEST SCREENING PROGRAM FOR ALREADY. IT WOULD BE WAY BATTER IF THIS VACCINE WERE FOR A CANCER WE'RE& NOT ALREADY DOING A PRETTY GOOD JOB OF CONTROLLING BUT IT'S IMPORTANT TO POINT OUT THAT CURRENT PAP OR HPV DNA SCREENING IS WHAT WE CALL SECONDARY PREVENTION, THAT IT TARGETS ADULT WOMEN, AND INFECTION OCCURS, IF IT'S NOT CLEARED, AT LEAST ABNORMALITIES, CYTOLOGICAL ABNORMALITIES WHICH THEN LEADS TO A FOLLOW-UP EVENTUALLY REQUIRING ABLATIVE THERAPY IF PRECANCEROUS DISEASE IS IDENTIFIED. WHEREAS HPV VACCINATION IS PRIMARY PREVENTION. WE REMOVE THE INITIATING FACTOR IN THE DEVELOPMENT OF THIS CANCER. YOU AVOID ALL THESE OTHER THINGS AND THE EXPENSE OF THIS IN THE TRAUMA ASSOCIATED WITH ALL OF THIS. NOW OF COURSE THE PROBLEM WITH THIS TYPE OF PREVENTION IS THE WOMAN WHO'S PROTECTED FROM GOING THROUGH ALL THIS AND GETTING CANCER DOESN'T KNOW SPECIFICALLY THAT SHE WAS PROTECTED. OKAY? IT'S A SILENT BENEFIT. NOW MOVING ON TO THE VACCINES, SO THE VACCINES ARE SOMETHING THAT WE FIRST STARTED WORKING ON IN 1992, WHERE DOUG LOWY AND I THOUGHT THAT HAVING BEEN STUDYING HOW THE VIRUS CAUSED CANCER, THAT WE COULD MAYBE DO SOMETHING. SO WE DECIDED THAT MAYBE WE WOULD TRY TO MAKE A VACCINE BASED UPON THE OUTER SHELL OF THE VIRUS AND SEE WHETHER THIS ONE MAJOR PROTEIN, L1, COULD SELF-ASSEMBLE. WHAT EVENTUALLY THIS LED TO IS THREE COMMERCIAL VACCINES THAT ARE BASED UPON THIS TECHNOLOGY. L1 VIRUS-LIKE PARTICLES THAT ESSENTIALLY MIMIC THE OUTER SHELL OF THE VIRUS, BOTH IN TERMS OF HOW THEY LOOK MORE OF LOGICALLY BUT MORE IMPORTANTLY, WHEN YOU INJECT IT INTO AN ANIMAL OR LATER INTO A HUMAN, IT INDUCES A WHOLE LOT OF ANTIBODIES THAT THEN RECOGNIZE THE REAL VIRUS DURING INFECTION AND PREVENT THAT INFECTION FROM OCCURRING. I HAVE TO SAY WHEN WE FIRST DEVELOPED THIS TECHNOLOGY, THERE WAS A LOT OF SKEPTICISM AS TO WHETHER THIS COULD WORK. THAT WAS PROBABLY AS MUCH OR MORE SKEPTICISM THAT HPV BASED UPON THIS TECHNOLOGY COULD WORK AT THAT TIME THAN IT IS THAT AN HPV VACCINE COULD BE EFFECTIVE SO WE WILL TO TALK TO A WHOLE LOT OF DIFFERENT DRUG COMPANIES BEFORE FINALLY A COUPLE, MERCK AND GSK, AGREED TO TRY TO MOVE FORWARD AND SPENT HUNDREDS OF MILLIONS OF DOLLARS TO SEE IF THIS IDEA WAS CORRECT. AND WHAT YOU CAN SEE IS THAT ONE -- THE FIRST VACCINE CONTAINS THE LPs OF 16 AND 18 WHICH AGAIN CAUSE 70% OF CERVICAL CANCER, WHEREAS THE ORIGINAL GARDASIL IS QUADRA VALENT, 6 AND 11 WHICH CAUSE ABOUT 90% OF GENITAL WARTS BUT RARELY, IF EVER, CAUSE CANCER, SO IT'S REALLY FIGHTING TWO DIFFERENT DISEASES. THE VACCINES ARE DEVELOPED BY THREE -- WERE ORIGINALLY DEVELOPED FOR THREE INTRAMUSCULAR INJECTIONS OVER SIX MONTHS. MORE RECENTLY THERE'S BEEN A DEVELOPMENT OF GARDASIL 9, WHICH INCLUDES FIVE ADDITIONAL ONCOGENIC TYPES. NOW IN ADDITION TO VARYING IN TERMS OF THE NUMBER OF VLP TYPES, THE VACCINES ALSO VARY IN THE ANL VANT, THE IMMUNOSTIMULATORY COMPOUND. SO THE GARDASIL VACCINES CONTAIN THE TRADITIONAL ALUMINUM SALT ADJUVANTS WHEREAS CERVARI IM. CONTAINS A SPECIAL ADJUVANT THAT CONTAINS A TLR AGONUS THAT BINDS TO TLR4, IT'S A DETOX FIED FORM OF LPS, AND IT'S THE FIRST TIME THAT THIS TYPE OF ADJUVANT HAS BEEN FDA-APPROVED FOR A PROPHYLACTIC VACCINE. VACCINES ALSO DIFFER IN THEIR PRODUCTION SYSTEMS ALTHOUGH IT'S NOT CLEAR WHETHER THAT MAKES MUCH DIFFERENCE. THIS SLIDE SHOWS YOU THE TIMELINE OF DEVELOPING THE VACCINES VERSUS THE TIMELINE FOR UNDERSTANDING OF ITS ASSOCIATION WITH CANCER. IT'S REALLY IMPORTANT THAT THESE TWO THINGS DEVELOPED CHRONOLOGICALLY OR SUCCESS PHILADELPHIA BECAUSE WE DIDN'T HAVE THIS UNDERSTANDING OF CANCER CAUSATION, WE WOULDN'T HAVE BEEN ABLE TO DEVELOP THE VACCINES. AND SO FIRST LOOKING AT THE TOP, IT WAS ANOTHER 10 YEARS BEFORE WE FIRST PRODUCED THE VLPs, AND DURING THESE EIGHTIES AND 90s, THERE WAS A WHOLE SERIES OF CASE CONTROL AND PROSPECTIVE EPIDEMIOLOGICAL STUDIES AND ALSO EPIDEMIOLOGICAL STUDIES WHICH ARE THE KIND OF STUDIES DOUG AND I WERE INVOLVED WITH, THAT THEN SHOWED BEYOND ANY REASONABLE DOUBT, HPV WAS CONSIDERED TO BE A NECESSARY CAUSE OF CERVICAL CANCER. IT'S THE FIRST TIME AN AGENT HAS BEEN DESIGNATED TO BE ESSENTIALLY A NECESSARY CAUSE SO IT DOESN'T TAKE MUCH OF A SCIENTIST TO FIGURE FOUGHT THIS IS A NECESSARY CAUSE AND YOU PREVENT THE INFECTION, THEN YOU'LL PREVENT CERVICAL CANCERMENT ON THIS TIMELINE, THIS LED TO ANIMAL STUDIES AND FIRST CLINICAL TRIALS, AND WHICH ACTUALLY COINCIDED ABOUT THE TIME THAT HPV WAS DECLARED TO BE A NECESSARY CAUSE OF CANCER, AND THEN FINAL LICENSURE OR INITIAL LICENSURE IN 2006 IN FEMALES IN 2009. SO YOU CAN SEE THAT THIS WHOLE TIMELINE SPANS ABOUT 15 YEARS A LOT OF YOU ARE INTERESTED IN CANCER PREVENTION. DON'T GET INVOLVED IN CANCER PREVENTION WHEN YOU'RE 60, OKAY? GET INVOLVED WHEN YOU'RE FAIRLY YOUNG . TO GIVE YOU THE SORT OF IDEA OF LENGTH OF TIME IT TOOK TO DEVELOP THE VACCINE, IT'S A LITTLE BIT OF A PERSONAL STORY. SO YOU SEE THAT BUDDHA BABY ON THE LEFT? THAT'S MY DAUGHTER, WHO WAS BORN THE YEAR THAT WE DEVELOPED -- WE FIRST MADE THE INITIAL OBSERVATION THAT VLPs COULD DEVELOP INTO VIRUS-LIKE PARTICLES AND INDUCE NANOBODIES IN AN ANIMAL MODEL. THE GIRL ON THE LEFT, THAT'S MADELEINE RECEIVING HER FIRST DOSE OF HPV VACCINE, ME HOLDING HER HAND AS A BEAUTIFUL YOUNG ADOLESCENT GIRL. AND THAT'S THE TIME THAT IT TOOK TO DEVELOP THIS VACCINE. SO THOSE OF YOU WHO ARE INTO CANCER PREVENTION, BE IN IT FOR THE LONG HAUL, BECAUSE YOU'RE GOING TO NEED TO BE IN IT FOR THE LONG HAUL. SO ONE OF THE REASONS WHY IT WAS SO IMPORTANT TO UNDERSTAND THE NATURAL HISTORY OF HPV IN ASSOCIATION WITH CANCER IS BECAUSE WE COULDN'T USE CANCER AS AN END POINT IN THE CLINICAL TRIAL. OBVIOUSLY WE WANTED THE FDA TO SAY THIS VACCINE IS GOING TO PREVENT CANCER, BUT YOU CAN'T USE CANCER AS AN END POINT BECAUSE ONE THING, THE TRIALS WOULD HAVE TO BE 20 OR 30 YEARS, WHICH WOULD BE MUCH TOO LONG, AND SECONDLY, IN TRIALS WITH ACTIVE FOLLOW-UP, WE IDENTIFIED PREMALIGNANT LESIONS BY PAP SCREENING AND WE HAVE TO REMOVE THEM SO WE CAN'T LET ANYBODY GET CANCER. FORTUNATELY FOR US, WE UNDERSTOOD THAT THE NECESSARY PRECURSOR LESIONS FOR CANCER WERE HIGH GRADE DYSPLASIAS, ESPECIALLY CIN 3. THE FDA AGREED BECAUSE WE HAD THIS KNOWLEDGE IN HOW THESE LESIONS DEVELOP, THAT WE COULD USE AS A PRIMARY END POINT IN THE INITIAL PHASE 3 TRIALS PREVENTION OF CIN 2 AND CIN 2-# AS AN END POINT FOR LICENSURE FOR PREVENTION OF CANCER. AND TO MAKE A LONG STORY SHORT, THE VACCINES WORKED AWESOME AT PREVENTING THIS END POINT. YOU CAN SEE HERE THAT BOTH VACCINES PREVENTED 100% OF HIGH GRADE DYSPLASIAS. IF YOU LOOK AT, IF YOU RESTRICT THE ANALYSIS TO THE TYPES TARGETED BY THE VACCINE, NOT ALL TYPES, AND IN WOMEN WHO DIDN'T HAVE THOSE INFECTIONS AT THE TIME OF VACCINATION. THAT'S THE PER-PARTICLE PROTOCOL POPULATION. NO GENITAL HPV DETECTED AT ENTRY. GARDASIL, WHICH AGAIN CONTAINS 16-11, SO IT ATTACKS GENITAL WARTS, ALSO HAD A HIGH EFFICACY AGAINST GENITAL WARTS. SO THE EFFICACY AGAINST ANAL INTRAEPITHELIAL NEOMALACIA AND GENITAL WARTS IN MEN LOOK LIKE IT'S SOMEWHAT LESS. WE ACTUALLY DON'T FEEL LIKE THE VACCINE IS LESS EFFECTIVE IN MEN. THE IMMUNE RESPONSE, AS I'LL GO INTO A LITTLE BIT, IS THE SAME IN MEN AS IT IS IN WOMEN, BUT THE REASON WHY WE THINK THE EFFICACY LOOKS LOWER IS THAT WE MISS MORE PREVALENT INFECTION ON THE MALE GENITALIA WHEN YOU WERE TRYING TO DETECT IT THAN AT THE FEMALE IN A CERVIX. SO THAT'S WHY IT LOOKS LIKE IT'S NOT QUITE AS EFFECTIVE. NOW JUST TO GET INTO GARDASIL 9, WHICH IS INCIDENTALLY THE ONLY VACCINE THAT'S NOW CURRENTLY AVAILABLE IN THE UNITED STATES, THERE WAS AN ISSUE WHEN YOU DID THE CLINICAL TRIALS ON GARDASIL 9 BECAUSE THERE WERE TWO EFFECTIVE VACCINES THAT WERE ALREADY ON THE MARKET. AND SO IT WAS CONSIDERED UNETHICAL TO DEPRIVE PEOPLE IN A TRIAL OF THOSE VACCINES. AND SO WE COULDN'T HAVE A PLACEBO-CONTROLLED TRIAL SO WHAT MERCK DID IS THEY COMPARED GARDASIL 9 TO GARDASIL 4, THE ORIGINAL GARDASIL. AND THE END POINTS WERE TO SHOW PROTECTION AGAINST THE FIVE NEW TYPES AND IT WORKED VERY WELL PREVENTING 96% EFFICACY AGAINST THE NEW TYPES IN COMPARISON TO GARDASIL 4 AND THEY HAD TO SHOW THAT THE ANTIBODIES TO THE ORIGINAL FOUR TYPES WERE NOT INFERIOR, THAT IF YOU ADDED THESE NEW TYPES, IT DIDN'T AFFECT THE ANTIBODY RESPONSE AND IT MET BOTH THESE CRITERIA. SO IF YOU JUST LOOK AT TYPE-SPECIFIC PROTECTION, GARDASIL 4 WOULD PROTECT AGAINST ABOUT 90% OF CERVICAL CANCERS, 70%, WHEREAS IF YOU ADD THESE NEXT FIVE TYPES, YOU'RE ALMOST UP TO 90%. NOW IN ADDITION TO PROTECTING AGAINST CERVICAL, AND I GAVE YOU A LITTLE BIT OF INFORMATION ABOUT ANAL INTRAEPITHELIAL NEOMALACIA, THERE'S ALSO SOME DATA IT PROTECTS GO AGAINST VAGINAL AND VULVAR INTRAEPITHELIAL NEOMALASIA. PENILE LESIONS ARE RELATIVELY RARE ALTHOUGH CANCERS ARE QUITE COMMON, IN PART BECAUSE WE DON'T HAVE THOSE TRANSFORMATION ZONE ISSUES, AND SO THERE'S NO DATA FOR THAT. OROPHARYNGEAL, AGAIN, THERE'S BEEN THIS EPIDEMIC SO WE'RE VERY INTERESTED IN OROPHARYNGEAL CANCER BUT THE PREMALIGNANT LESIONS HAVE NOT EVEN BEEN IDENTIFIED, THEY'RE PROBABLY LOST SOMEPLACE DOWN IN THE DON'S LAR CRYPTS SO WE DON'T EVEN KNOW WHAT THE LESIONS ARE SEW WE CAN'T IDENTIFY THEM AND SHOW THAT YOU GET PROTECTION. THERE'S PRELIMINARY EVIDENCE THAT THE VACCINES DO PREVENT ACQUISITION OF INFECTION IN OROPHARYNGEAL TISSUES. ONE THING I THINK WE HAVE TO STOP DOING IS THINKING OF THE HPV VACCINE AS THE NEW KID ON THE BLOCK. THERE ARE STILL PEOPLE WHO SAY THIS IS A NEW VACCINE, I'M GOING TO WAIT A WHILE BEFORE I VACCINATE MY KIDS, AND ACTUALLY, IT'S BEEN ON THE MARKET FOR 12 YEARS, LICENSED IN 82 COUNTRIES, AND THERE'S OVER 280 MILLION DOSES THAT HAVE BEEN GIVEN AND I'LL GO OVER THE SAFETY RECORD OF THE VACCINE BASED UPON THAT ANALYSIS IN A FEW MINUTES. NOW WE THINK HOW DOES THIS VACCINE WORK? WE THINK WHAT IT DOES IS, AS I'VE MENTIONED, IS THAT IT INDUCES ANTIBODIES. THESE ANTIBODIES FLOAT AROUND AND PREVENT INITIAL INFECTION EVENT BECAUSE WE THINK WE'RE GETTING STERILIZING IMMUNITY, WE NEVER GET INFECTION. IT'S NOT LIKE YOU GET INFECTION THEN IT GOES AWAY BECAUSE EVEN BY SENSITIVE PCR TESTS, WHEN YOU SCREEN WOMEN IN THE TRIALS, THEY& NEVER TEST POSITIVE FOR THE MOST PART FOR THE HPV. THE INTERESTING THING IS THAT WHEN WE GET WHAT YOU CALL BREAK-THROUGH INFECTIONS, WHERE WOMEN DO TEST POSITIVE, MOST OF IT HAPPENS AT THE BEGINNING OF THE TRIAL. THE LONGER WE'VE GONE OUT NOW TO EIGHT OR 12 YEARS, PROTECTION GETS BETTER AND BETTER AS WE GO OUT. WHY WOULD IT BE BETTER AFTER A WHILE THAN AT THE BEGINNING? THE OBVIOUS ANSWER IS THAT WHAT WE'RE DETECTING EARLY ON ARE EMERGENCE OF PREVALENT INFECTION THAT WE JUST MISSED IN THE INITIAL SCREEN. IT WAS THERE, AND WE JUST MISSED IT AND NOW IT EMERGES. ONE OF THE THINGS ABOUT THIS VACCINE IS THAT IT DOES NOT INDUCE CLEARANCE OF PRE-EXISTING LESIONS OR PREVENT PROGRESSIONS OF LESIONS ONCE THEY OCCUR. THIS HAS BEEN SEEN WITH BOTH VACCINES. THAT IF YOU HAVE AN INFECTION, IT'S NOT GOING TO MAKE IT GO AWAY. THAT'S WHY IT'S IMPORTANT TO BE VACCINATED EARLY, BEFORE YOU HAVE YOUR INFECTIONS. AND THE OTHER THING IT DOESN'T DO IS IT DOESN'T PROTECT AGAINST MOST HETEROLOGOUS HPV TYPES THAT AREN'T TARGETED. WE CALL THE VACCINE NOP TYPE-SPECIFIC BUT TYPE-RESTRICTED. THAT'S ONE OF THE REASONS WHY GARDASIL 9, THEY ADDED ALL THESE OTHER TYPES. BECAUSE IT WASN'T PROTECTING AGAINST THEM BUT WITH THE ORIGINAL VACCINE. CONTRARY TO WHAT YOU MIGHT READ ON THE INTERNET BY GOING HPV AND VACCINE SAFETY, IT ACTUALLY HAS AN EXCELLENT SAFETY RECORD. SO IT IS CLEAR THERE'S LOW GRADE AND TRANSIENT INJECTION-SITE PAIN LIKE ANY KIND OF INTRAMUSCULAR INJECTION THAT YOU GET. IF THERE ARE SYSTEMIC REACTIONS LIKE A LITTLE RAISE IN TEMPERATURE OR SOMETHING, THEY'RE MILD AND SELF-LIMITING. . SO BOYS AND GIRLS DO FAINT WHEN THEY GET THIS VACCINE BUT THAT'S ACTUALLY TRUE OF ANY OTHER VACCINE THAT YOU GIVE WITH A NEEDLE SO IT'S REALLY NEEDLE FEAR THAT'S CAUSING THE FAINTING, NOT ANYTHING THAT YOU'RE PUTTING IN TO THE PEOPLE SO THAT'S WHY IT'S REALLY IMPORTANT TO ADMINISTER THE VACCINE THAT THE KIDS SIT DOWN FOR 15 MINUTES TO MAKE SURE THAT THEY'RE NOT GOING TO FAINT. IMPORTANTLY THERE'S NO PATTERNS OF SERIOUS ADVERSE EVENTS IN TRIALS OR POST LICENSURE SURVEILLANCE THAT SUGGEST A CAUSAL RELATIONSHIP WITH THE VACCINE, AND THIS HAS ACTUALLY BEEN LOOKED AT QUITE EXTENSIVELY IN A NUMBER OF DIFFERENT COUNTRIES. THERE'S NOTHING THAT LOOKS LIKE THERE'S A MARK FOR A SPECIFIC SERIOUS ADVERSE EVENT. NOW IT IS TRUE THAT CERTAIN NUMBER OF GIRLS GET VACCINATE VACCINATED THEN WALK OUT IN FRONT OF A BUS SO THERE'S ALWAYS GOING TO BE A SITUATION WHERE THERE'S GOING TO BE A TEMPORAL RELATIONSHIP WITH AN ADVERSE EVENT BUT TEMPORALITY DOES NOT NECESSARILY MEAN CAUSATION, BUT IT'S HARD IF SOMETHING HAPPENS SOON AFTER VACCINATION NOT TO MAKE THAT ASSOCIATION. NOW WHAT I TALKED ABOUT BEFORE WAS CALLED VACCINE EFFECTIVENESS. VACCINE EFFICACY. I EVEN GET THEM CONFUSED. VACCINE EFFICACY IS WHAT YOU MEASURE IN A CONTROLLED CLINICAL. EFFECTIVENESS IS WHAT YOU SEE IN GENERAL USE, LIKE IN THE NATIONAL IMMUNIZATION PROGRAM. THERE'S GETTING TO BE MORE AND MORE DATA COMING OUT, ALMOST EVERY WEEK THERE'S ANOTHER STUDY THAT SAYS THESE VACCINES REALLY ARE EFFECTIVE IN GENERAL USE. THIS JUST SHOWS THAT THE TYPES OF DATA WE HAVE IS PROTECTION FROM INFECTION, GENITAL WARTS, AND ALSO CERVICAL LESIONS IN FEMALES. AND ITLE COMING -- THIS IS JUST SORT SORT OF SOME OF THE COUNTRIES WHICH IT'S COMING FROM. I'M GOING TO SHOW YOU A EXAMPLES, REPRESENTATIVE OF THE TYPE OF DATA THAT WE'RE NOW SEEING IN NATIONAL IMMUNIZATION PROGRAMS. SO THIS SHOWS DATA FROM ENGLAND WHERE THEY WERE USING CERVARIX, THE VACCINE THAT HAS A LITTLE BIT STRONGER ADJUVANT. AND IN THE PRE-VACCINATION ERA, LET'S JUST LOOK AT THE 16 TO 18-YEAR-OLDS, YOU CAN SEE THAT THE RATE OF HPV PREVALENCE FOR 16 AND 18 WAS ABOUT 18%. TWO OR THERE' YEARS LATER WHEN 60% OF THIS POPULATION WAS VACCINATED, IT HAD DROPPED 52%, AND BY YEAR FOUR OR FIVE WHEN 73% WAS VACCINATED, THERE WAS A 76% VACCINATION IN THE ENTIRE POPULATION. THIS ISN'T RESTRICTED TO THOSE WHO HAVE THE VACCINE. SO YOU CAN SEE IT'S WORKING QUITE WELL AT THE LEVEL OF INFECTION. THIS IS DATA FROM GARDASIL IN AUSTRALIA, WHERE THEY LOOK AT INTERMEDIATE AND HIGH GRADE DYSPLASIA. YOU CAN SEE IN THE WOMEN WHO WEREN'T BEING VACCINATED, THERE WAS NO CHANGE IN THE RATES OVER TIME. THIS DOTTED LINE IS WHEN THEY STARTED VACCINATION. IN THE UNDER 18-YEAR-OLDS PART OF THE VACCINATION PROGRAM, YOU CAN SEE THERE'S A VERY RAPID DECLINE IN THE RATES OF HIGH GRADE DISPLAY IS DYSPLASIA, AND IT LOOKS LIKE THERE ARE STARTING TO BE SOME IN THE SLIGHTLY OLDER GROUP AS THEY BECOME PART OF THE VACCINATED COHORT. DOES IT PREVENT CERVICAL CANCER? THAT'S REALLY WHAT WE WANT TO SEE. I TOLD YOU THAT CERVICAL CANCER GENERALLY TAKES DECADES. THERE ARE A CERTAIN AMOUNT OF EARLY ONSET CERVICAL CANCERS, SO IN THE UNITED STATES AND ELSEWHERE, PEOPLE ARE LOOKING TO SEE WHETHER THERE'S ANY SIGNAL THAT WE'RE ACTUALLY PREVENTING CANCER. THIS IS THE FIRST DATA THAT'S COME OUT IN THE EU.D STATES. IT'S JUST COME OUT. AND WHAT IT SHOWS IS THAT IF YOU LOOK AT THE ANNUAL RATE OF CERVICAL CANCER IN U.S. WOMEN, AND THIS IS THE GROUP OF YOUNG WOMEN WHO PRESUMABLY HAD A REASONABLE CHANCE OF BEING VACCINATED, YOU CAN SEE IN THE DATA THEY SAY THERE'S AN INFLECTION POINT IN ABOUT 2009, 2010, AND THE VACCINATION PROGRAM STARTED IN 2006, 2007. AND SO IS THIS DROP DUE TO THE HPV VACCINE? IT'S QUITE LIKELY THAT IT IS, BUT I STILL PUT A QUESTION MARK HERE BECAUSE WE'RE NOT SURE, BUT OBVIOUSLY WE'RE GOING TO HAVE TO LOOK AND SEE IF THIS TREND DECREASES, BUT IT IS A STATISTICALLY SIGNIFICANT 29% DECREASE BETWEEN THIS LATTER TIME AND THE TIME PRE-VACCINATION. SO I THINK THIS IS A VERY ENCOURAGING TREND AS WE GO FORWARD TO HOPEFULLY SEE REAL DECREASES IN CERVICAL CANCER RATES. SO WHY IS THE VACCINE SO GOOD AT PREVENTING INFECTIONS, PREMALIGNANT DISEASES AND HOPEFULLY CANCERS? THIS IS SOMETHING THAT I'M REALLY EXCITED AND I LIKE TO TALK ABOUT AND OFTENTIMES MY WHOLE LECTURE IS ABOUT THIS IF I'M TALKING TO IMMUNOLOGISTS AND VIROLOGISTS BUT YOU'RE CANCER PREVENTION PEOPLE SO I'M ONLY GOING TO GIVE YOU A BRIEF KIND OF INTRODUCTION TO WHY IT WORKS SO WELL. THIS SLIDE GIVES THE MAIN REASON. IT'S BECAUSE ESPECIALLY IF YOU LOOK IN THE YOUNG PEOPLE TARGETED BY VACCINATION, IT'S INCREDIBLY GOOD AT INDUCING DURABLE ANTIBODY RESPONSES. SO THE ANTIBODY RESPONSES GO UP AND RATHER THAN CONTINUING TO GO DOWN LIKE TETANUS VACCINES, THEY STABILIZE. THIS IS THE TYPE OF IMMUNE RESPONSE YOU'D EXPECT AFTER HAVING A LIVE INFECTION, NOT A SUBUNIT VACCINE. SO THIS IS VERY UNEXPECTED THAT YOU GET THE STABILIZATION, A PLATEAUING OF THE AND BODY RESPONSE. SO WHY IS THIS HAPPENING? THERE ARE SEVERAL REASONS. BUT THE MAIN THING IS WE THINK IT HAS TO DO WITH THE STRUCTURE OF THE IMMUNOGEN THAT WE'RE USING. MOST SUBUNIT VACCINES ARE SIMPLE COMPOSED OF A SINGLE OR A FEW LITTLE SUBUNITS. WHEN THEY BIND, THE B CELERY ACCEPTORS, WHICH ARE JUST ANTIBODIES BOUND TO THE SURFACE AND IEB CELLS, YOU GET A RELATIVELY WEAK ACTIVATION SIGNAL, RELATIVELY LOW ANTIBODIES THAT GO AWAY. ABOUT YOU IN CONTRAST, WHEN THE B CELLS SEE SOMETHING THAT LOOKS LIKE THE OUTER SHELL OF A REAL VIRUS, IT GETS SPECIFICALLY ACTIVATED BY LIGAMERRIZATION OF THESE B CELERY CELL RECEPTORS THROUGH STRONG SIGNALING THAT LEAD TO HIGH LEVELS OF ANTIBODIES IN LONG DURATION. SO WE THINK THIS IS REALLY KEY TO INDUCING LONG-LIVED ANTIBODY RESPONSES WHICH ARE GENERATED BY WHAT'S CALLED PLASMA CELLS, WHICH HOME TO YOUR BONE MARROW AND KICK OUT ANTIBODIES THE REST OF YOUR LIFE, EVEN IN THE ABSENCE OF FURTHER EXPOSURE TO ANTIGEN. WE KNOW THIS CAN OCCUR UP TO REAL VIRUS INFECTION AND WHAT THIS SAYS IS WHAT'S REALLY KEY TO REAL VIRUS INFECTION IS NOT BECAUSE IT'S INFECTION, BUT YOU GET EXPOSED TO REAL VIRUS PARTICLES AND THIS MIMICS THE REAL VIRUS PARTICLES. I COULD GO ON AND ON ABOUT THIS BUT WE HAVE TO MOVE. SO NOW LET'S GET INTO THE LITTLE DARKER SIDE OF THINGS. WHICH IS IMPLEMENTATION. WHICH I AM NOT AN IMPLEMENTATION SCIENTIST, I HAVE TO TELL YOU THIS. I'M A BASIC MOLECULAR BIOLOGIST, VACCINOLOGIST, BUT I'M NOT AN IMPLE ANIMPLEMENTATION SCIENTIST SO YOU CAN'T BLAME ME. LET'S LOOK AT WHAT HAPPENS TO CERVICAL CANCER IF THERE'S NO VACCINE. SO RECENTLY IT'S BEEN ESTIMATED THAT IN A NON-VACCINE SCENARIO, WE CAN EXPECT OVER THE NEXT 65 YEARS, 19 MILLION CASES AND 10 MILLION DEATHS FROM CERVICAL CANCER. AND THE MAJORITY OF THESE ARE GOING TO OCCUR IN LOWER, MIDDLE AND LOWER INCOME COUNTRIES. SO WHAT HAVE WE DONE SO FAR? SHOULD WE BE PROUD ABOUT OUR ACCOMPLISHMENTS? SO FAR WITH HPV VACCINATION, IT'S PROJECTED WE WILL HAVE PREVENTED APPROXIMATELY -- LESS THAN 400,000 CASES AND 150,000 DEATHS. IF YOU LOOK IN THE STRIPE WHERE THESE CASES HAVE BEEN PREVENTED, THEY'RE ALMOST ENTIRELY IN HIGHER INCOME AND TO SOME EXTENT UPPER MIDDLE INCOME COUNTRIES. WE'VE BARELY MADE ANY DENT WHATSOEVER WITH CURRENT PROGRAMS IN ALLEVIATING SUFFERING FROM CANCER, CERVICAL CANCER, IN LOW RESOURCE SETTINGS. AND IT'S NOT JUST IN LOW RESOURCE SETTINGS THAT WE'RE DOING POORLY. EVEN IN THE UNITED STATES, WHICH IS FAR FROM BELOW RESOURCE SETTING, WE'RE STILL NOT DOING VERY WELL. SO IF YOU LOOK AT THE UPTAKE RATES, THIS IS IN GIRLS, UPTAKE RATES IN BOYS ISN'T AS GOOD, 13 TO 17, YOU CAN SEE TWO OTHER VACCINES THAT ARE GIVEN TO ADOLESCENTS, THE TDAP, WHICH IS TETANUS, DIP TIER TIER -- AT THE SAME VISI T, THESE KIDS SHOULD BE GETTING THE HPV VACCINE. AND OBVIOUSLY A LOT OF THEM ARE NOT. EVEN THE ONE DOSE RATE IS MUCH LOWER. NOT TO EVEN TALK ABOUT THE THREE-DOSE RATE. SO WHAT ARE WE GOING TO DO TO TRY TO INCREASE THE RATE OF UPTAKE IN THE UNITED STATES, AND PARTICULARLY WORLDWIDE? IT'S IMPORTANT TO NOTE THAT BOTH MERCK AND GSK ARE COMMITTED TO SALE TO GAVI, WHICH BUYS VACCINE FOR DISTRIBUTION TO THE 72 POOREST COUNTRIES IN THE WORLD AT $5 A DOSE, BUT EVEN AT $5 A DOSE, THIS IS STILL MORE THAN THE WHOLE EPI VACCINE SCHEDULES THAT THESE PEOPLE ARE GETTING. TO TOP THAT, THERE'S A CURRENT SHORTAGE, SO MERCK HAS NOT BEEN ABLE TO KEEP UP WITH DEMAND FOR THE VACCINE. IT IS INCREASING, AND ALTHOUGH THERE'S BEEN A LOT OF PROMISES TO HAVE A LOT OF VACCINE, THERE ACTUALLY IS A SHORE STAJ SHORTAGE INTERNATIONALLY. SO ONE OF THE SOLUTIONS, AND WEE WORKING HARD ON THIS, IS TO DEVELOP VACCINE MANUFACTURING IN EMERGING COUNTRIES. AND THIS IS MOVING FORWARD ACTUALLY RELATIVELY FAST, PARTICULARLY IN INDIA AND CHINA. AND THE FIRST EMERGING COUNTRY VACCINE IS LIKELY TO BE LICENSED IN CHINA BY A COMPANY CALLED INNOVAX WITHIN THE NEXT YEAR, AND THERE PROBABLY ARE 11 OR 12 OTHER COMPANIES IN CHINA THAT ARE IN VARIOUS STAGES OF DEVELOPMENT BEHIND IT. MULTIPLE COMPANIES IN INDIA, ALSO IN BRAZIL, ARE ALSO DEVELOPING IT. SO THAT'S A VERY GOOD SIGN THAT THERE IS INTEREST AND SPER TEASE TO DEVELOP THESE VACCINES IN THOSE SETTINGS WHICH SHOULD PROVIDE THE VACCINE AT LOWER COST THAN WHAT THE TWO CURRENT MANUFACTURERS CAN MAKE THEM FOR. AND WE OBVIOUSLY HAVE TO ADJUST VACCINE HESITANCY OF FAMILIES, AND PARTICULARLY HEALTHCARE PROVIDERS. THERE'S QUITE A BIT OF EVIDENCE THAT UP WITH OF THE BIG PROBLEMS IN THE UNITED STATES IS NOT JUST THAT FAMILIES DON'T KNOW ENOUGH OR APPRECIATE HPV VACCINES OR HAVE PROBLEMS WITH IT, BUT THAT HEALTHCARE PROVIDERS SINGLE OUT THE HPV VACCINE AS SOMETHING SPECIAL. IT'S NOT LIKE YOU SAY ROLL UP YOUR ARM, YOU'RE SUPPOSED TO GET THESE THREE VACCINES. YOU SAY HERE'S THESE TWO VACCINES AND OH, BY THE WAY, IF YOU WANT TO, YOU CAN GET THE HPV VACCINE, BUT I'D RATHER NOT TALK ABOUT IT. SO IT'S NOT ALL PHYSICIANS BUT THERE CERTAINLY IS SOME -- THERE'S AN ISSUE OF GETTING PHYSICIANS TO RECOMMEND IT MORE STRONGLY, OR TO NOT MAKE ANY DISTINCTION BETWEEN IT IN THE OTHER ADOLESCENT VACCINES. THEN THE FINAL THING I THINK THAT COULD BE TRANSFORMATIVE IS IF RATHER THAN GIVE TWO OR THREE DOSES, AND I ALWAYS FORGET TO DO THIS, I FORGOT TO MENTION THAT FAIRLY RECENTLY, THERE'S BEEN A CHANGE IN TERMS OF DOSE SAJ SO THAT IF YOU'RE UNDER 15, YOU ONLY NEED TWO DOSES BECAUSE I MY KNOW GENICITY BRIDGING CLINICAL TRIALS HAVE SHOWN THAT TWO DOSES AT ZERO AND SIX MONTHS AND UNDER 15 GIVES AS HIGH AN IMMUNE RESPONSE AS THREE DOSES IN WOMEN 16 TO 26. SO THE CURRENT RECOMMENDATIONS IN THE UNITED STATES, EUROPE AND OTHER COUNTRIES IS THAT YOU'RE UNDER 15, YOU JUST NEED TWO DOSES. BUT WHAT HAPPENS IF WE COULD DO G. TO A GO TO A SINGLE DOSE CAMPAIGN PROGRAM, GIVE EVERYBODY A SINGLE DOSE AND MOVE ON? WE ACTUALLY HAVE SOME PRELIMINARY DATA THAT THIS COULD POTENTIALLY WORK. THE FIRST DATA CAME OUT FROM -- I HAVE TO EMPHASIZE, THIS IS POST HOC ANALYSIS OF AN NCI TRIAL NCI SPONSORED -- TRIAL WHERE EVERYBODY WAS SUPPOSED TO GET THREE DOSES BUT FOR VARIOUS REASONS, A RELATIVELY SMALL NUMBER OF WOMEN ONLY GOT ONE DOSE. IN THIS CASE, 134 VERSUS 2000. BUT WHAT CAN YOU SEE IF YOU LOOK AT THE END OF HPV16 INFECTION, THE TWO TYPES TARGETED BY THE VACCINE, THERE'S ABSOLUTELY NO DIFFERENCE IN PROTECTION. THE CONFIDENCE INTERVALS COMPLETELY OVERLAP. IF YOU LOOK AT CROSS PROTECTION, BY THESE THREE TYPES WHICH THE VACCINE IS KNOWN TO CROSS PROTECT BY THREE DOSES, THERE'S NO DIFFERENCE IN THE LEVEL OF CROSS PROTECTION. IMPORTANTLY, IF YOU LOOK AT THE INFECTION RATES BY THE TYPES THAT AREN'T PROTECTED, EITHER CAN SEE THERE'S, AGAIN, NO, YOU- DIFFERENCE, MUCH HIGHER. WHAT THAT SAYS IS THAT IT'S UNLIKELY THAT THE ONE DOSE WOMEN HAVE A LOW RISK, THEY'RE A GROUP THAT HAS AN UNUSUALLY LOW RISK OF EXPOSURE TO SEXUALLY TRANSMITTED HPVs BECAUSE THE VACCINE TYPES THEY'RE NOT GETTING PROTECTED AGAINST, THEY'RE GETTING THE SAME RATE OF INFECTION. THIS IS JUST ANOTHER WAY OF LOOKING AT THE DATA, SO THIS WHAT I SHOWED YOU HERE IS CUMULATIVE HPV INCIDENT INFECTION. THIS IS LOOKING AT THE END OF SEVEN YEARS AND JUST SAYING WHO'S GOT AN INFECTION NOW. WHAT YOU CAN SEE IN COMPARISON TO CONTROL, THERE'S NO DIFFERENCE IN THE TYPES THAT AREN'T BEING PROTECTED WHEREAS THE CONTROLS HAVE APPRECIABLE INFECTIONS WITH HPV16/18 IN THESE CROSS PROTECTIVE TYPES BUT THERE'S NO DIFFERENCE IN PREVALENCE OF INFECTION AT THIS PARTICULAR TIME. WE HAVE UNPUBLISHED DATA THAT'S NOT QUITE READY FOR PRIME TIME THAT BY 10 OR 11 YEARS, THESE ONE DOSE WOMEN STILL HAVE HAD NO 16 OR 18 INFECTIONS. NOW THIS IS OBVIOUSLY REALLY ENCOURAGING AND THE REASON WHY WE THINK THAT WE'RE GETTING STRONG PROTECTION EVEN AFTER ONE DOSE IS BECAUSE WE'RE GETTING REALLY STRONG ANTIBODY RESPONSES EVEN AFTER ONE DOSE. THIS AGAIN WAS COMPLETELY UNEXPECTED, WHERE IF YOU LOOK AFTER A SINGLE DOSE, YOU CAN SEE FOR BOTH 16 AND 18, THE DOTTED LINE, THE LEVELS ARE COMPLETELY FLAT. THERE'S NO DIMINUTION IN ANTIBODY RESPONSES BETWEEN TWO AND SEVEN YEARS AND WE'RE NOW LOOKING AT THE 10 AND 11 YEAR DATA. WHAT'S SURPRISING IS THAT YOU REALLY DON'T GET MUCH BANG FOR YOUR BUCK BY ADDING TWO MORE DOSES SO IF YOU LOOK AT THE TOTAL LEVELS OF ANTIBODIES AT THE END OF SEVEN YEARS, IT'S ONLY FOUR FOLD HIGHER FOR THREE DOSES THAN ONE DOSE. IT'S ALMOST LIKE FOR LONG TERM ANTIBODY RESPONSES, VACCINATION IS JUST SIMPLY ADDITIVE. AND WE'RE STILL ALMOST A LOG HIGHER THAN WHAT WE SEE AFTER NATURAL INFECTION. SO WE ACTUALLY THINK THAT THIS STRONG ANTIBODY RESPONSE IS REALLY WHAT'S GIVING US THIS LONG TERM PROTECTION EVEN AFTER A SINGLE DOSE. I'M GOING TO SKIP THAT. SO THERE IS ACTUALLY SOME OTHER DATA, ONCE WE GOT THIS DATA FROM THE NCI TRIAL, OTHER STUDIES LOOKED, SO THE TRIAL OF CERVARIX, THE GSK-SPONSORED TRIAL, THEY LOOK BACK AT THEIR ONE, TWO, THREE-DOSE RECIPIENTS AND AGAIN, VERY FEW THREE-DOSERS AND THEY FOUND SIMILAR EFFICACY AFTER FOUR YEARS. AND FOR GARDASIL, THERE WAS AN INDIAN CLUSTER RANDOMIZED TRIAL WHERE DIFFERENT VILLAGES WERE SUPPOSED TO GET EITHER TWO DOSES OR ONE DOSE, BUT THE GOVERNMENT SHUT DOWN THE TRIAL FOR POLITICAL REASONS AND SO SOME OF THE CLUSTERS AND SOME OF THE WOMEN IN SOME OF THE CLUSTERS ONLY GOT ONE DOSE, AND AGAIN, THIS IS POST HOCK ANALYSIS, BUT EVEN AFTER SEVEN YEARS, THERE WAS SIMILAR PROTECTION IN YOUNG WOMEN RECEIVING ONE, TWO AND THREE DOSES. IMPORTANTLY TERMS OF IMMUNOGENICITY, IT ALSO LOOKS LIKE GARDASIL IS ALLOWING STABLE ANTIBODY RESPONSES LONG TERM, IN THIS CASE OUT TO FOUR YEARS, AND AGAIN, THE DIFFERENCE BETWEEN ONE AND THREE DOSES IS ABOUT FOUR FOLD. THIS IS ACTUALLY A VERY IMPORTANT OBSERVATION. REMEMBER WHAT I SAID ABOUT THE DIFFERENT TYPES OF ADJUVANTS? THIS EEN DOESN'T HAVE THAT EXTRA STRONG ADJUVANT. IT JUST GOT THE TYPICAL ALUMINUM LIKE IN THE DTP VACCINE. SO WHAT THAT TELLS US IS IT'S UNLIKELY THAT YOU NEED THAT STRONG ADJUVANT IN ORDER TO GET A STABLE ANTIBODY RESPONSE THAT LASTS A LONG TIME. IT'S REALLY THE STRUCTURE OF THE VIRUS THAT'S MAKING THE DIFFERENCE, AGAIN, NOT THE ADJUVANT. SO IS IT TIME TO ADOPT SINGLE DOSE HPV VACCINATION PROGRAMS? IF ANYBODY IS EXCITED ABOUT THIS, IT'S ME, BUT EVEN I SAY WE REALLY THINK THAT THESE POST HOC, IN OTHER WORDS, WE'RE NOT RANDOMIZED, THESE ARE POST HOC FINDINGS THAT PROVIDE INSUFFICIENT EVIDENCE TO GENERALLY PROMOTE IMPLEMENTATION OF SINGLE DOSE HPV VACCINATION PROGRAMS. SO I THINK THAT'S IMPORTANT TO STRESS, THAT WE'RE NOT ADVOCATING THAT PEOPLE JUST GO OUT AND JUST DO ONE-DOSE TRIALS. NOW IN SOME SETTINGS WHERE THERE'S SUFFICIENTLY LIMITED RESOURCES, ONE COULD PERHAPS JUSTIFY EARLY ADOPTION OF A SINGLE DOSE PROGRAM WITH THE PROVISO THAT THERE WOULD BE BOOSTING OF ANOTHER DOSE IN IT STARTS TO LOOK LIKE THERE'S BREAKTHROUGH INFECTIONS IN THAT POPULATION. THAT MAY BE A RATIONAL AND ETHICAL THING TO DO. AGAIN WE'RE NOT STRONG PROPONENTS OF THAT. BUT WHAT WE THINK THAT REALLY NEEDS TO HAPPEN IS TO HAVE A RANDOMIZED CONTROL TRIAL WHERE WE FORMALLY LOOK AT ONE VERSUS TWO DOSE OF VACCINE AND SEE IF IT PROTECTS AGAINST INFECTION. AS MUCH ACE FEEL WE ALREADY KNOW THE ANSWER, WE STILL HAVE TO SPEND TENS OF MILLIONS OF DOLLARS TO PROVE IT SO THAT WE CAN ACTUALLY PROVIDE THE TYPE OF DATA SO THAT NATIONAL REGULATORS AND ADVISORY GROUPS CAN BE ON BOARD FOR SINGLE DOSE VACCINATION. SO THIS IS WHAT THE TRIAL WHICH HAS JUST BEGUN IN COSTA RICA AGAIN, IT'S FUNDED BY THE GATES FOUNDATION AND NCI, IT'S GOING TO BE A FOUR-ARM TRIAL WHERE WE'RE GOING TO PAIR ONE AND TWO DOSES OF CERVARIX, ONE AND TWO DOSES OF GARDASIL 9, EACH ARM WILL HAVE 5,000 YOUNG WOMEN BETWEEN 12 TO 16 YEARS OLD, WE'LL LOOK AT PERSISTENT HPV INFECTION AS THE PRIMARY END POINT, AND WE'LL ALSO DO A SURVEY OF HPV PREVALENCE IN THIS AGE GROUP IN THAT POPULATION, SO WE'LL CALL THE GIRLS IN, FIGURE OUT IF THEY HAVE HPV FEX, IMMEDIATELY VACCINATE THEM, SO WE CAN DO SORT OF A QUASI CONTROL GROUP BUT THEY WILL BE IMMEDIATELY VACCINATED SO THEY WON'T BE A TRUE CONTROL GROUP. THEN LOOK AT THE END OF FOUR YEARS TO SEE WHETHER THERE'S ANY DIFFERENCE IN HPV16-18 INFECTION RATES. WE'LL ALSO LOOK AT THE OTHER TYPES. SO WHAT ABOUT OLDER WOMEN? IS THERE ANYTHING WE CAN DO TO MOVE FORWARD? THE CURRENT VACCINES ARE FOR YOUNG WOMEN, AND WE THINK THAT ESPECIALLY IF ONE DOSE CAN WORK AND WE CAN GET MORE UP TAKE, WE'VE REALLY GOT IT COVERED FOR YOUNGER WOMEN, BUT WHAT ABOUT THE CURRENT WOMEN, CAN WE DO ANYTHING FOR THEM? ONE OF THE THINGS THAT'S BEEN PROPOSED IS WHAT'S CALLED HPV FASTER WHICH WOULD BROADEN THE SCOPE FOR HPV-RELATED CANCERS, SO THE IDEA IS TO TAKE WOMEN SOMEWHERE IN THEIR 30s AND DO A ONE OR TWO-TIME POINT OF CARE TEST FOR HPV DNA. AND IF THEY'RE POSITIVE -- AS YOU GET OLDER, IF YOU HAVE HPV DNA, THERE'S MORE AND MORE CHANCE THAT IT'S A PERSISTENT INFECTION, THEREFORE POTENTIALLY ON THE CAUSAL PATHWAY OF CANCER, BECAUSE MOST INFECTIONS ARE ACQUIRED AT A YOUNGER AGE. AND THEN THIS WOULD LEAD TO IMMEDIATE TREATMENT. IT'S NOT QUITE CLEAR WHAT THIS TREATMENT WOULD BE. MAYBE CRYOTHERAPY RIGHT NOW. BUT ONE OF THE THINGS WE'RE WORKING ON IS THERAPEUTIC VACCINES SO WE COULD MAYBE TREAT THEM WITH A THERAPEUTIC VACCINE WHICH POTENTIALLY MIGHT HAVE FEWER SIDE EFFECTS AND BE EASIER TO ADMINISTER IF THEY'RE POSITIVE. AGAINTHEN THE IDEA WOULD BE TO GIVE EVERYBODY THE HPV VACCINE. THIS WILL BE MUCH MORE DOABLE IF WE CAN DO ONLY ONE DOSE AND PROTECT THEM. WE'RE NOT REALLY THAT SURE THAT IF YOU GET YOUR PRIMARY HPV INFECTION IN YOUR 30s, WHAT'S REALLY THE CHANCES, WHAT'S THE ABSOLUTE RISK OF GOING ON TO CANCER IF YOU ACQUIRE YOUR INFECTION LATER IN LIFE? 30s IS LATER IN LIFE IN THIS CASE. BECAUSE THERE'S SOME EPIDEMIOLOGICAL EVIDENCE THAT AGE OF SEXUAL DEBUT IS A RISK FACTOR FOR CERVICAL CANCER. SO THE IMMATURE CERVIX MAY BE MORE SUSCEPTIBLE TO CARCINOGENESIS THAN A MATURE CERVIX, SO EPIDEMIOLOGICALLY, THIS IS A VERY IMPORTANT QUESTION BEFORE WE CAN REALLY EVALUATE THE POTENTIAL FOR THIS TYPE OF PROGRAM. PEOPLE ARE TRYING TO LOOK AT THIS RIGHT NOW. SO WHAT I'D LIKE TO CLOSE WITH IS THIS IDEA OF ELIMINATION OF CERVICAL CANCER. I GET GOOSE BUMPS JUST THINKING ABOUT IT, BUT FIRST I WANT TO SAY THAT ELIMINATION AND ERADICATION ARE DIFFERENT AND PEOPLE CONFLATE THE TWO. ERADICATION IS WHAT WE'VE DONE WITH SMALLPOX AND ARE TRYING TO DO WITH POLIO, WHERE YOU ELIMINATE THE VIRUS OR THE INFECTIOUS DISEASE FROM THE FACE OF THE EARTH AND NO ONE NEEDS TO HAVE ANY PREVENTION. ELIMINATION MEANS THAT YOU ELIMINATE THE THAT DISEASE AS A SUBSTANTIAL OR SIGNIFICANT HEALTH PROBLEM IN A GIVEN POPULATION. SO FOR CERVICAL CANCER, IT'S SORT OF BEEN DESIGNATED IF THE RATES ARE LESS THAN 4 PER 100,000, IT'S CONSIDERED RELATIVELY INSIGNIFICANT. AND WHAT'S IMPORTANT TO KNOW IS THAT IN THEORY, THIS COULD HAPPEN WITH HPV. WE REALLY HAVE THE TOOLS IN PLACE TO ELIMINATE HPV. AND HPV DOESN'T HAVE A RESERVOIR IN ANIMAL POPULATIONS, IT'S ONLY IN HUMANS. SO IF WE CAN PREVENT HPV INFECTION IN HUMANS, IT'S GOT NO OTHER PLACE TO GO. AND SO WHAT I'D LIKE TO CLOSE WITH IS SOME STATEMENTS WHICH I THINK SUMMARIZE THINGS VERY WELL THAT WERE MADE ONLY A MONTH OR TWO AGO BY THE DIRECTOR GENERAL OF THE WORLD HEALTH ORGANIZATION, WHERE THEY ESPOUSE THIS IDEA OF HAVING ELIMINATION OF CERVICAL CANCER. AND WHAT HE SAID WAS, CERVICAL CANCER IS ONE OF THE MOST PREVENTABLE AND TREATABLE FORMS OF CANCER. PREVENTION AND EARLY TREATMENT ARE ALSO HIGHLY COST-EFFECTIVE. HPV VACCINES ARE TRULY WONDERFUL INVENTIONS. IF ONLY WE HAD VACCINES AGAINST EVERY FORM OF CANCER. TRUE, TRUE. AND WE SHOULD BE WORKING ON THEM. AND FINALLY, HE SAID, OUR CHALLENGE IS TO ENSURE THAT ALL GIRLS GLOBALLY ARE VACCINATED AGAINST HPV AND THAT EVERY WOMAN OVER 30 IS SCREENED AND TREATED FOR PRECANCEROUS LESIONS. NOW, THERE IS A LOT OF SPACE BETWEEN WANTING THIS AND ACCOMPLISHING THIS. BUT IT REALLY IS EXCITING TO THINK ABOUT THAT THERE'S ONE CANCER THAT, GIVEN THE TOOLS THAT WE HAVE TODAY, WE COULD LARGELY ELIMINATE. SO THANK YOU VERY MUCH. [APPLAUSE] ARE THERE ANY QUESTIONS? IF THERE ARE, PLEASE TAICT MICROPHONE TAKE THE MICROPHONE AND SPEAK LOUDLY. >> THANK YOU FOR THE COMPREHENSIVE TALK. I'M FROM INDIA, MY QUESTION IS RELATED TO THE NUMBER OF STRAINS WHICH HPV HAS, LIKE THERE'S MORE THAN 140 OR 150. SO IF YOU TRY TO SUPPRESS THE ONCOGENIC STRAINS AT PRESENT, LIKE 10 OR 15, IS THERE ANY POSSIBILITY OF OTHER STRAINS BECOMING ONCOGENIC OR POPPING UP AND CAUSING -- >> YOU'RE TALKING ABOUT TYPE REPLACEMENT. SO THERE'S ALWAYS A POSSIBILITY WE NEED TO SCREEN FOR THIS. I THINK BIOLOGICALLY IT'S QUITE UNLIKELY BECAUSE HPV16, THERE'S OTHER TYPES THAT ARE RELATIVELY COMMON BUT HPV16, GIVEN INFECTION, IS MORE LIKELY TO GO ON TO CANCER. SO IT JUST HAPPENS TO BE MORE ONCOGENIC. AND BEING ONCOGENIC ISN'T SOMETHING THAT'S DIRECTLY SELECTED DURING EVOLUTION OF THE VIRUS BECAUSE THE CANCERS ARE TOO DEDIFFERENTIATED TO CAUSE VIRUS. SO IT'S A DEAD END FOR THE VIRUS AS MUCH AS IT IS FOR THE HOST SO THERE'S NO DIRECT COMPELLING EVOLUTION TO BECOME MORE CARCINOGENIC. THE OTHER THING I WOULD SAY IS THAT IN EPIDEMIOLOGICAL EXPERIMENTS, PEOPLE HAVE LOOKED TO SEE IF THERE'S INTERACTION AMONG TYPES, AND WHAT IT LOOKS LIKE IS THAT THEY'RE ALL INDEPENDENT PENTS, SO YOU CAN GET MULTIPLE TYPES, YOU CAN LOSE ONE, ACQUIRE ONE. IT DOESN'T LOOK LIKE HAVING ONE TYPE EITHER INFLUENCES ACQUISITION OR LOSS OF ANOTHER TYPE. THERE'S PLENTY OF ROOM AT THE CERVIX FOR ALL THESE TYPES, BECAUSE IT'S NOT LIKE A BACTERIAL INFECTION WHERE THEY SPREAD OVER ENTIRE SURFACES. THEY'RE VERY FOCAL LESIONS SO THERE DOESN'T SEEM TO BE COMPETITION AMONG TYPES. >> THANK YOU. >> THANK YOU SO MUCH FOR A WONDERFUL PRESENTATION. MY NAME IS AMIRA, I'M ORIGINALLY FROM INDONESIA. MY QUESTION IS, DO YOU SEE ANY DISTRIBUTION ESPECIALLY SUBTYPE 16 AND 18, AND DOES IT MEAN THAT WE WOULD HAVE TO CUSTOMIZE THE VACCINE ON THIS DISTRIBUTION -- AND MADE BASED ON ETHNICITY OR RACE? >> ONE QUESTION AT A TIME. SO HPV16 PREDOMINATE WORLDWIDE. THERE'S SOME VARIATION IF YOU GO PAST THAT, BUT THEY'RE NOT THE MAIN PLAYERS IN CANCER. THE OTHER THING IS, THERE ARE SOME STRAINS OF HPV16 THAT CLEARLY SEEM TO BE MORE ONCOGENIC, BUT THE VACCINE EQUALLY PROTECTS AGAINST ALL THE DIFFERENT STRAINS OF HPV16. SO I THINK THAT OVERALL, FOR THE MOST PART, UNLESS YOU START TALKING ABOUT NUMBER 5, 6, 7 DOWN THE ROAD, THE VACCINES DON'T NEED TO BE PARTICULARLY GEARED TOWARDS SPECIFIC ENVIRONMENTS. >> MY NAME IS RONCI FROM NIGERIA. THANK YOU SO MUCH FOR YOUR PRESENTATION AND THANK YOU FOR THIS GREAT INNOVATION FOR THE WORLD. SO I WANT TO ASK THE FIRST QUESTION WHICH HAS TO DO WITH -- YOU MENTIONED THAT BOTH COMPANIES, THAT'S GSK AND MERCK, WHICH IS THE PRODUCER OF GARL SILL, ACTUALLY ENTRUSTED EVEN GIVEN THE VACCINES TO GAVI FOR LESS THAN $5. SO PLEASE, I JUST WANTED TO ASK IF IT'S POSSIBLE YOU CAN TALK MORE ABOUT THAT TO UNDERSTAND WHAT HAS BEEN THE IMPEDIMENT IN TRYING TO INCREASE HOW PEOPLE CAN ACCESS THIS VACCINE GLOBALLY. MOST ESPECIALLY IN LOW AND MIDDLE INCOME COUNTRIES. >> SO TWO THINGS. ONE, $5 IS A LOT, OKAY, WHEN YOU TALK ABOUT THE BIRTH COHORT THAT YOU'D HAVE TO VACCINATE. SECONDLY, THE IMPLEMENTATION PROGRAMS, WE'RE PRETTY GOOD AT VACCINATING INFANTS. AND THE INFRASTRUCTURE IS IN PLACE TO VACCINATE INFANTS. IN MANY LOWER, MIDDLE INCOME COUNTRIES, ADOLESCENT BOYS AND GIRLS JUST DON'T HAVE ACCESS TO HEALTHCARE. AND SCHOOL BASED VACCINATION IS ONE THING THAT COULD POTENTIALLY WORK, BUT AGAIN, IT COSTS QUITE A BIT OF MONEY TO SHIP THE VACCINE, IT REQUIRES A COLD CHAIN, AND TO HAVE THE PEOPLE THERE TO DO THE VACCINATION. SO IMPLEMENTATION COSTS FOR MANY VACCINES COST MORE THAN THE COST OF THE PRODUCT ITSELF. AND SOME OF IT IS JUST, YOU KNOW, IT'S MOVING FORWARD. THINGS ARE MOVING FORWARD, PROBABLY TOO SLOW, BUT AGAIN, THAT'S ONE OF THE REASONS WHY WE'RE VERY HIGH ON THE THE IDEA OF HAVING SINGLE DOSE VACCINATION, BECAUSE THEN YOU WOULDN'T HAVE TO GET TRACK OF WHO GOT VACCINATED, WHO DIDN'T GET VACCINATED, TO GIVE ANOTHER DOSE AND YOU COULD DO VACCINATION CAMPAIGNS TO SAY EVERY YOUNG GIRL WITHIN A FIVE-YEAR SPAN WOULD JUST COME IN AND GET VACCINATED IN MASS VACCINATION PROGRAMS SO IT WOULD REALLY HELP WITH THE COST OF IMPLEMENTATION. >> THANK YOU VERY MUCH. MY SECOND QUESTION. I JUST WANTED TO ACTUALLY SAY THAT FOR ME, I KNOW SO MANY PHYSICIANS AND SO MANY DOCTORS AND SO MANY SCIENTISTS, EVEN BACK IN NIGERIA WHO I ENGAGE IN RESEARCH, YOU ALWAYS WANT TO MAKE MON EE THE MONEY, OR BE A CLINICIAN, BE IN A HOSPITAL AND THAT KIND OF STUFF, BUT SOMETIMES BEING A RESEARCHER, YOU DON'T REALLY HAVE THAT KIND PHOTOGRAPH CUSS. SO MY QUESTION FOCUS. SO MY QUESTION IS IF YOU CAN SHARE BITS WITH US, WHAT HAS -- WHAT REALLY MOTIVATED YOU TO CONTINUE DOING WHAT YOU'RE DOING OVER THIS VERY LONG SPAN OF YEARS? THANK YOU. >> A LOT OF DIFFERENT THINGS -- THANK YOU FOR YOUR QUESTION -- INSPIRE YOU, BUT I THINK FOR ME THE MOST BASIC THING WAS JUST THE THIRST FOREKNOWLEDGE. I WANTED TO KNOW NEW THINGS. I WANTED TO DO SOMETHING WHERE I WOULD BE THE FIRST TO KNOW SOMETHING. SO I STARTED OUT AS A BASIC RESEARCHER AND ONLY THEN SECONDLY BECAME MORE INTERESTED IN MORE TRANSLATIONAL RESEARCH. SO QUITE FRANKLY, UNLIKE SOME PEOPLE, MY INITIAL GOAL WAS NOT TO SAVE LIVES. MY INITIAL GOAL WAS TO UNDERSTAND BIOLOGY AND TO REALLY, YOU KNOW, MAKE NEW KNOWLEDGE, BE THE FIRST PERSON TO KNOW SOMETHING. AND THEN IT BECAME MORE AND MORE OF AN INTERESTING CHALLENGE TO LEARN SOMETHING, BUT DO IT IN A WAY THAT COULD HELP PEOPLE, AND THEN IT BECAME MORE OF A CHALLENGE TO DO SOMETHING THAT COULD HELP PEOPLE IN A COST-EFFECTIVE WAY, SOMETHING THAT COULD ACTUALLY BE USED WORLDWIDE AND NOT JUST FOR A VERY SMALL PERCENTAGE OF VERY RICH PEOPLE. SO IT ADDS COMPLEXITY TO TRY TO ADDRESS THE QUESTION, BUT IT ALSO ADDS A LOT OF INTEREST IN TRYING TO FIGURE OUT SOLUTIONS. IT'S LIKE A PUZZLE. YOU'RE TRYING TO -- YOU HAVE A PROBLEM AND YOU'RE TRYING TO ANSWER THAT PROBLEM, TRYING TO FIGURE OUT AN ANSWER TO THAT PROBLEM. AND THAT'S KIND OF THE MOTIVATION FOR ME PERSONALLY. >> HI, I'M KERI FROM IRELAND INVOLVED IN EDUCATING CLINICIANS IN THE SCREENING PROGRAM. I'D LIKE TO THANK YOU ON BEHALF OF ALL WOMEN AND MEN EVERYWHERE BECAUSE IT ISN'T JUST WOMEN WHO HAVE HPV-RELATED CANCERS, FOR YOUR CONTRIBUTION BECAUSE JUST BEING HERE FOR ME IS VERY INSPIRING AND I DON'T THINK I SPEAK FOR JUST MYSELF. I'D LIKE TO JUST ASK YOU ABOUT WHERE WE ARE, IF YOU COULD SPEAK TO BRIEFLY ABOUT THE PROGRESS AS FAR AS THERAPEUTIC VACCINES ARE. WHERE ARE WE IN THAT SPACE AT THE MOMENT? >> OKAY. SO IT'S HARD TO GIVE A REAL SHORT SUCCINCT ANSWER TO THAT. THE BOTTOM LINE IS, THERE ARE NO THERAPEUTIC VACCINES THAT HAVE BEEN LICENSED. ALMOST ALL THE THERAPEUTIC VACCINES HAVE BEEN TARGETING DYSPLASIAS. MY PERSONAL FEELING IS THAT ALL THE VACCINES HAVE BEEN TRYING TO GENERATE SYSTEMIC T-CELL RESPONSES, AND THE REASON THAT ALL THESE OTHER ONES HAVE FAILED ISN'T BECAUSE THEY DIDN'T GENERATE REASONABLE SYSTEMIC IMMUNE RESPONSES, BUT THE T-CELLS DIDN'T EFFICIENTLY GO TO THE SITE OF THE LESIONS WHICH ARE INTRAEPITHELIAL. WE'VE SHOWN IN ANIMAL MODELS THAT YOU JUST DON'T GET THE T-CELLS WHERE YOU WANT THEM WHICH IS ACROSS THE BASEMENT MEMORY AND UP TO THE EPITHELIUM AND WE'RE WORKING ON WAYS TO TRACK THE T-CELLS TO THE PLACE WHERE THE LESIONS ARE, WHICH IS IN THE EPITHELIUM. AND THERE ARE SOME COMPANIES WHO NOW ARE THINKING ABOUT MOVING IN THAT DIRECTION, AND I'M QUITE ENCOURAGED THAT EVENTUALLY WE'LL HAVE SOME. THE BIG PROBLEM WITH THERAPEUTIC VACCINES, INCIDENTALLY, IS TYPE-SPECIFIC AS WELL. THIS IS SOMETHING PEOPLE KIND OF HIDE UNDER THE RUG SO IF YOU WANT TO GET PROTECTION AGAINST A WHOLE BUNCH OF TYPES, IT'S PROBABLY THAT YOU'RE GOING TO HAVE TO HAVE A MULTIVALENT VACCINE. >> THANK YOU. >> KERI STOLE MY QUESTION BUT I HAVE MANY MORE. SO I GET AS A CLINICIAN -- UNIVERSITY OF MISSISSIPPI. AS A CLINICIAN, I GET A LOT OF QUESTIONS ABOUT VACCINATION OVER 30, PARTICULARLY PATIENTS WHO ARE DIVORCED AND ARE HAVING CHILDREN LATER IN LIFE. SO US A MENTIONED, OF COURSE, THE TRANSFORMATION ZONE DECREASES AS WE AGE, BUT DURING PREGNANCY FOR MAYBE SOMEBODY WHO'S IN THEIR 40s, WHICH IS BECOMING MORE COMMON, THE TRANSFORMATION ZONE MIGHT BE MORE EXPOSED, SO DO YOU THINK THAT THAT MIGHT BE A WAY OF MAYBE LOOKING AT VACCINATION FOR THAT AGE GROUP? IS THAT SOMETHING WE COULD USE AS A POSSIBLE MEANS TO KIND OF PROMOTE, IS THIS POSSIBLE, CAN WE PROMOTE OVER 26? >> I THINK THAT'S AN INTERESTING QUESTION. SO I THINK THE MOST INTERESTING PART OF THAT QUESTION IS, DOES THE TRANSFORMATION ZONE CHANGE APPRECIABLY DURING PREGNANCY THAT IT'S MORE SUSCEPTIBLE TO CARCINOGENIC PROGRESSION. AND I THINK WE DON'T KNOW THE ANSWER TO THAT QUESTION. IN TERMS OF INFECTION, PREGNANT WOMEN, SOMETIMES YOU HAVE REACTIVATION OF INFECTION. AND THE VACCINE WON'T PREVENT THAT. BUT WHAT IT COULD PREVENT IS THE ANTIBODIES ARE SHED INTO THE CERVICAL VAGINAL MUCUS, AND LET'S SAY SHE HAS A VAGINAL INFECTION, BUT NEVER GOT CERVICAL INFECTION. NOW IF SHE HAS THOSE ANTIBODIES AND HASN'T GENERATED A GOOD ABT BODY RESPONSE HERSELF, IT COULD PREVENT HER FROM SECONDARILY GETTING THIS NOW INFECTION OF A MORE SUSCEPTIBLE CERVICAL TRANSFORMATION ZONE. IN THEORY, THAT SEEMS LIKE IT'S A POSSIBILITY. BUT THERE'S NO DATA RIGHT NOW TO SUPPORT THAT. SEE, I ACTUALLY THOUGHT SORT OF IN LINE WITH THIS, I THOUGHT THAT IF YOU VACCINATE A WOMAN LIKE SHORTLY AFTER SHE BECAME INFECTED, YOU WOULD ACTUALLY REDUCE THE RATE IN WHICH YOU WOULD GET CERVICAL ABNORMALITIES, ESPECIALLY HIGH GRADE DEEDS WHICH CAUSE THE TRANSFORMATION ZONE, BECAUSE YOU PREVENT THE SUCCESSIVE ROUNDS OF AUTO INOCULATION. AND I REALLY THOUGHT WE'D SEE THAT, BUT WE HAVEN'T SEEN IT IN THE CLINICAL TRIALS. SO I'M NOT QUITE SURE WHY, WHETHER THIS ALL SORT OF HAPPENS QUICKLY OR WHATEVER, BUT IT'S NOT WHAT I HAD PREDICTED. SO I WOULD THINK THAT YOU ARE RIGHT THAT THIS WOULD HAPPEN, BUT AGAIN, I WAS WRONG LAST TIME SO MAYBE I'LL BE WRONG THIS TIME. >> I THINK YOU'VE BEEN MORE RIGHT THAN WRONG. THANK YOU. >> HELLO. GOOD AFTERNOON. I'M FROM INDIA. AND MY QUESTION IS WITH REFERENCE TO INDIA. WHILE WE ARE STILL SOMEWHAT UNDECIDED ABOUT INCLUSION OF THE HPV VACCINATION IN A NATIONAL IMMUNIZATION PROGRAM AND THAT'S GOT TO DO WITH THE PROBABLE CONCERN ABOUT OVERDIVERSE EFFECT -- TRIALS AND COUPLE OF TEENAGERS ENROLLED IN THAT TRIAL, THEY PASSED AWAY, THE REASON FOR THAT STILL REMAINS UNCLEAR, BUT I THINK TO THE BEST OF MY KNOWLEDGE, WE ARE WAITING TO SEE THAT AFTER THAT TRIAL PROGRAM, HOW IT WORKS OUT. THERE ARE MORE ADVERSE EFFECTS JUST BECAUSE OF THE CONFUSION AND DOUBT OVER THAT PARTICULAR INCIDENT AFTER THAT, IT'S NOT BEEN THAT EASY FOR BODIES TO PROPERLY IMPLEMENT THAT INTO A NATIONAL IMMUNIZATION PROGRAM. SO IF YOU COULD JUST THROW SOME LIGHTS ON POSSIBLE RISK OF THIS VACCINATION. >> COULD YOU REPEAT THE FINAL QUESTION ONE MORE TIME? >> ANY POSSIBLE ADVERSE EFFECTS OF HPV VACCINATION. >> ANY -- WHAT? I'M SORRY? >> ADVERSE EFFECTS. >> AS I WENT THROUGH THE ONE SLIDE, WHERE PEOPLE WILL HAVE ADVERSE EVENTS, BUT IF YOU LOOK AT THE DATA AS A WHOLE, FOR INSTANCE AUTOIMMUNE DISEASES LIKE LUPUS AND EVERYTHING, PEOPLE ARE ALWAYS CONCERNED THAT IT MAY CAUSE AUTOIMMUNE DISEASES, BUT THIS HAS BEEN LOOKED AT VERY CAREFULLY AND THERE'S NO EVIDENCE THAT THERE'S ANY PARTICULAR TYPES OF AUTOIMMUNE DISEASES THAT GO UP AFTER HPV VACCINATION. SO NO, THERE'S -- IT IS AN ISSUE BECAUSE THIS AGE GROUP, YOUNG WOMEN, THIS IS SORT OF AT THE AGE GROUP, AGE THAT OFTENTIMES AUTOIMMUNE DISEASES MANIFEST THEMSELVES. SO -- BUT THEY'VE DONE CALCULATIONS THAT IF YOU VACCINATE SO MANY WOMEN -- YOUNG WOMEN, WHAT'S THE CHANCES DRK THE RATIO THAT WILL GET LUPUS, WHAT PERCENTAGE WILL GET GENOGILLIAN BA RAY. SO REALLY, THERE IS ONE IN A MILLION OR VERY, VERY SMALL CHANCE OF ANAPHYLACTIC SHOCK, BUT AGAIN, IT'S THE NO MORE THAN IT IS WITH OTHER VACCINES. SO THAT WOULD BE PROBABLY THE WORST THING THAT COULD HAPPEN. BUT AGAIN, IT'S NOT UNUSUAL FOR A VACCINE. IT SEEMS TO BE AT THAT LEVEL. IT'S VERY, VERY RARE. I GUESS THAT'S IT. >> THANK YOU VERY MUCH. >> THANK YOU.