February 2014 ACIP Meeting — Human Papillomavirus (HPV) Vaccine

OKAY, WE’RE BACK IN SESSION AND WILL ASK DR. BOCCHINI TO GET US STARTED ON THE HUMAN PAPILLOMAVIRUS VACCINE SESSION THANK YOU, GOOD MORNING WE’RE NOW GOING TO BEGIN A VERY IMPORTANT HPV VACCINE SESSION, AND WE’LL DESCRIBE THAT FOR YOU IN THE NEXT COUPLE OF SLIDES TODAY WE’RE GOING TO HAVE PRESENTATION BY MERCK FOR A REVIEW ON THE INVESTIGATIONAL 9-VALENT HPV VACCINE, WHICH CONTAINS THE QUADRIVALENT VACCINE AND HAVE FIVE ADDITIONAL SEROTYPES TO THE PRODUCT IN ADDITION, WE’RE GOING TO REVIEW AND APPROVE THE UPDATED HPV VACCINE ACIP STATEMENT, EACH OF THE COMMITTEE MEMBERS HAS REVIEWED THE MOST RECENT DRAFT AND WE THANK MANY OF YOU FOR THE COMMENTS THAT YOU’VE GIVEN US TO IMPROVE THE DRAFT THIS STATEMENT THAT INCLUDES RECOMMENDATIONS FOR THE HPV 16 AND 18 BIVALENT VACCINE AND THE QUADRIVALENT VACCINE AND CONSOLIDATES THE INFORMATION AVAILABLE FOR MALES AND FEMALES JUST A REVIEW, IN OCTOBER, WE PROVIDED AN UPDATE ON HPV VACCINATION COVERAGE IN THE UNITED STATES, AND WE HEARD FROM MERCK ON THE NINE-VALENT HPV DEVELOPMENT PROGRAMS, SO YOU HEARD ABOUT THE STUDIES INVOLVED IN THE DEVELOPMENT OF THIS VACCINE YOU ALSO SAW AND CONTRIBUTED TO A DISCUSSION ON AN OVERDRAFT, OVERVIEW, OF WHAT WAS THEN THE CURRENT DRAFT OF THE UPDATED ACIP STATEMENT SINCE THAT TIME, THE WORK GROUP HAS HAD A NUMBER OF CONFERENCE CALLS AND WE’VE REVIEWED DATA FROM THE 9-VALENT CLINICAL TRIALS AND HPV PIPE ATTRIBUTION AND HPV ASSOCIATED DISEASES AND HAVE NOW INITIATED DISCUSSIONS FOR GRAVE CONSIDERATION FOR POSSIBLE LICENSURE OF THE 9-VALENT HPV VACCINE DERATION OF THE ROPOSED TIME 9-VALENT HPV VACCINE TODAY, I’LL FLUSH THIS OUT A LITTLE BIT FURTHER, WE’RE GOING TO TALK ABOUT ATTRIBUTION OF TYPES HPV ASSOCIATED DISEASE AND YOU’LL HEAR THE FIRST PRESENTATION OF CLINICAL TRIAL DATA IN JUNE YOU’LL HEAR ADDITIONAL INFORMATION ABOUT CLINICAL TRIAL RESULTS AND A HEALTH ECONOMICS PRESENTATION WE ANTICIPATE IN OCTOBER TO HAVE THE GRADE EVALUATION COMPLETED WITH RECOMMENDATION OPTIONS AND DISCUSSION FOR ACIP, AND FEEDBACK TO MAKE THE FINAL RECOMMENDATIONS, WHICH WE EXPECT TO HAVE IN FEBRUARY OF 2015 AND PENDING THE DECISION BY FDA FOR LICENSURE, A VOTE, AND THEN A VSC VOTE, AS WELL SO TODAY, THE FIRST TWO TALKS ARE ON TYPE ATTRIBUTION, HPV TYPE ATTRIBUTION IN CERVICAL PRECANCERS BY SUSAN HARIRI FROM THE CDC, AND THAT WILL BE FOLLOWED BY HPV TYPE ATTRIBUTION AND HPV ASSOCIATED CANCERS BY DR. MONA SARAIYA, WHO’S ALSO FROM THE CDC OUR PLAN, AND I’LL TALK MORE ABOUT TYPE ATTRIBUTION IN A SECOND, BUT FOLLOWING THESE TWO TALKS TO OPEN THIS FOR QUESTIONS, FOR THOSE TWO PRESENTATIONS, WE’LL FOLLOW THAT WITH A PRESENTATION BY DRDR. A DRDR. ALAIN LUXEMBOURG FROM MERCK ON THE CLINICAL TRIAL DATA, THEN DR. LAURI MARKOWITZ WILL PROVIDE A SUMMARY AND THE NEXT STEPS RELATED TO THE 9-VALENT HPV VACCINE PROGRAM, AND THEN SHE WILL REVIEW WITH US THE UPDATED STATEMENT AND GET ADDITIONAL FEEDBACK FROM THE ACIP AND THEN FOLLOW THAT BY AN ACCEPTANCE OF THAT SO, JUST TO TALK BRIEFLY ABOUT BURDEN OF DISEASE, CLEARLY, AS WE ADVANCE VACCINE DEVELOPMENT, IT BECOMES VERY IMPORTANT TO UNDERSTAND THE ROLE THAT VARIOUS SEROTYPES PLAY IN THE DEVELOPMENT OF THE CANCERS, PRECANCERS ASSOCIATED WITH DIFFERENT SEROTYPES OF HPV IN ADDITION, IT’S ALSO IMPORTANT FOR US TO ESTABLISH GUIDES FOR FUTURE EVALUATION OF THE IMPACT OF THESE VACCINES SO, THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER HAS DEFINED SOME CANCERS AS HAVING A STRONG EVIDENCE OF CAUSAL IDEOLOGY, SO FOR HPV-ASSOCIATED CANCERS, THEY INCLUDE CERVICAL, VAGINAL, LOBAR, PENIL, ANAL CANCERS AND

THE PRESENCE OF HPV IN THESE CANCERS IS CONSIDERED TO BE INDICATION OF CAUSALITY HOWEVER, THE DETERMINATION OF THE TYPE OF HPV THAT’S INVOLVED IN A PARTICULAR DISEASE REALLY DEPENDS ON A NUMBER OF FACTORS, WHICH INCLUDE THE QUALITY OF THE SPECIMEN THAT’S BEING EVALUATED, THE ASSET USED TO DETECT HPV, THE ALGORITHM TO ASSIGN ATTRIBUTABLE TYPE WHEN MULTIPLE TYPES ARE DISCOVERED IN THE SAME PREPARATION, AND THEY CAN VARY BASED ON A POPULATION SAMPLE AND THAT’S WHY IT’S IMPORTANT TO HAVE THESE TWO PRESENTATIONS, WHICH WILL GIVE US SOME UNDERSTANDING OF WHERE WE ARE AND THE PROGRAMS THAT ARE AVAILABLE FOR US TO GET A BETTER PICTURE OF THE RELATIVE ROLES OF THE VARIOUS SEROTYPES AND PRECANCER AND CANCER LESIONS I WANT TO THANK THE WORK GROUP, THE MEMBERS OF THIS WORK GROUP HAVE BEEN VERY ACTIVE AND INVOLVED IN OUR CONVERSATIONS ON THE PHONE AND IN OTHER EFFORTS, PARTICULARLY WANT TO THANK LAURI MARKOWITZ FOR HER ORGANIZATIONAL SKILLS AND ABILITY TO KEEP THIS COMMITTEE ON TASK ANDIR CONTRIBUTIONS, AS WELL SO WITH THAT, I’D LIKE TO TURN THIS OVER TO DR. HARIRI, WHO WILL PROVIDE THE FIRST PRESENTATION THANK YOU I FORGOT TO MENTION ONE THING, THE ACIP MEMBERS HAVE A FULL COPY OF DR. LUXEMBOURG’S PRESENTATION, HOWEVER, WHAT WE FOUND IS THAT FOR THE PUBLIC AND THOSE AROUND OUTSIDE THE TABLE, THE ONLY HALF OF THE TALK HAS BEEN COPIED YOU’RE MISSING EVERY OTHER PAGE AND SO WE APOLOGIZE FOR THAT, AND SO THE PLAN IS TO MAKE SURE THAT YOU’RE ALL AWARE THAT THESE SLIDES WILL BE PUBLISHED ON THE WEB WHEN THE SLIDES BECOME AVAILABLE, SO THANK YOU GOOD MORNING TODAY I’M GOING TO BE PRESENTING DATA ON HPV TYPETHE U.S I’M GOING TO START WITH BRIEFLY REVIEWING THE NATURAL HISTORY OF CERVICAL HPV INFECTION AND ASSOCIATED OUTCOMES AND THEN I’LL REVIEW SOME PUBLISHED DATA ON THE DISTRIBUTION OF HPV TYPES IN HIGH GRADE CERVICAL LESIONS IN WOMEN FROM THE DIFFERENT AREAS OF THE WORLD, AND I’LL ALSO REVIEW METHODS USED FOR ATTRIBUTION AND THE REASON FOR THEM THEN FINALLY, I’M GOING TO PRESENT DATA FROM THE U.S. ON HPV TYPE ATTRIBUTION TO NONINVASIVE HIGH GRADE CERVICAL LESIONS AS YOU KNOW, INFECTION WITH GENITAL HPV IS RESPONSIBLE FOR A SPECTRUM OF CERVICAL ABNORMALITIES THE MAJORITY OF THESE ABNORMALITIES ARE BENIGN AND DON’T PROGRESS THE DISEASE IN FACT, ABOUT 90% OF INFECTIONS BECOME UNDETECTABLE WITHIN TWO YEARS WITHOUT CAUSING ANY SYMPTOMS HOWEVER, INFECTION WITH HIGH RISK HPV TYPES CAN PERSIST AND THAT COULD LEAD TO MILD CERVICAL ABNORMALITIES THAT TEND TO REGRESS WITHOUT TREATMENT OR HIGH GRADE LESIONS THAT ARE MORE LIKELY TO PROGRESS INVASIVE CERVICAL CANCER IF THEY ARE NOT TREATED AND ROUTINE CERVICAL CANCER SCREENING WITH THE PAP AND MORE RECENTLY WITH HPV BASED TESTS IS USED TO DETECT PRECANCEROUS LESIONS AS A STRATEGY THE FOCUS OF THIS PRESENTATION IS ON NONINVASIVE HIGH GRADE CERVICAL LESIONS, SPECIFICALLY ON GRADE TWO AND THREE AND SITE TWO, WHICH I WILL BE COLLECTIVELY REFERRING TO AS BINT PLUS THEY ARE THE MOST LIKELY TO PERSIST OF ALL HPV TYPES ABOUT 30% OF CIN TWO-PLUS LESIONS ARE ESTIMATED TO PROGRESS TO CERVICAL CANCER HPV 16 IS THE MOST COMMON TYPE IN CIM LESIONS, WHERE AS HPV 18 IS THE MOST COMMON TYPE IN AIS LESIONS SIN-TWO PLUS WERE USED IN THE TRIALS AND ALSO USED AS INTERMEDIATE END POINTS TO MONITOR POST LICENSURE IMPACT IN SOME COUNTRIES THAT HAVE ESTABLISHED SCREENING PROGRAMS SO THIS GRAPH WAS ADAPTED FROM A META ANALYSIS OF INTERNATIONAL STUDIES THAT WERE CONDUCTED TO DETERMINE HPV TYPE DISTRIBUTION IN NONINVASIVE HIGH GRADE CERVICAL LESIONS IN WOMEN AROUND THE WORLD, AND THE HIGH RISK HPV TYPES HERE ARE COMBINED INTO TWO

GROUPS THE BLUE BARS REPRESENT HPV TYPES 16 AND 18 AND THE RED BARS INCLUDE HPV TYPES 31, 33, 45, 52, AND 58, WHICH ARE THE FIVE ADDITIONAL TYPES IN THE CANDIDATE 9-VALENT VACCINE SO YOU CAN SEE FROM THE BLUE BARS THAT THERE’S VARIATIONS GLOBALLY IN THE PROPORTION OF HPV 16 AND 18 DETECTED IN HIGH GRADE CERVICAL LESIONS FROM 66, OVER 60% IN WOMEN IN NORTH AMERICA, EUROPE, AND SOUTH AND CENTRAL AMERICA TO LESS THAN 50% IN WOMEN IN EAST ASIA AND AFRICA THERE IS LESS VARIABILITY IN THE FIVE ADDITIONAL TYPES, WITH ABOUT 40% DETECTED IN WOMEN ACROSS ALL REGIONS, EXCEPT FOR IN EAST ASIA, WHERE IT WAS DETECTED IN 60% OF LESIONS SO THE OBJECTIVE OF THIS ANALYSIS WAS TO EVALUATE HIGH GRADE HPV TYPE ATTRIBUTIONS TO CERVICAL TYPE TWO AMONG U.S WOMEN AGE 21 TO 39 WHO WERE DIAGNOSED FROM 2008 THROUGH 2011 AND WE ALSO WANTED TO EXAMINE WHETHER HPV TYPE ATTRIBUTION DIFFERED BY RACE AND ETHNICITY SO THESE DATA COME FROM THE HPV IMPACT PROJECT, WHICH IS A POPULATION BASED SURVEILLANCE SYSTEM THAT WAS ESTABLISHED IN 2008 TO MONITOR HPV VACCINE IMPACT ON HIGH GRADE CERVICAL LESIONS AND HPV TYPES ASSOCIATED WITH THEM THIS IS A CDC COLLABORATION WITH FIVE EMERGING INFECTIONS SITES AND IT INCLUDES SIMILAR SIZES WITH ABOUT 300,000 WOMEN IN EACH CATCHMENT, IN CALIFORNIA, CONNECTICUT, NEW YORK, OREGON, AND TENNESSEE AND EACH SITE ARE RATED AND ASKED TO REPORT CONFIRMED IN 18 AND OLDER LABS ARE ALSO ASKED TO SUBMIT ARCHIVE DIAGNOSTIC TISSUE FROM WOMEN DIAGNOSED BEFORE THE AGE OF 40 FOR HPV TYPING DEPENDING ON THE NUMBER OF WOMEN WHO REPORTED AND RESOURCES AVAILABLE, THE SITES REQUEST ALL OR A RANDOM SAMPLE OF SPECIMENS FROM WOMEN FROM EACH REPORTING LAB, AND LABS ARE ASKED TO SELECT TISSUE THAT’S MOST REPRESENTATIVE OF THE DIAGNOSTIC LESION AND TO CUT AND PROCESS THE TISSUE ACCORDING TO STANDARD PROTOCOL FOR SPECIMENS THEN THE PROCESS SPECIMENS ARE SENT TO CDC AND HERE THEY ARE REVIEWED AGAIN BY A PATHOLOGIST TO ENSURE THE TISSUE IS ADEQUATE FOR TYPING, AND IF IT IS, THEN DNA IS EXTRACTED AND TESTED FOR 37 INDIVIDUAL HPV TYPES USING AN ARRAY GENE TYPING AND FOR SPECIMENS NEGATIVE, THEY ARE RETESTED USING A SECOND GENOTYPING AND THAT REPRESENTS THE 10% OF SPECIMENS OVERALL SO BETWEEN 2008 AND 2011, WE HAD ADEQUATE TYPING RESULTS FOR OVER 5,000 SPECIMENS AND ALMOST ALL OF THEM, 97%, WERE POSITIVE FOR HPV AND ONLY A SINGLE TYPE WAS DETECTED IN 79% OF THE SPECIMENS HPV 16 AND 18 WAS DETECTED IN A LITTLE OVER HALF OR 53% OF ALL SPECIMENS, AND HPV 31, 33, 35, 52 AND 58 WERE DETECTED IN 31% OF THE SPECIMENS OVERALL SO THESE ARE TYPING RESULTS BROKEN OUT BY SEVERITY OF LESION, WHICH IS THE LOWEST GRADE, OR THE HIGHEST GRADE LESION IT’S COMBINED BECAUSE OF SMALL NUMBERS, BECAUSE IT REPRESENTS LESS THAN 2% OF ALL THE REPORTED CASES AND THERE’S ALSO ABOUT 900 SPECIMENS IN WHICH SPECIFIC GRADE WAS NOT DISCRIMINATED AND ARE NOT INCLUDED HERE IN THIS TABLE, BUT DO REPRESENT THE TWO GRADES, AND SOME THINGS TO NOTE HERE IS THAT CIM TWO ACCOUNTS FOR A LARGER FRACTION OF ALL DIAGNOSES AND THAT 16 AND 18 TYPES ARE MORE COMMON IN CIN 3 COMPARED TO CIN 2, 63% VERSUS 40%, WHEREAS THE OTHER FIVE ADDITIONAL TYPES IN THE CANDIDATE VACCINE ARE MORE COMMON IN CIN 2 THAN CIN 3 AND AIS THIS GRAPH SHOWS THE P PREVALEN OF INDIVIDUAL HPV TYPES BY HIS LOGIC GREAT GRADE AND JUST TO

ORIENT YOU, THE BLUE BAR INDICATE CIN 2, RED BARS ARE NOT DISCRIMINATED AND ARE LABELED AS FLASH THREE AND THE GREEN BARS ARE CIN 3 OR AIS THE HPV TYPES ARE GROUPED ALONG THE X AXIS, SO THE FIRST GROUP, HPV 16 AND 18 AND WHAT’S NOTABLE HERE IS THAT 16 IS DETECTED BY FAR THE MOST DETECTED TYPE IN ALL OF THE LESIONS, ALTHOUGH IT DOES INCREASE FROM 35% IN CIN 2 LESIONS TO 60% IN CIN 3 AND AIS AND HPV 18 IS RELATIVELY UNCOMMON AND ACCOUNTS FOR ABOUT 5% TO 6% OF LESIONS THEN THE NEXT SET OF TYPES ARE THOSE IN THE CANDIDATE 9-VALENT VACCINE AND HERE, HPV TYPE 31 IS THE MOST COMMON, FOLLOWED BY HPV TYPES 52 AND 58, WHICH ARE BOTH MORE COMMON IN CIN 2 THAN CIN 3 AND 33 AND 35 WERE DETECTED IN LESS THAN 5% OF SPECIMENS ACROSS ALL HISTOLOGIC GRADES THE LAST SET ARE OTHER HIGH RISK TYPES NOT INCLUDED IN ANY VACCINE AND HERE YOU CAN SEE THAT TYPES 31 AND 55 ARE THE MOST COMMON AND THAT THE OTHER TYPES OCCUR IN 5% OR LESS OF SPECIMENS ACROSS ALL HISTOLOGIC GRADES SO FOR THE PURPOSE OF HPV TYPE ATTRIBUTION FOR CERVICAL LESIONS, USUALLY WHEN ONLY A SINGLE HPV TYPE IS DETECTED IN A LESION, THAT TYPE IS CONSIDERED TO BE CAUSED ASSOCIATED WITH THE LESION HOWEVER, MORE THAN ONE HPV TYPE IS DETECTED IN ABOUT 20% OF CINC PLUS LESIONS AND THE ROLE OF EACH TYPE IN THE COINFECTED LESIONS IS LESS CLEAR, SO DIFFERENT METHODS ARE USED TO ATTRIBUTE INDIVIDUAL HPV TYPE OR GROUP OF TYPES TO CERVICAL LESIONS AND THESE METHODS ARE USED TO EVALUATE THE POTENTIAL IMPACT OF HPV VACCINE SO IN THIS ANALYSIS, WE APPLIED THE TWO MOST COMMON METHODS THAT ARE USED FOR HPV TYPE ATTRIBUTION THE FIRST IS HIERARCHICAL, WHICH BASICALLY ASSIGNED ATTRIBUTION TO THE MOST OCOGENIC TYPE IN A LESION SO TO GIVE AN EXAMPLE, IF YOU HAVE A CIN 3 SPECIMEN WITH HPV 16 AND 31 DETECTED IN THE LESION, THE WHOLE SPECIMEN WOULD BE ATTRIBUTED TO HPV 16 SO THIS TEND TO OVERESTIMATES BECAUSE THEY ARE THE MOST OCOGENIC TYPES OF ALL THE HIGH RISK TYPES THE SECOND METHOD IS THE PROPORTIONAL ATTRIBUTION METHOD AND WEIGHTS ARE ASSIGNED TO FREQUENCY IN SINGLE INFECTIONS IN EACH DISEASE GRADE, SO TO USE THE SAME EXAMPLE, WE WOULD CALCULATE THE PROPORTION OF EACH TYPE THAT OCCUR AS A SINGLE INFECTION IN THAT HISTOLOGIC GRADE SO HERE IT WOULD BE 61% OF HPV 16 AND 9% FOR HPV 31, AND THEN THAT IS DIVIDED BY THE SUM OF THE TOTAL ATTRIBUTION OF ALL THE TYPES IN THE LESIONS AND WE FOUND THAT THERE WAS A LESS THAN 2% DIFFERENCE BETWEEN THE TWO METHODS THAT WE APPLIED, SO THE RESULTS I’M GOING TO BE PRESENTING ARE BASED ON THE PROPORTIONAL ATTRIBUTION METHOD OKAY SO HERE IS THE PROPORTIONAL TYPE ATTRIBUTION BY HISTOLOGIC GRADE THE BLUE BARS, AGAIN, ARE CIN 2, CIN 3, AND AIS THE LIGHTER PORTION OF EACH BAR REPRESENTS LESIONS WITH SINGLE TYPE INFECTION AND THE DARK PART AT THE TOP IS MULTIPLE INFECTIONS AND AS YOU CAN SEE, 38% OF CIN 2 LESIONS WERE ATTRIBUTABLE TO HPV 16 AND 18 TYPES AND THE PERCENT ATTRIBUTION OF 16 AND 18 INCREASED WITH THE VARIETY OF LESION UP TO 64% IN CIN 3 AND AIS 28% OF CIN 2 AND SLIGHTLY LESS OF HIGHER GRADES WERE ATTRIBUTABLE TO THE FIVE ADDITIONAL TYPES IN THE CANDIDATE VACCINE AND THE OTHER HIGH RISK TYPE ATTRIBUTION RANGED FROM 21% IN CIN 2 TO LESS THAN 10% IN CIN 3 AND AIS

SO THIS GRAPH SHOWS YOU THE PROPORTIONAL HPV TYPE ATTRIBUTION BY AGE GROUP, AND HERE THE BARS REPRESENT THE GROUPS OF HPV TYPES THE BLUE BARS ARE 16 AND 18, THE RED BARS ARE THE FIVE ADDITIONAL TYPES, AND THE GREEN BARS ARE THE OTHER HIGH RISK TYPES AND AS YOU CAN SEE, HPV TYPE 16 AND 18 ARE ATTRIBUTABLE TO THE HIGHEST PROPORTION OF LESIONS ACROSS ALL AGE GROUPS, HOWEVER, THERE IS A DECLINE IN THE PROPORTION OF HPV 16 AND 18 IN THE OLDEST AGE GROUP, AND IN THAT GROUP, WE SEE AN INCREASE IN THE FIVE ADDITIONAL TYPES AS FAR AS THE OTHER HIGH RISK ATTRIBUTIONS, IT’S FAIRLY SIMILAR ACROSS ALL AGE CATEGORIES THIS GRAPH IS SIMILAR TO THE PREVIOUS ONE, EXCEPT THAT THIS IS PROPORTIONAL TYPE ATTRIBUTION DONE BY RACE AND ETHNICITY AGAIN, I WANT TO POINT YOUR — BRING YOUR ATTENTION TO THE FACT THAT HPV 16 AND 18 ARE ATTRIBUTABLE TO THE HIGHEST PROPORTION OF LESIONS ACROSS ALL RACIAL AND ETHNIC GROUPS, HOWEVER, HPV 16 AND 18 ATTRIBUTION IS HIGHER AMONG NONHISPANIC WHITES, COMPARED TO THE OTHER RACE AND ETHNIC GROUPS CONVERSELY, THE FIVE ADDITIONAL TYPES ARE MORE COMMON IN RACIAL AND ETHNIC MINORITIES COMPARED TO NONHISPANIC WHITES AND THE OTHER HIGH RISK TYPES ARE SIGNIFICANTLY HIGHER IN NONHISPANIC BLACKS COMPARED TO THE OTHER RACIAL AND ETHNIC GROUPS SO THE PREVIOUS SLIDES SHOWED YOU ATTRIBUTION BY GROUPS OF TYPES, AND HERE YOU CAN SEE BROKEN UP BY INDIVIDUAL TYPES, AGAIN, BY RACE AND ETHNICITY, AGAIN, I WANT TO POINT OUT THAT HPV 16 IS THE PREDOMINANT TYPE ACROSS ALL RACIAL AND ETHNIC GROUPS IT IS HIGHER IN NONHISPANIC WHITES COMPARED TO THE NONHISPANIC BLACKS HPV 45, 52, AND 58 WERE SIGNIFICANTLY DIFFERENT BY RACE AND ETHNICITY AMONG THOSE THAT ARE IN THE CANDIDATE 9-VALENT VACCINE, AND THEN THE LAST TWO TYPES ON THIS GRAPH ARE THOSE THAT OCCURRED IN AT LEAST 5% OF LESIONS IN AT LEAST ONE OF THE RACIAL AND ETHNIC GROUPS, AND YOU CAN SEE THAT HPV 35 HERE IS SIGNIFICANTLY HIGHER IN NONHISPANIC BLACKS COMPARED TO THE OTHER TWO GROUPS SO, IN SUMMARY, THESE DATA FROM A LARGE POPULATION BASED SAMPLE OF WOMEN IN THE U.S. SHOWED THAT 50% OF LESIONS ARE ATTRIBUTABLE TO HPV 16 AND 18, AND THE ATTRIBUTION RANGES FROM 40% IN CIN 2 LESIONS TO OVER 60% IN CIN 3 AND AIS ANOTHER 25% OF CIN 2 PLUS LESIONS ARE ATTRIBUTABLE TO HPV 31, 33, 35, 52, AND 58, WHICH ARE INCLUDED IN THE CANDIDATE NINE VALENT VACCINE WE FOUND THAT THERE WAS A HIGHER PROPORTION OF LESIONS DUE TO HPV 16 AND 18 IN WOMEN WHO WERE UNDER THE AGE OF 35, AND THIS IS CONSISTENT WITH EVIDENCE THAT INDICATES HPV 16 AND 18 ARE STRONGER CARCINOGENS AND MORE LIKELY TO PROGRESS FASTER TO DISEASE WE ALSO FOUND THAT THE HIGHEST PROPORTION OF CIN 2 LESIONS WERE ATTRIBUTABLE TO HPV 16 AND 18, IRRESPECTIVE OF RACIAL AND ETHNIC CATEGORY, HOWEVER, THERE WAS A HIGHER PROPORTION OF LESIONS ATTRIBUTABLE TO 16 AND 18 IN NONHISPANIC WHITE WOMEN COMPARED TO OTHER RACIAL AND ETHNIC GROUPS AND THE REASONS FOR THESE DIFFERENCES ARE NOT CLEAR AND PROBABLY MULTIFACTORIAL, BUT MAY BE DUE TO DIFFERENCES IN THE UNDERLYING PREVALENCE OF HPV INFECTION AND THE DIFFERENT SUB POPULATION OR TO DIFFERENCES IN SCREENING AND TREATMENT THANK YOU THANK YOU MUCH WE’RE GOING TO HOLD A COMMENT AND QUESTION UNTIL AFTER THE NEXT PRESENTATION BY DR. SARAIYA >> GOOD MORNING THE OTHER WAY? GOOD MORNING BEFORE I START TALKING ABOUT ATTRIBUTION, I WANTED TO REVIEW THESE DATA FROM THE ANNUAL REPORT TO THE NATION PUBLISHED LAST YEAR SHOWING THE INCIDENCE RATE OF CERVICAL, VAGINAL CANCERS THE ORANGE BAR REPRESENTS ALL

RACE ETHNICITY AND THE TEAL BAR, HISPANIC AND THE PURPLE BAR BLACK AND SO ON, AND I WANTED TO SHOW THE BLACK WOMEN AND HISPANIC WOMEN HAVE THE HIGHEST RATE OF CERVICAL CANCER AND BLACK WOMEN ALSO HAVE THE HIGHEST RATE OF VAGINAL CANCER THE RATE OF ORAL AND ANAL CANCERS BY RACE ARE SEEN HERE, AND HERE WHAT I WANT TO POINT OUT IS BLACK MALES AND FEMALES, AS NOTED BY THE PURPLE BAR, HAVE THE SECOND HIGHEST RATE OF ORAL CANCER AND FOR ANAL CANCER, BLACK MALES HAVE THE HIGHEST RATE THESE ARE INTERNATIONAL DATA ARCHIVED CERVICAL CANCER SPECIMENS, INVASIVE CERVICAL CANCER SPECIMENS COLLECTED ALL AROUND THE WORLD AND TYPED BY ONE LAB AND THE ADDITIONAL TYPES AND THE CANDIDATE 9-VALENT HPV VACCINE, AND THE TITLE IS CALLED “RELATIVE CONTRIBUTION,” BECAUS HPV-POSITIVE CANCERS AND WHEN THE DENOMINATOR DATA IS AMONG ALL CANCERS, THE TERMINOLOGY USED IS ATTRIBUTION IMPORTANT ISSUES TO HIGHLIGHT HERE ARE THE MAJORITY OF CANCERS, WHETHER THEY ARE IN IA, OR EUROPE, HAVE 16, 18, USUALLY IN THE RANGE OF AROUND 70% AND AN ADDITION TO 20% HAVE CONTRIBUTION BY THE OTHER FIVE TYPES THE OTHER THING I WANTED TO POINT OUT HERE WAS THAT THERE HAVE ASES THAT HAVE BEEN ANALYZED IN NORTH AMERICA, AROUND 160, FROM THIS COMPARATIVE STUDY AND THAT’S WHY WE UNDERTOOK THE CDC STUDY I WILL DESCRIBE LATER THE SAME GROUP THAT DID THIS PARTICULAR STUDY HAS ALSO CONDUCTED RELATIVE CONTRIBUTIONS FOR OTHER CANCERS, BUT MOST OF THOSE DATA ARE NOT AVAILABLE THIS SLIDE SUMMARIZES LITERATURE FROM U.S. STUDIES PRIOR TO 2006 THAT HAVE EXAMINED TISSUES FROM THESE PARTICULAR CANCERS AND ATTRIBUTED THEM TO HPV SO THE FIRST COLUMN SUMMARIZES THE ATTRIBUTION TO ANY HPV AND THE SECOND COLUMN SUMMARIZES ATTRIBUTION TO 16 AND 18, SO FOR CERVICAL, FOR EXAMPLE, USING 96% WAS ATTRIBUTABLE TO HPV AND AMONG ALL CERVICAL CANCERS, 76% WERE ATTRIBUTABLE TO 16, 18, AND FOR VAGINAL, 64% FOR ANY HPV AND 56% TO 16, 18 THE OBJECTIVE OF THIS PARTICULAR ANALYSIS WERE TO ESTABLISH SYSTEMIC POPULATION BASED APPROACH TO MONITORING THE HPV TYPES AND CERVICAL, AS WELL AS OTHER HPV ASSOCIATED CANCERS AND TO DETERMINE THE ATTRIBUTION OF 16, 18, AND ADDITIONAL TYPES IN THE CANDIDATE 9-VALENT VACCINE AND SEE IF THERE WERE DIFFERENCES BY RACE ETHNICITY SO THE STUDY, BASICALLY, WE USED CANCER CASES THAT WERE IDENTIFIED THROUGH CANCER REGISTRIES MOST OF WHICH COLLECTED FROM 2004 TO ’05, RIGHT BEFORE THE VACCINE WAS LICENSED TO HELP US GET A BASE LINE THE REGISTRIES HAVE INFORMATION ABOUT THE CANCER DIAGNOSIS, BUT IN ORDER TO GET THE ACTUAL TISSUE SPECIMEN FOR THE CANCER REGISTRIES, WENT TO PATHOLOGY LABS AND THREE HAD EXISTING REPOSITORY MOST OF THE CANCERS THAT WERE COLLECTED WERE INVASIVE CANCERS, BUT WE DID HAVE A FEW CANCERS LIKE CERVICAL INSITU, BECAUSE OF REGISTRIES HAD THE LEGAL AUTHORITY TO COLLECT THESE DATA THE HPV GENOTYPING WAS DONE BY THE CDCSUSAN HARI HARIRI THE ADDITIONAL FIVE TYPES AND THE VALENT VACCINE, ANY OTHER HPV TYPES AND HPV NEGATIVES, AND THE DENOMINATOR INCLUDED ALL CANCERS THIS FIGURE IS A SCHEMATIC OF THE TISSUE SAMPLE REQUEST AND SUBMISSION PROCESS, SO ON THE LEFT-HAND SIDE, THE FOUR CANCER REGISTRY, LOUISIANA, CALIFORNIA, KENTUCKY, GENERATED ELIGIBLE CANCER CASES, SAMPLE THEM, THEN REQUESTED THE LOCAL HOSPITAL PREPARE SEND TO H THE TISSUE THE CDC HPV LAB ON THE — ON THE RIGHT-HAND SIDE WHAT YOU SEE IS HAWAII, IOWA, AND LOS ANGELES COUNTY WHAT THEY DID WAS THEY ALREADY HAD EXISTING TISSUE REPOSITORIES, SO THEY PREPARED THE SAMPLE AND THE TISSUE IN HOUSE AND SENT THEM DIRECTLY TO THE CDC HPV LAB AND IN THE PATH LAB, THE TISSUE SPECIMENS WERE PREPARED ACCORDING TO A COMMON STANDARD PROTOCOL AND THE COMPLETE RESULTS WERE LINKED WITH THE DEMOGRAPHIC DATA COLLECTED BY EACH OF THE CANCER REGISTRIES, AND SO WE HAD 3,017 TISSUE SPECIMENS THAT MADE IT TO THE CDC HPV LAB AND DUE TO EITHER SPECIMEN INADEQUACY OR OTHER ISSUES, WE HAD A FINAL SAMPLE OF

2,670 CANCERS THIS SLIDE SHOWS THAT PERCENT HPV DETECTION BY CANCER SITE, SO IN THE STUDY, YOU ALSO SEE THE NUMBER OF CANCER CASES FOR EACH OF THE SITES 91% HAD HPV OF CERVICAL CANCERS HAD HPV DNA DETECTED 99% OF CERVICAL CANCER, 69% OF BULVAR CANCERS HAD HPV DETECTED, 75% FOR VAGINAL CANCERS, 91% FOR ANAL, 61% FOR PENILE THIS SHOWS THE TOP FIVE CANCER TYPES AND THE SLIDE MIGHT BE DIFFICULT TO SEE IN TERMS OF THE SPECIFIC TYPES, BUT THE BIG, BROAD PICTURE IS HPV 16 IS THE MOST COMMON TYPE IN ALL OF THESE CANCERS AND I WILL GO OVER THESE CANCERS IN A LITTLE BIT MORE DETAIL HERE WE HAVE ATTRIBUTION BY THE FOUR HPV GROUPS, BLUE BEING 16, 18, AND YELLOW THE ADDITIONAL FIVE TYPES AND THE CANDIDATE VACCINE, GREEN BEING OTHER HPV TYPES, AND GRAY, HPV NEGATIVE SO FOR CERVICAL CANCER, YOU SEE 66% OF THE CANCERS HAD 16, 18, ATTRIBUTED TO 16, 18, ADDITIONAL 15% ATTRIBUTED TO THE CANDIDATE OF THE FIVE TYPES IN THE CANDIDATE VACCINE, 10% FOR OTHER TYPES, AND 9% WERE NEGATIVE SO ANAL CANCER HAS THE HIGHEST PROPORTION OF 16, 18 DETECTED AND FOR THE ADDITIONAL FIVE TYPES AND THE CANDIDATE VACCINE, THE CANCERS WITH THE HIGHEST ATTRIBUTION WERE CERVICAL CANCERS, VAGINAL, AND VULVAR CANCERS SO WE CONDUCTED LOTS OF ANALYSES AND THE GENERAL FINDINGS, WHICH WE’LL GO INTO MORE DETAIL, WERE BY AGE, THERE WAS DEFINITELY A HIGHER PROPORTION OF CANCERS IN YOUNGER AGE ATTRIBUTABLE BY RACE ETHNICITY, THERE WAS NO SIGNIFICANCE EXCEPT THE CERVICAL CANCERS AND ORAL CANCERS AND BY GENDER, NO DIFFERENCE EXCEPT FOR ORAL CANCER THIS SLIDE LOOKS AT THE ATTRIBUTION BY RACE ETHNICITY FOR INVASIVE CERVICAL CANCER ON TOP AND INSITU CERVICAL CANCER ON BOTTOM AND THERE ARE DIFFERENCES IN TERMS OF A LOWER PROPORTION OF — LOWER PROPORTION OF 16, 18 LOWER PROPORTION OF 16, 18, FOR BLACK — AMONG BLACK, NONHISPANIC POPULATION, AS WELL AS LOWER PROPORTION AMONG HISPANIC POPULATION SO THIS PATTERN IS SIMILAR TO WHAT WAS SEEN BY HARIRI, BUT WE HAVE TO KEEP IN MIND FOR INSITU CERVICAL CANCERS, WE HAD A LOWER NUMBER OF SAMPLES BUT WE HAVE A PRETTY GOOD SAMPLE SIZE HERE, WHAT YOU SEE IS HPV NEGATIVE PROPORTION WAS LOWER AMONG BLACKS AND HISPANICS THAN WHITES, BUT MORE IMPORTANTLY, THERE WERE NO DIFFERENCES IN THE PROPORTIONS OF 16 AND 18 67%, 68%, AND 64%, OF THE DIFFERENT RACIAL ETHNIC GROUPS MANY OF YOU MIGHT ASK HOW CAN CERVICAL CANCERS BE NEGATIVE? WE HAVE THIS PREVIOUS STUDY THAT’S FOUND 99.7% TO BE HPV POSITIVE, BUT WE HAVE TO KEEP IN MIND THAT THE STUDY WAS BASED ON MULTIPLE HPVS THAT WERE DONE AND CANCERS THAT MATCHED SELECT CRITERIA AND WHAT WE’RE DOING IS A POPULATION BASED SURVEILLANCE STUDY THERE MAY BE MISCALCULATION OF THE ANATOMIC SITE IN THAT THE LOWER SEGMENT UTERINE CANCERS CANNOT BE DISTINGUISHED FROM THE UPPERS, THERE MAY BE FALSE NEGATIVES IN THERE IS HPV, BUT WE CAN’T DETECT IT OR THE SPECIMEN AND TISSUE IS NOT WELL PRESERVED, THEN THERE ARE ACTUALLY TRUE HPV NEGATIVE HPV NEGATIVE CERVICAL CANCERS ALBEIT THE RARE HISTOLOGY 1% TO 2% AT THE MOST THIS SLIDE LOOKS AT ANAL CANCERS HERE ON THE LEFT-HAND SIDE WHAT YOU SEE THERE’S NOT MANY DIFFERENCES BY RACE ETHNICITY FOR 16/18 ATTRIBUTION ABOUT 80% IS ATTRIBUTED BY AGAINER ON THE RIGHT-HAND SIDE THERE ARE NO DIFFERENCES, 79% COMPARED TO 80% AMONG FEMALES ALTHOUGH IT APPEARS THAT FEMALES MAY HAVE A HIGHER PERCENTAGE OF THE ADDITIONAL FIVE TIMES THAN THE CANDIDATE VACCINE THIS DIFFERENCE WAS NOT SIGNIFICANT THIS IS OROPHARYNGEAL CANCER, AN

HPV ATTRIBUTION ON THE LEFT-HAND SIDE WHAT WE SEE IS THE RACE FOR 16/18 WHAT WE SEE IS THAT THERE’S A HIGHER PERCENTAGE OF NEGATIVE CANCERS FOR BLACKS 50% COMPARED TO 25% TO 27% FOR WISE AND HISPANICS AND A LOWER PROPORTION OF 16/18 CANCERS OVERALL AMONG BLOCKS EVEN WHEN THE CANCER ARE LIMITED TO HPV POSITIVE CANCERS BY AGAINER HIGHER PROPORTION OF HPV NEGATIVE CANCERS AMONG FEMALE AND LOWER PROPORTION OF HPV 16/18 CANCERS AS WELL SO IF WE USE THE DATA FROM THIS PARTICULAR STUDY AND REVISED OUR ESTIMATED PERCENTAGES, WE CAN DEFINITELY SAY WITH MORE AUTHORITY THAN POPULATION BASED THAT OUR ATTRIBUTION RATE FOR POSITIVITY WOULD BE SLIGHTLY REVISED FOR CERVICAL WE SEE 91% WITH HPV ATTRIBUTES 61% THE CERVICAL CANCER 58% AND 15% FOR THE ADDITIONAL ON THE SAME NOTE LIKE FOR EXAMPLE FOR OROPHARYNGEAL, FOR MALES 72% WOULD BE HPV ATTRIBUTABLE AND 63% FOR 16/18 AND 4% OF THE NINE TIMES VACCINE 62% OF INVASIVE CANCERS ARE ATTRIBUTABLE TO 16/18 THIS RANGES FROM PENILE AND ANAL CANCERS AND WHEN YOU LOOK AT IT BY GENDER 62% OF IF HE MALES ATTRIBUTABLE TO 16/18 COMPARED TO MALES THIS TRANSLAYS TO 25,000 CASES ANNUALLY 11% OF THE INVASIVE CANCERS ARE ATTRIBUTABLE TO THE ADDITIONAL FIVE TIMES THIS RANGES BASED ON THE CANCER TYPE 6% FOR OROPHARYNGEAL AND 18% FOR VAGINAL DIFFERENCE BY AGAIN GENDER FOR RACIAL ETHNIC DIFFERENCES THE ATTRIBUTION IT WAS ATTRIBUTABLE TO HPV POSITIVE OR HPV 16/18 AMONG BLACKS THIS DATA WILL BE USEFUL IN ESTIMATING THE CANDIDATE VACCINE ON CANCERS AS WELL AS COST EFFECTIVE ANALYSIS I WOULD LIKE TO ACKNOWLEDGE THE CO-AUTHORS FOR THIS PARTICULAR STUDY AS WELL AS THIS PRESENTATION >> THANK YOU I THINK WE’RE OPEN FOR QUESTIONS VERY HELPFUL PRESENTATION SUSAN I THINK YOU KNOW I’M A BIG FAN OF THE IMPACT STUDIES BUT I WONDER IF I UNDERSTAND CORRECTLY THE CASES THAT YOU ARE LOOKING AT HERE, THEY SPAN A TIME RANGE OF BEFORE AND AFTER WHEN THE VACCINE WAS BEING USED AND GIVEN WHAT WE KNOW ABOUT COVERAGE WHICH WAS GIVEN LOW, I’M WONDERING WHETHER WE MIGHT BE UNDERESTIMATING THE AMOUNT WE CAN ATTRIBUTE TO AND 18 IF WE’RE INCLUDING IN THE STUDIES SOME OF THE CASES OCCURR BASICALLY AFTER THE VACCINE IS ALREADY BEING UTILIZED OR IF YOU THINK THAT’S AN ISSUE OR NOT SURE, THAT’S QUITE POSSIBLE FOR THAT THANK YOU FOR THAT COMMENT AS YOU KNOW, WITHIN HPV PROJECT ONE OF THE THINGS THAT WE TRY TO DO IS COLLECT HPV VACCINATION HISTORY ON ALL THE CASES AND WE CAN’T, SOMETIMES CAN’T FIND HPV VACCINATION HISTORY ON EVERYBODY BUT WE DO HAVE VACCINATION HISTORY ON ABOUT 50% OF THE CASES, AND AMONG THOSE THAT WE HAD VACCINATION HISTORY FOR THERE WAS A PRETTY SIZABLE PROPORTION IN THE 18 TO 20-YEAR-OLD FEMALES AND I DID NOT PRESENT THAT DATA HERE I ACTUALLY EXCLUDED THOSE THERE WERE A FEW IN THE 21 TO 29-YEAR-OLD GROUP BUT WHEN WE EXCLUDED THOSE FROM THE ANALYSIS IT DIDN’T SIGNIFICANTLY CHANGE THE RESULTS SO, IT’S POSSIBLE THAT THERE IS SOME IMPACT, BUT BECAUSE WE DON’T HAVE, YOU KNOW, VACCINATION HISTORY ON 50% OF THE CASES, IT’S REALLY HARD TO KEEP THAT APART THANK YOU VERY MUCH FOR THIS PRESENTATION

I WONDER IF YOU COULD REMIND US ABOUT COST PROTECTION AGAINST NON16/18 FROM THE VACCINES WHICH TYPES MIGHT THERE BE PROTECTION AGAINST AND DO THE VACCINES DIFFER IN THEIR ABILITY TO DO THAT? >> SO, THERE HAS BEEN SOME CROSS PROTECTION SHOWN FOR BOTH VACCINES, MOSTLY IN TYPE 31, 33 AND 45, AND I THINK THE CROSS PROTECTION HAS BEEN A LITTLE BIT STRONGER FOR THE VACCINE ALTHOUGH IT’S DIFFICULT TO COMPARE THE TWO VACCINES HEAD-TO-HEAD SO, YES, THERE’S SOME CROSS PROTECTION THAT’S BEEN DEMONSTRATED, THE DURATION OF PROTECTION IS UNKNOWN BUT, YEAH THERE DOES SEEM TO BE SOME CROSS PROTECTION >> CAROL HAYES WITH AMA DR. HARIRI I HAD A QUESTION RELATED TO YOUR SLIGHT 17 AND 11 YOU MAY NOT BE ABLE TO ANSWER THE QUESTION WHEN I LOOK AT THE DATA IT APPEARED TO ME THERE WERE TWO STRAINS OF HPV THAT SEEM TO BE HIGHER THAN THE ONES USED IN THE NEW 9-VALENT VACCINE AND I’M CONFUSED BY THAT THE ONES OVER ON THE RIGHT YOU CAN SEE THAT 51 AND 35 ARE HIGHER THAN 33 AND 45 SO WHY WERE 35 AND 51 NOT INCLUDED IN THE VACCINE AND WHY WAS 33 AND 45? I’M NOT SURE THAT I CAN REALLY ANSWER THAT QUESTION ONE THING THAT I WANT TO POINT OUT, THOUGH, IS THAT THIS PREVALENCE IS VERY LOW COMPARED TO TYPE 16 ACROSS THE BOARD FOR ALL OF THE TYPES AND YOU’RE RIGHT THAT 35 AND 51 ARE MORE COMMON BUT THAT’S MOSTLY IN THE CIN2 LESIONS WHICH ARE KIND OF A LOWER HISTOLOGIC RATE AND ARE PROBABLY NOT THE TRUE PRE-CANCERS THE PREVALENCE IS SIGNIFICANTLY LOWER IN THE CIN3 AND AIS LESIONS BUT AS FAR AS, YOU KNOW, THE DECISION TO — WHICH TYPES TO INCLUDE IN THE VACCINE I CAN’T REALLY SPEAK TO THAT AND JUST TO — THESE ARE PRE-CANCERS AND MOST OF THE DECISIONS ARE BASED ON TYPE OF CANCE ARE LESS LIKELY TO PRODUCE CANCERS THAN 16 AND 18? [ INAUDIBLE ] THEY ARE IN THE CURRENT VACCINE THERE’S A LITTLE BIT OF A DIFFERENCE BETWEEN THE U.S. DATA SHOWN HERE AND THE GLOBAL RATE >> THANK YOU DR. BENNETT >> THANK YOU THANK YOU FOR THIS GREAT PRESENTATION IT’S TERRIFIC I’M INTERESTED IN THE RACIAL DIFFERENCES COULD YOU REMIND US WHAT WAS SHOWN IN THE CARRIAGE DATA WHICH FROM THE NA SURVEY WHAT THE RACIAL DIFFERENCES IN THOSE AT THAT TIME AS WELL? SO, WE CAN ACTUALLY MONITOR HPV PREVALENCE USING THE NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY WHICH IS THE NATIONAL SURVEY OF THE NON-INSTITUTIONALIZED U.S POPULATION WE LOOKED AT HPV TYPE PREVALENCE OVER TIME AND, YES, IT’S TRUE THAT THERE ARE RACIAL DIFFERENCES, BUT MOSTLY THE DIFFERENCES ARE THAT THERE’S A HIGHER PREVALENCE OF TYPES, OF ALL TYPES IN NON-HISPANIC BLACKS COMPARED TO NON-HISPANIC WHITES AND WE’RE SORT OF — WE’RE IN THE PROCESS LOOKING AT THE DATA MORE CLOSELY BUT THERE DOESN’T SEEM TO BE A DIFFERENTIAL INCREASE OR DECREASE IN THE PREVALENCE OF THE TYPES OF 16 AND 18 SO IT’S JUST HIGHER FOR ALL THE TYPES WE’RE LOOKING AT THAT DATA NOW >> SO, YOU HAVE ANY THOUGHTS ABOUT WHY WE WOULD FIND THAT PATTERN IN THE EARLY LESIONS AND IT SOUNDS LIKE NOT IN THE EITHER — DIFFERENCES IN 16 AND 18? >> YEAH AS I SAID 16 AND 18 ARE MORE OF MORE ONCOGENIC POTENTIAL THAN THE OTHER TYPES AS YOU SAW IN DR. SARAIYA’S

PRESENTATION WE DON’T SOME ANY DIFFERENCE IN RACE WHEN WE LOOK AT CANCERS AND LESIONS YOU KNOW, LIKE I SAY, IT’S REALLY — WE’RE NOT REALLY SURE WHAT ATTRIBUTES THE DIFFERENCE, RACIAL DIFFERENCES TO BUT IT COULD HAVE SOMETHING TO DO WITH THE PREVALENCE COMBINED WITH THE DIFFERENTIAL ONCOGENIC DIFFERENCES OF THE TYPE BUT THAT’S SOMETHING THAT NEEDS BE FURTHER INVESTIGATED >> ANY OTHER COMMENT OR QUESTIONS? ALL RIGHT THANK YOU I GUESS WE MOVE ALONG TO THE PRESENTATION FROM DR LUXEMBOURG GOOD MORNING, EVERYONE. IN O OF LAST YEAR AND THIS TIME WE ARE GOING TO SHOW YOU SOME OF THE KEY DATA FROM THE PROGRAM JUST A FEW ABBREVIATIONS FOR EVERYONE TO BE ON THE SAME PAGA HERE SO WE TALK ABOUT 2 HPV VACCINE ONE IS 9-VALENT VACCINE WHICH IS THE INVESTIGATIONAL VACCINE AND 9 VH HPV AND LICENSED VACCINE IS QHPV GENITAL LESIONS THAT WE TALK ABOUT HAVE ALSO BEEN MENTIONED CIN, CERVICAL VIN, VUL SAR INTRAEPITHE LYNCH AL VEIN VAGINAL INTRAEPITHELIAL GRADE 2/3 HIGH GRADE LESION, PRE-CANCER A FEW SLIDES EXISTING VACCINE COVERS 70% OF CANCERS WORLDWIDE NEXT MOST FREQUENT TYPES WITH POTENTIAL TO REACH 90% PREVENTION SO TO ANSWER THE QUESTION THAT WAS ASKED PREVIOUSLY, FIVE NEW TYPES WAS THE FREQUENCY IN CANCER, NOT IN PRE-CANCER AND DYSPLASIA AND CANCER WORLDWIDE THE FIVE TYPES THAT ONCOGENIC REPRESENT TYPE TO 6% TOTAL CANCER WORLDWIDE LOOKING NOW AT PRE-CANCERS, AGAIN WORLDWIDE, THERE IS ALSO A POTENTIAL FOR ADDITIONAL COVERAGE WITH THE NEW TYPES AND ESPECIALLY THE PRE-CANCERS THERE’S A POTENTIAL TO INCREASE PROTECTION FROM 50% WITH THE VACCINE TO 80% WHICH EXCEEDS THE BEST CERVICAL CANCER SCREENING PROGRAMS IT’S AN EXCITING POSSIBILITY AS YOU CAN SEE CONTRIBUTION IN CANCER IS SLIGHTLY LOWER THAN IN PRE-CANCER, AND MOST LIKELY DUE TO A FASTER PROGRESSION OF CANCER WITH TYPE 16 AND 18 AS WAS DISCUSSED BEFORE SO, YOU KNOW, THE POTENTIAL, YOU KNOW, IN THE PREVIOUS SLIDE, THE POTENTIAL IS NOT ONLY PREVENTION OF CANCER WORLDWIDE BUT ALSO POTENTIAL OF PREVENTION OF PRE-CANCER LESION WHICH MEANS IN COUNTRIES WHICH CERVICAL CANCER SCREENING PROGRAM, LOWER NEED FOR INVASIVE PROCEDURES BECAUSE THESE PRE-CANCER CELLS ARE

TREATED BY SURGERY LOWER COST, LOWER HEALTH CARE, BETTER QUALITY OF LIFE, LOWER RISK THEY ARE A WIDE RANGE OF BENEFIT THAT COULD BE INCUBATED ON THIS SLIDE YOU SEE THE VACCINE, IT’S AN LPV VACCINE IT LOOKS LIKE A VIRUS OUTSIDE IT LOOKS LIKE A VIRUS, IT IS SEEN AS A VIRUS IT CONTAINS TYPES 6 AND 11 WHICH ACCOUNT FOR 60% OF THE GENITAL WARTS AND BENIGN LESIONS 16 AND 18 RESPONSIBLE FOR MOST CERVICAL CANCERS THE INTERVENTION IS THE SAME THE AMOUNT HAS BEEN INCREASED TO KEEP IT TO 20 RATIO THE SAME AND AMOUNT OF ANTIGEN FOR THE ORIGINAL TYPES HAS ALSO BEEN INCREASED TO PRESERVE IT THE GOAL IS TO TRANSFER FROM FOUR TO NINE VALENT IT WAS DESIGNED TO ASSESS THAT THE GOAL IS TO SHOW FOUR ORIGINAL TYPES, THE TWO VACCINES ARE THE SAME WE WANT TO TRANSITION FULLY WE WANT THE VACCINE TO DO THE SAME AS THE ORIGINAL VACCINE IN ADDITION FOR THE NEW ADDITIONAL TYPES WE WOULD LIKE TO DEMONSTRATE THAT THE NEW VACCINE PROVIDES SUBSTANTIAL BENEFIT, WHICH MEANS IT’S HIGHLY PRODUCTIVE AGAINST INFECTION DUE TO ADDITIONAL TYPES THIS IS THE TARGET POPULATION HOWEVER WE CANNOT ASSESS BECAUSE THEY ARE NOT EXPOSED TO HPV MOST OF THEM AND SO SIMILAR TO WHAT WAS DONE IN THE VALENT PROGRAM, THE FINDINGS IN YOUNG WOMEN EXPOSED TO HPV WILL BE EXTENDED BASED ON ETHNICITY THE PROGRAM IS DESIGNED TO DEMONSTRATE THAT FINALLY OBVIOUSLY WE WANT TO DEMONSTRATE THE SAFETY TOLERABILITY IS ACCEPTABLE IT WOULD SHINE OUR MINDS THAT THIS IS DONE WITH SIX STUDIES WHICH ARE INCLUDED IN THE INITIAL FINDING ON THIS SLIDE YOU HAVE THE THREE STUDIES THAT SUPPORT THE KEY INDICATION, WE HOPE AND THE STUDY RESULTS WILL BE PRESENTED TODAY ONE IS THE PROGRAM IN YOUNG WOMEN STUDIES COMPLETED AND THE EXTENSION IS ON GOING TO ASSESS LONG TERM EFFECTIVENESS AS I MENTIONED WE CONDUCTED IMMUNOBRIDGING STUDY.ED STUDY I EXTENSION IS ON GOING FOR TEN YEARS OR SO TO ASSESS LONG TERM EFFECTIVENESS PROTOCOL NINE IS TO ASSESS WHETHER THERE’S A VALENT IN THE SAME ETHNICITY NEXT SLIDE IS GOING TO SHOW STUDIES, THE THREE MOST STUDIES WE INCLUDED IN THE INITIAL FINDINGS AND WILL BE PRESENTING THAT AT THE NEXT HPV MEETING SEEN TWO VACCINES THAT ARE COMMONLY USED AND WITH 9-VALENT FIVE ADDRESSES THE VACCINE AND VACCINE COMMONLY USED IN AMERICAS AND SEVEN REPRESENTS REPEVAX COMMONLY USED IN THE EUROPEAN UNION AND FINALLY THERE’S ONE STUDY THAT YOU NEED, WHICH IS TO ASSESS THE VACCINES, THE 9-VALENT VACCINE HPV RECIPIENTS AMONG THEM EVEN A SMALL FRACTION IS INTERESTED IN VACCINATION WITH 9-VALENT, WE FEEL OBLIGED TO PROVIDE DATA AND YOU CAN MAKE

THE CHOICE WE LOOK FOR AN INDICATION IN THAT CASE BUT FEEL IT’S IMPORTANT TO DISCUSS AND FINALLY YOU COULD ASK THE YOUNG MEN BECAUSE THE INITIAL FIND CIGARETTE IN BOYS 9 TO 15 YEARS OF AGE GIRLS AND YOUNG 920 YEARS OF AGE THE YOUNG MEN’S STUDIES IS ONGOING, STARTED LATER BUT WE’LL HAVE THE RESULTS LATER THIS YEAR THESE ARE NOT THE ONLY STUDIES ONGOING FOR THE 9-VALENT PROGRAM FOR SAKE OF TIME WE CANNOT PRESENT EVERYTHING BUT I WOULD LIKE TO MENTION ALSO ONE STUDY THAT MAY BE OF INTEREST OF THIS GROUP, WE HAVE RECENTLY STARTED AN EVALUATION OF THOSE MEN FOR THE 9-VALENT VACCINE WHY THE 9-VALENT VACCINE BECAUSE THE FOCUS IS ON THE 9 VA LENT AND NOT ON THE 4-VALENT WE EXPECT FULL TRANSITION VERY RAPIDLY IN THE U.S. AND SO THE FOCUS OF THE DOSE IS ON 9-VALENT WE HAVE INITIAL STUDIES TO ADDRESS THE QUESTION OF FEASABILITY TODAY WE’LL TALK ABOUT STUDY RESULTS DATA AND THE DATA WILL FOCUS ON YOUNG WOMEN AND SAFETY FROM PROTOCOL ONE THEN WE TURN TO — PROTOCOL 2 AND 9, TWO EMERGING STUDIES PROTOCOL ONE IS A VERY LARGE STUDY IT’S ENROLLED MORE THAN 14,000 YOUNG WOMEN IT WAS A BLIND STUDY WE DIDN’T CHOOSE PLACEBO FOR ETHICAL REASONS IT’S WILDLY RECOMMENDED, WIDELY AVAILABLE AND WE CAN’T HAVE PEOPLE WITH PRE-CANCER IN OUR STUDIES SO KEEP IN MIND THE STUDY WAS CONDUCTED IN 2007, CONDUCTED ONE YEAR AFTER THE DRUG WAS LICENSED AND AT THAT TIME FOCUS WAS REALLY TO BRIDGE TO THE 9-VALENT THE KEY POINT, WOMEN WITH GENITAL, BEGGYNOCOLGY EXAMINATI AND PAP TEST EVERY SIX MONTHS THERE’S A TRIAGE TO ASSESS ETHNICITIES WERE ASSESSED FOR ALL HPV TYPES AND ALSO ASSESSED THROUGH STAND OUT METHODS SO ONCE AGAIN VERY LARGE EFFORT, VERY LARGE TRIAL IT’S BEEN GOING ON FOR ALMOST SIX YEARS NOW AND SUBJECTS HAVE HAD FOLLOW UP UP TO FOUR YEARS POST-VACCINATION A SCREENING EVERY SIX MONTHS TO MAKE SURE WE DON’T MISS ANY LESIONS SO WE HAVE A VERY HIGH QUALITY DATA PACKAGE HERE NEXT SLIDE IS SHOWING THE PRIMARY OBJECTIVE ONCE AGAIN WE DON’T HAVE A PLACEBO CONTROL A CONTROL IS EXISTS FOR THE VALENT VACCINE WHICH WE KNOW IS HIGH LLY EFFICACIOUS AND IF IT’S SUCCESSFUL WE EXPECT VERY FEW 9-VALENT FROM THE ORIGINAL TYPES WHICH MEANS HEAD-TO-HEAD COMPARISON BASED ON EFFICACY AND PARTS IS NOT FEASIBLE WE’LL HAVE TOO FEW END POINTS TO MAKE A COMPARISON BASED ON THAT THE DEMONSTRATION OF EFFICACY, PRIMARY DEMONSTRATION ON ETHNICITY ORIGIN THE GOAL TO BRIDGE THE EFFICACY FINDINGS WITH THE VACCINE TO THE 9-VALENT VACCINE FOR THE ADDITIONAL TYPES WE EXPECT A DIFFERENCE BETWEEN THE TWO VACCINES IN TERMS OF THE END POINTS AS MENTIONED THERE’S SOME CROSS PROTECTION BUT IT IS STILL, YOU

KNOW, INSUFFICIENT TO COVER ALL THE TYPES AND SO WE SHOULD USE THE VALENT TO VACCINATED TYPES IF KNIGANYTHIN ANYTHING, IT MEA UNDERVACCINATION SO HERE WE HAVE TWO TYPES THE POPULATION THAT I USED FOR THE PRIMARY, WE WANT TO ANALYZE THE VACCINE IN WOMEN THAT ARE NOT INFECTED FOLLOW THEM DURING THE STUDY FOR INFECTION AND INCIDENT OF INFECTION SO SIMILAR — DEFINITION VERY SIMILAR TO THE ONE USED PREVIOUSLY IN VALENT PROGRAM SUBJECTIVE TO BE NEGATIVE FOR HPV AND DURING THE VACCINATION PERIOD AND RECEIVE THREE VACCINATIONS WE ALSO HAVE PROTOCOL DEFINITION AS WELL SUBJECT RECEIVED THREE DOSE, COMPLIANCE WITH THE STUDY WAS VERY GOOD AND THERE WAS NO DIFFERENCE BETWEEN THE TWO VACCINE CALLS AND 90% CONTINUED IN THE EFFICACY EVALUATION PHASE WE’RE LOOKING HERE AT, YOU REMEMBER WE’RE LOOKING AT ORIGINAL TYPES FIRST AND LOOKING AT ETHNICITY WE’RE LOOKING AT SEVEN ANTIBODY WHICH IS CONCOMITANT AND USED FOR ALL FOUR TYPES WITH GENDER RATIOS CLOSE TO ONE, AND, YOU KNOW, THESE DEMONSTRATE PRIMARY EFFICACIES EVERY INDIVIDUAL VANED WITH THE REGIMENT AFTER THREE DOSES LET’S EXAMINE THE DATA FOR THE ADDITIONAL TYPES THAT’S PRIMARY OBJECTIVE YOU ARE LOOKING AT THREE EFFICACY POINTS LOOKING AT DISEASE OR INFECTION CAUSED BY ANY OF THE FIVE NEW TYPES ON THE FIRST OUR PRIMARY POINT HIGH GRADE CERVICAL AND VAGINAL DISEASE DUE TO ANY OF THE NEW TYPES AND THEN WE HAVE CERVICAL OF ANY GR IN THE HIGH 90s WE NOW HAVE TWO VACCINES THAT ARE BASED ON THE SAME TECHNOLOGY, AND TWO DIFFERENT CLINICAL TRIALS TO BE SHOWED HIGHLY EFFICACIOUS WE HAVE TWO VACCINE FROM THE SAME FAMILY OR FAMILY OF VACCINE, FAMILY OF PRODUCT NEXT SLIDE HERE WE’RE LOOKING AT CERVICAL AND VAGINAL DISEASE TAKEN SEPARATELY FOR HIGH GRADE CERVICAL, ALL GRADE CERVICAL DISEASE, HIGH GRADE VAGINAL DISEASE, IT WAS VERY HIGH AS WELL AND I WOULD LIKE TO MENTION THAT WE HAVE ONE CASE OF HIGH GRADE CERVICAL DISEASE IN THIS CASE IT’S CO-INFECTED WITH A KNOWN VACCINE TYPE, TYPE 56 AND IT MOST LIKELY TYPE 56 IS A

CAUSAL OF, CAUSAL VIRUS BECAUSE THE SUBJECT WAS INFECTED FROM DAY ONE AND THROUGH THE FIRST TWO YEARS WHEREAS 58 WAS FOUND ONLY, ONLY AT THE TIMES THE EFFICACY WAS DONE IT WAS MOST LIKELY A TRANSIENT INFECTION SLIDE NEXT SLIDE SHOWS PROCEDURES THAT ARE RELATED, SEE ADDITIONAL TYPES YOU CAN SEE HERE THAT DIFFERENT THERAPI THERAPIES IT IS DECREASED IN VERY SUBSTANTIAL AS WELL WHICH TELLS YOU THAT NOT ONLY THE VACCINE HAS A POTENTIAL PUT TO PRESENT PROCEDURES NOW VACCINE RELATED EXPERIENCES ARE SUMMARIZED HERE AND HERE COMPARISON BETWEEN THE TWO VACCINES IT LOOKS THE SAME WITH VERY FEW VACCINE-RELATED ADVERSE EXPERIENCE NO VACCINE RELATED DEATHS VERY FEW DISCONTINUATION REALLY THE ONLY DIFFERENCE THAT CATCHES THE EYE SO TO SPEAK IS AT INJECTION SITE WHERE THERE’S A HIGHER FREQUENCY FOR INJECTION SITE SO WE’LL LOOK AT THE DATA IN MORE DETAIL I WOULD LIKE TO SAY IT’S NOT A SURPRISE WE HAVE KNOWLEDGE OF THAT AND MORE LET’S LOOK AT THE INJECTION SITE DATA HERE WE’RE NOT SEEING SWELLING WHICH IS BY FAR THE MOST COMMON AND WE CAN SEE THAT THERE IS A DIFFERENCE FOR ALL THREE IN PARENTHESIS IT’S STATISTICAL DIFFERENCE FROM THE CLINICAL STANDPOINT MOST INJECTION SITES WERE OF LOWER INTENSITY WITH BOTH VACCINES SO WE ANTICIPATE THAT THE CLINICAL SIGNIFICANCE OF IT WILL BE MINIMAL LOOKING NOW AT SYSTEMIC VACCINE-RELATED EVENTS, HERE WE HAVE ALL SYSTEMIC VACCINE-RELATED WITH MORE THAN 2% I WANT TO REMIND YOU WE’RE LOOKING AT A STUDY OF 14,000 SUBJECTS ALL EVENTS ARE EVERY DAY LIFE EVENTS, ú COMMONLY USED IN MANY VACCINE STUDIES AND THERE’S REALLYLY NO SUBSTANTIAL DIFFEREE BETWEEN THE TWO VACCINES WE HAVE OBSERVED — WE HAVE OBSERVED FOUR VACCINE RELATED EVENTS, TWO IN THE 9-VALENT GROUP AND TWO IN THE 4-VALENT GROUP THESE IN TERMS HAVE ALREADY BEEN SEEN PREVIOUSLY IN THE 4-VALENT GROUP, IN THE 4-VALENT CLINICAL PROGRAM AND ALL EVENTS WERE PROMPTLY RESOLVED IN CONCLUSION FOR PROTOCOL ONE, IN TERMS OF EFFICACY WE DEMONSTRATED NON-INFERIOR IMMUNE RESPONSE DEMONSTRATED 97% REDUCTION IN DISEASE THE VACCINE THAT APPEAR WELL TOLERATED IN MORE THAN 7,000 YOUNG WOMEN AND ADVERSE EXPERIENCES PROFILE WAS GENERALLY COMPARABLE BETWEEN THE TWO VACCINES WE NOTED HIGHER FREQUENCY OF INJECTION SITE ADVERSE EVENT WITH 9-VALENT VACCINE BUT MOST WERE OF MILD OR MODERATE INTENSITY LET’S GO TO PROTOCOL TWO NOW LET’S SWITCH GEARS AND WE HAVE FOUR GOALS AND ONE IMPORTANT GOAL IS TO ASSESS PROTOCOL TWO IS INTERNATIONAL STUDY TO DEMONSTRATE NON-INFERIOR IMMUNIMMUNOGENICIT WE WANT TO DEMONSTRATE THE SAME SAFETY HERE, STUDY INCLUDES BOYS AND GIRLS

AND AS WELL AS YOUNG WOMEN THEY RECEIVED A VACCINE THREE DOSE REGIMEN AND ACCESSED DAY ONE TO MONTH 12 IN TERMS OF ANTIBODY, YOU SEE HERE THE GMT IN GIRLS VERSUS YOUNG WOMEN GIRLS ARE IN PINK AND YOUNG WOMEN ARE IN RED AND IT’S CLEAR THAT WE MET NON-INFERIORITY IS HIGH IRIN SOME GIRLS COMPARED TO YOUNG WOMEN IT’S DIFFERENT FROM WHAT HAS BEEN SEEN IN THE 4-VALENT PROGRAM THE GMT RATIO IS AROUND TWO ONCE AGAIN, ANOTHER SIMILARITY SIMILAR SAFETY, SIMILAR EFFICACY LET’S GO NOW TO BOYS, NEXT SLIDE AND THE BOYS ALSO — I’M SORRY BEFORE WE GO TO BOYS LET’S LOOK AT RATES THIS SLIDE SHOWS GO FROM NINE TYPES AFTER THE REGIMEN BOTH IN GIRLS AND YOUNG WOMEN NOW WE’LL TALK ABOUT THE BOYS AND AS YOU CAN ANTICIPATE, THE BOYS ARE IN BLUE SO WE HAVE BOYS IN BLUE AND YOUNG WOMEN IN RED HERE, AND LIKE THE COMPARISON BETWEEN THE GIRLS AND THE YOUNG WOMEN, BOYS HAVE A HIGHER IMMUNOGENOCITY WE HAVE CLEARLY SUPERIOR IMMUNOGENOCITC AS WELL RATES WERE VERY GOOD THROUGH ALL SUBJECTS IN ALL NINE TYPES SAFETY, THIS IS A SAFETY SCENARIO OF VACCINE ADVERSE EVENTS ONE TO 15 FOLLOWING VACCINATION AND IT’S APPARENT THAT THE SAFETY PROFILE IS SIMILAR BETWEEN THE THREE DEMOGRAPHIC GROUPS SAFETY MIGHT EVEN LOOK SLIGHTLY MORE FAVORABLE WITH THE BOYS, WHICH IS SIMILAR TO WHAT HAS BEEN SEEN FOR THE 4-VALENT VACCINE FOR THE VALENT PROGRAM IN CONCLUSION WE’VE DEMONSTRATED NON-INFERIOR IMMUNOGENICITY WHICH SUPPORTS THE FINDINGS IN YOUNG WOMEN TO THE OTHER SAMPLE POPULATION AND VACCINE WAS GENERALLY WELL TOLERATED AT ALL AGE AND GENDERS LET’S FINISH NOW WITH PROTOCOL NINE PROTOCOL NINE WAS AN IMMUNOBRIDGING STUDY IT ASKED A DIFFERENT QUESTION HOW ABOUT IMMUNOGENICITY LET’S LOOK AT THE NEXT SLIDE A SMALLER STUDY, DOUBLE BLINDED AND WE LOOKED AT SEVEN COMPLIANCE WAS VERY GOOD MOST SUBJECTS COMPLETED THE STUDY, RECEIVED THE THREE DOSE REGIMEN AND NON-INFERIORITY WAS DEMONSTRATED HERE WE’RE LOOKING AT THE TWO TYPES 16 AND 18 AND IT’S COMPARABLE BETWEEN TWO VACCINES IT MIRRORS IN THE YOUNG WOMEN AND THE TWO VACCINES HAS THE SAME PROFILE NEXT PROFILE SHOWS 16 AND 11 AND SIMILAR OBSERVATION, WE HAVE ETHNICITY MOST SUBJECTS HAD 100% SUBJECTS AFTER THREE DOSE REGIMEN IN BOTH VACCINE GROUPS WHICH SHOWED THE VACCINE WAS HIGHLY IMMUNOGEN IN CONCLUSION WE DEMONSTRATED COMPARABLE IMMUNIMMUNOGEN VACCI YOUNG GIRLS IN THE POPULATION IT WAS BETWEEN 9-VALENT AND 4-VALENT FOR SAKE OF TIME I DIDN’T SHOW THE DATA MOST INJECTION SITES WERE

MODERATE INTENSITY IN CONCLUSION, WE BELIEVE WE HAVE SUCCESSFUL CLINICAL PROGRAM WE’VE MET ALL EFFICACY AND IMMUNOAGAIN — IMMUNOGENOCITY AND ALSO IN ADULTS VACCINE WAS GENERAL WELL TOLERATED THESE THREE STUDIES TAKEN TOGETHER INCLUDE MORE THAN 10,000 SUBJECTS AND THE PROFILE WAS GENERALLY SIMILAR THERE ARE MORE DATA TO PRESENT AND, YOU KNOW, WE’LL KEEP THAT FOR THE NEXT TIME WE MENTIONED ASSESSMENT IN STUDYING YOUNG MEN HOPEFULLY IT’S GOING TO BE AVAILABLE BEFORE THE END OF THE YEAR AND WE WOULD LIKE TO SHOW THAT ALSO TO THIS GROUP PRESENTLY, THE 9-VALENT VACCINE IS STILL UNDER INVESTIGATION EVEN THOUGH THE STUDY HAS COMPLETED THE PRODUCT IS UNDER NO FDA REVIEW AND IT’S UNDER STANDARD REGULAR REVIEW AND HAS RECENTLY BEEN ACCEPTED AND VALIDATED AND WE EXPECT REGULATORY ACTION WITHIN THE NEXT FEW MONTHS THANK YOU VERY MUCH THANK YOU LET’S OPEN IT FOR QUESTIONS? YES, DR. JENKINS >> IN TERMS OF ADVERSE EVENTS FOR THE 4-VALENT VACCINE, THE EFFICACY FOLLOWING THE VACCINATION AND I DIDN’T SEE THAT AS ANYTHING YOU MENTIONED WE MENTIONED THE EVENT SO IT WAS THE MOST FREQUENT THERE WAS NO EVENT OF 4 DURING THE STUDY AND OBVIOUSLY WE’VE TAKEN ALSO PRECAUTIONS SO SUBJECT TO OBSERVE AND, YOU KNOW, THERE WAS NO, THERE WAS NO EVENT LIKE THAT THERE WAS ONE EVENT OF SYNCOPY PRIOR TO BE OBSERVATION >> THANK YOU YOU MAY HAVE MENTIONED IT WHAT DOES THIS LOOK LIKE IN HPV POSITIVE? >> THE QUESTION HIV POSITIVE WOMEN HAVE NOT BEEN STUDIED ALL THE STUDIES HAVE BEEN DONE IS COMMON IN VACCINE STUDY IN HEALTHY SUBJECTS THERE’S A STUDY IN HIV POSITIVE CHILDREN, 7 TO 12 YEAEARS OF AG FOR 4-VALENT VACCINE AND GIVEN THAT THE IMMUNOGENOCITY PROFILES THE TWO VACCINES ARE VERY SIMILAR WE WOULD EXPECT THE SAME SAFETY AND IMMUNOGENOCITY PROFILE ONE THAT POPULATION AS WELL >> ALL RIGHT ANY DIFFERENCES IN SIDE EFFECT BETWEEN THE FIRST, SECOND AND THIRD DOSE? THIRD DOSE OF THE PROFILE? THERE ARE DIFFERENCES, AND IN TERMS OF FREQUENCY OF INJECTION SITES SWELLING AND INJECTION SITE THE FREQUENCY INCREASE BY DOSE AND IT’S SIMILAR TO WHAT’S BEEN OBSERVED PREVIOUSLY WITH THE 4-VALENT VACCINE AS A FOLLOW UP TO THAT DO YOU HAVE ANY DATA ON WOMEN WHO MAY BE, MAY HAVE RECEIVED THREE DOSES OF HPV-4 WITH REGARDS TO INJECTION SITE REACTION IN THESE WOMEN IF THEY RECEIVED THIS HPV-9 VACCINE? >> YOU KNOW, THEY MENTIONED AT THE BEGINNING OF THE TALK WE CONDUCTED ONE STUDY AND ONE OF THE PRIMARY GOALS WAS TO LOOK AT THREE AND WE HAVE FOUND THE SAFETY PROFILE WAS ACCEPTABLE AND THAT THERE WAS NO, YOU KNOW, MAJOR INCREASE IN TERMS OF INJECTION SITE >> THANK YOU THAT WAS REALLY VERY COMPREHENSIVE AND CLEAR AND

REALLY ACROSS MULTIPLE STUDIES AND POPULATIONS, YOU’RE SHOWING THIS NON-VALENT VACCINE TO BE COMPARABLE TO GARDASIL WHICH IS GREAT NEWS THERE WAS A PRESS RELEASE TODAY THAT REPORTED THAT GARDASIL RECEIVED A POSITIVE OPINION FROM EMA FOR A PSEUDO SCHEDULE I’M WONDERING YOUR CLINICAL DEVELOPMENT PLAN FOR THE NO NON-PSEUDO SCHEDULE WE’RE RECOGNIZING THE TOPIC TO THE STUDY HAS BEEN INITIATED FOR THE 9-VALENT AND WE WANT, OBVIOUSLY, FIRST TO DEMONSTRATE THE FEASIBILITY WE RECOGNIZE ALSO LONG TERM FOLLOW UP IN TERMS OF LONG TERM EFFECTIVENESS, IN TERMS OF THE DURATION OF PROTECTION FROM TWO DOSE VERSUS THREE DOSE IS A CRITICAL QUESTION WE NEED TO TALK MORE ABOUT THE PLANS AT THIS STAGE BUT WE HAVE STUDIES STARTED AS A FOLLOW UP TO THAT, HOW LONG HAS YOUR LONG TERM FOLLOW UP OF THE VALENT TO THOSE PROGRAMS HAVE BEEN AND, THEREFORE, WHAT COULD BE EXPECTED WITH THE 9-VALENT? SO, JUST TO MAKE SURE I UNDERSTAND THE QUESTION, WE HAVE LONG TERM FOLLOW UP FOR THREE DOSE REGIMEN FOR THE 4-VALENT, THAT’S YOUR QUESTION, RIGHT? >> I WAS REACTING TO THE COMMENT THAT THE EMU JUST APPROVED TWO DOSE FAVORABLE OPINION >> AT THIS TIME THERE IS NO EVALUATION OF LONG TERM EFFECTIVENESS FOR TWO DOSE REGIMEN >> OKAY THANK YOU >> ANY ADDITIONAL QUESTIONS? OKAY, SEEING NONE, DR MARKOWITZ I’LL GO A FEW THINGS ABOUT FLANS AND GO KNOW THE UPDATED ACIP STATEMENT WE WOULD LIKE AFFIRMATION OF TODAY WE HEARD THE HIGH GRADE IS CERVICAL LESIONS ABOUT 11% TO THE FIVE ADDITIONAL TYPES AND LARGEST PERCENT OF HPV CANCERS AATTRIBUTABLE TO 16/18 SOME DIFFERENCES FOR OROPHARYNGEAL BUT NOT FOR THE OTHER CANCERS WE HEARD THIS VERY CLEAR SUMMARY OF SOME OF THE DATA FROM THE NON-VALENT CLINICAL TRIALS AGAINST DISEASE RELATED TO THE FIVE ADDITIONAL TYPES AND IMMUNOBRIDGING STUDY THIS IS AN EXPAND VERSION OF THE TIMELINE THAT DR. BOCCHINI PRESENTED AND FOR CONSIDERATION OF THE VACCINE BY ACIP SO TODAY WE HEARD THE TYPES ON ATTRIBUTION WE HOPE TO HEAR ON ADMINISTRATION AND THE DATA ABOUT NON-VALENT VACCINE AND WE’RE ALSO PLANNING TO HEAR ECONOMIC DATA WE’RE HOPING THE DATA AT THAT TIME WILD BE AVAILABLE THAT’S CURRENTLY ON GOING IN MALES 16 TO 20 YEARS OF AGE DISCUSSION OF OPTIONS AND FOR RECOMMENDATIONS AND THEN IF THE VACCINE IS LICENSED THERE WOULD

BE A VOTE IN FEBRUARY THE CONSIDERATIONS ARE BEING UNDERTAKEN BY THE WORK GROUP, ONE OF COURSE IS FOR RECOMMENDATION OF ROUTINE VACCINATION AT AGE 11 OR 12 WE’RE CONSIDERING THE RECOMMENDATION FOR VACCINATION OF OLDER FEMALES AND MALES WHO WERE NOT VACCY NAETD AT THE RECOMMENDED AGE AND WE’RE DISCUSSING THE TIMING FOR CONSIDERATION EVER MALES 16 TO 26 BECAUSE WE ANTICIPATE THAT THE VACCINE WILL NOT BE LICENSED IN THIS AGE GROUP AT TIMES OF FIRES LICENSURE WE’RE CONSIDERING VACCINATION OF PERSONS PARTIALLY OR FULLY V Y VACCINATED OTHER HPV VACCINE WORK GROUP ACTIVITIES WE’RE FOCUSING ON THE NON-VALENT VACCINE WE HAVE ON GOING REVIEW OF POST-LICENSURE SAFETY AND COVERAGE DATA AND KEEPING ABREAST ON THE DATA OF REDUCED DOSE SCHEDULE ULS FOR HPV WE’LL REVIEW IT IN MORE DETAIL IN THE FUTURE I WANT TO MENTION BRIEFLY, SOMETHING ABOUT THE REDUCED DOSE SCHEDULES BECAUSE THERE WAS A QUESTION AT THE LAST MEETING, THERE IS GLOBAL INTEREST IN THESE SIMPLIFIED SCHEDULES IT WOULD REDUCE THE LOGISTICAL CHALLENGES THERE’S DATA AVAILABLE THESE ARE PRIMARILY IMMUNOGENOCITY STUDIES SOME JURISDICTIONS ARE USING TWO DOSE SCHEDULES IN THEIR NATIONAL PREVENTION IMMUNIZATION PROGRAMS THEY GRANTED MARKETING FOR CERVARIX FOR GIRS 20914 YEARS AS A TWO-DOES THE 9-VALENT VACCINE IS CURRENTLY IN TRIALS WHICH WE JUST HEARD WE’LL BE KEEPING ABREAST OF THESE DATA AND REPORT BACK TO ACIP NOW I WOULD LIKE TO TOTALLY CHANGE GEARS AND TALK ABOUT THE UPDATED HPV VACCINE ACIP STATEMENT WE TALKED ABOUT THIS AT THE LAST ACIP MEETING AS WELL THIS REVIEWS EVOLUTION OF VACCINE RECOMMENDATIONS IN THE U.S THE FIRST RECOMMENDATION WAS IN 2006 FOR QUADRIVALENT VACCINES IN FIANCE MEDALS THE TOP TWO BOXES ARE RECOMMENDATIONS FOR FEMALES THE BLUE BOXES IS FOR MALES THE MOST RECENT RECOMMENDATION WAS MADE IN 2011 FOR ROUTINE VACCINATION IN MALES BECAUSE OF THE EVOLVING RECOMMENDATIONS AFTER WHAT WAS PUBLISHED IN 2007 WE PUBLISHED THREE POLICY NOTES 2010 THERE WAS A RECOMMENDATION FOR ROUTINE VACCINATION IN FEMALES AND ALSO QUADRIVALENT VACCINES IN MALES IN 2011 WAS RECOMMENDATION OF ROUTINE VACCINATION OF MALES AND THIS IS THE ONLY RECOMMENDATION MADE USING GRADE BECAUSE GRADE HAD BEEN ADOPTED BY ACIP JUST BEFORE THAT POLICY NOTE SO THE OBJECTIVES OF THE UPDATED HPV VACCINE STATEMENT ARE TO CONSOLIDATE RECOMMENDATIONS FOR FEMALES AND MALES, TO CONSOLIDATE RECOMMENDATIONS FOR THE VA LENTZ AND QUADRI VALENT VACCINES AND THE WORDING THAT’S DIFFERENT AND UPDATE BACKGROUND INFORMATION AND DATA REGARDING EFFICACY, SAFETY AND ET CETERA THIS OVERLAPS WITH OUR CONSIDERATION OF THE 9-VALENT VACCINE BUT WE FEEL THAT THE UPDATED STATEMENT WILL FACILITATE FUTURE PROGRAMS THE COMMITTEE HAS SEEN THIS DOCUMENT BEFORE AND I’M GOING TO JUST GO THROUGH VERY BRIEFLY SOME PARTICULAR ISSUES THE SECTIONS THAT WE’VE INCLUDED IN THIS STATEMENT ARE VERY SIMILAR TO THE SECTION IN THE 2007 ORIGINAL DOCUMENT, THEY INCLUDE BACKGROUND ON BIOLOGY, NATURAL HISTORY WE INDIVIDUAL THE DATA ON CANCERS THAT WAS PRESENTED TODAY AND THE OTHER HPV RELATED OUTCOMES BUT WE HAVE A SECTION ON PREVENTION, TREATMENT AND CERVICAL CANCER SCREENING WHICH

WAS UPDATED WE HAVE A SECTION CALLED HEALTH CARE AND RESEARCH LABORATORY WORKERS DATA ON VACCINES HAS BEEN UPDATED WITH THE CLINICAL TRIAL DATA FROM THE END OF STUDY DATA WE HAVE DATA IN HERE ON THE CROSS PROTECTION WE TALK ABOUT THE POST-LICENSURE SAFETY DATA WHICH WAS NOT AVAILABLE AT THE TIME OF THEIR ORIGINAL STATEMENT, OF COURSE IN IN 2007 WE HAVE SECTIONS ON ECONOMIC BURDEN OF HPV DISEASE AND COST EFFECTIVENESS WE HAVE A SECTION ON THE VACCINATION PROGRAM IN THE U.S AGAIN THAT WAS NOT IN THE ORIGINAL DOCUMENT IN 2007 A SUMMARY OF OUR RATIONALE AND THEN THE STANDARD SECTIONS UNDER THE RECOMMENDATION THIS IS THE MAIN RECOMMENDATION IN HERE WE COMBINED THE WORDING FROM THE FEMALE AND MALE RECOMMENDATION WE INDIVIDUAL THIS WITH THE COMMITTEE IN OCTOBER WE HAD A SEPARATE STATEMENT FOR THE FEMALE AND MALES AND WE RECEIVED FEEDBACK THAT WE SHOULD COMBINE THIS SO CURRENTLY IT READS ACIP RECOMMENDS ROUTINE VACCINATION AT AGE 11 OR 12 YEARS WITH HPV 4 OR 2 FOR FEMALES AND HPV 4 FOR MALES IT CAN START AT AGE 9 YEARS WE TALK ABOUT THE DOSING INTERVALS AND THEN VACCINATION IS ALSO RECOMMENDED FOR FEMALES AGE 13 TO 26 YEARS AND FOR MALES AGE 13 TO 21 YEARS WHO HAVE NOT BEEN PREVIOUSLY VACCINATED SO THIS IS THE COMBINED STATEMENT FOR THE MAEMS AND THE FEMALES THE OTHER SUB SECTIONS IN THE RECOMMENDATION SECTION ARE THE SPECIAL POPULATIONS AND THE PRECAUTIONS AND CONTRAINDICATIONSES IN THE DOCUMENT THAT I DISTRIBUTED TO THE ACIP NUMBERS WE HAD LACTATING WOMEN IN THE WRONG SECTION SECTION HERE IS SEXUAL ASSAULT OR ABUSE WE DISCUSSED THIS WITH ACIP SEVERAL TIMES THEN PRECAUTIONS AND CONTRAINDICATIONS WE’VE HAD IN PREVIOUS STATEMENTS FOR IMMUNO COMPROMISED PERSONS THIS IS OUR RECOMMENDATION ROUTINE VACCINATION AT 11 OR 12 YEARS AND IT’S RECOMMENDED THROUGH AGE 26 YEARS IN COMPROMISED PERSONS WHO HAVE NOT BEEN VACCINATED PREVIOUSLY AND MEN WHO HAVE HAD SEX WITH MEN HAS BEEN UNCHANGED HISTORY OF SEX ABUSE OR ASSAULT WHILE HPV VACCINATION WILL NOT PROMOTE VIRAL COR PROTECT AGAINST DISEASE PROGRESSION DUE TO TYPES ALREADY ACQUIRED, VACCINATION WOULD PROTECT AGAINST VACCINE-PREVENTABLE TYPES NOT YET ACQUIRED ACIP RECOMMENDS HPV VACCINATION BEGINNING AT AGE 9 YEARS FOR CHILDREN AND YOUTH WITH ANY HISTORY OF SEXUAL ABUSE OR ASSAULT WHO HAVE NOT INITIATED SEX HERE WE SAY HPV-4 IS CONTRA INDICATED IN PERSONS WITH HISTORY OF HYPER SENSITIVITY TO YEAST AND SYRINGES OF HPV 2 HAVE LATEX IN THE RUBBER STOPPER AND SHOULD NOT BE USED IN PERSONS WITH ANAPHYLACTIC LATEX ALLERGY VACCINE IS NOT RECOMMENDED FOR PREGNANT WOMEN THE REST OF THE WORDING THE SAME WE HAD IN OUR PREVIOUS STATEMENTS WE HAVE A NEW SECTION INCLUDED ON MONITORING IMPACT OF VACCINATION WHICH INCLUDES LICENSURE IMPACT DATA AND AREA OF ONGOING RESEARCH, ACTIVITIES AND HERE AS WE MENTION AD VARIETY OF ISSUES VERY BRIEFLY INCLUDING INVESTIGATION OF 9-VALENT VACCINE AND REDUCED DOSE SCHEDULES WE RECEIVED MULTIPLE VERY HELPFUL COMMENTS FROM ACIP MEMBERS AS WELL AS OTHER REVIEWERS THESE WERE MULTIPLE SMALL EDITS, REQUEST FOR CLARIFICATION REQUEST FOR MODIFICATION OF WORDING OF SECTION ON HISTORY OF SEXUAL ABUSE BUT NO CHANGE IN THE RECOMMENDATION AND WE RECEIVED REQUEST ON POST-LICENSURE SAFETY EVALUATION THIS IS A TABLE THAT’S IN THE ACIP STATEMENT YOU’VE SEEN THIS I WANT TO POINT THIS OUT HERE WE HAVE LISTED THE POST-LICENSURE SAFETY STUDIES

THAT HAVE BEEN DONE THIS IS AN UPDATE OF A TABLE THAT WAS INCLUDED IN A MWR ON HPV LAST SUMMER AND IT INCLUDES THE DATA FROM THESE STUDIES WE ADDED ADDITIONAL TEXT TO THE ACIP STATEMENT TO DESCRIBE BRIEFLY EACH OF THESE STUDIES AND THESE ARE A FREMPBS THAT TABLE FOR YOUR INFORMATION SO IN SUMMARY THE DRAFT STATEMENT UPDATES BACKGROUND INFORMATION AND CLINICAL TRIAL DATA IT CONSOLIDATES AND CLARIFIES RECOMMENDATIONS I WANT INCLUDES A VARIETY OF NEW SECTIONS AND WE INCLUDED A SUBSTANTIAL AMOUNT OF DATA THIS HAS TO GO THROUGH CLEARANCE, EDITORIAL CLEARANCE I’M SURE THERE WILL BE A LOT OF ADDITIONAL CHANGES AND WE HOPE TO HAVE IT PUBLISHED IN THE SPRING, HOWEVER WE DO KNOW THAT THERE’S A LOT OF NEW DATA THAT’S GOING AVAILABLE AND WE UNDERSTAND THAT RECOMMENDATIONS WILL BE UPDATED IN THE FUTURE AS MORE DATA BECOME AVAILABLE SO I WANT TO THANK THE WRITING TEAM AND THE WORK AND THE LARGE NUMBER OF STAFF THAT HAVE BEEN INVOLVED IN ALL THESE EFFORTS I THINK WE’RE READY TO HAVE QUESTIONS AND A VOTE THANK YOU, DR. MARKOWITZ FOR A VERY THOROUGH REPORT I WANT TO REMIND THAT IT’S OUR GOAL AT ACIP TO RENEW, REVISE OR RETIRE STATEMENTS ABOUT EVERY FIVE YEARS SO THIS IS VERY TIMELY, WITH EVERYTHING THAT’S GONE THROUGH THIS AND THE OTHER MENTION FOR THE REST OF THE AUDIENCE HERE IS ALL THE ACIP MEMBERS HAVE RECEIVED THIS DOCUMENT AND HAVE REVIEWED AND SUBMITTED COMMENTS ON IT PREVIOUSLY BUT COMMENTS? BOY WE’RE CHIMING IN THERE’S A MOTION TO ACCEPT THE REVISED RECOMMENDATION YOU KNEW THAT, EXACTLY I’VE HAD A CHANCE TO REVIEW THE DOCUMENT I’VE SEEN THE WORK THAT’S GONE IN FROM EVERYONE SO THAT’S MY MOTION DO WE HAVE A SECOND? I SEE SEVERAL BUT WE’LL GIVE CREDIT TO DR. BENNETT >> I SECOND THE MOTION ADDITION COMMENT? I THINK THIS IS THE WORK DONE BY DR. MARKOWITZ AND THE REST OF THE HPV TEAM THIS I THINK FOR ALL OF US WAS A VERY READABLE — ANY TIME WE RECEIVE ANYTHING OF 50 PAGES TO REVIEW IS DAUNTING BUT THIS READ VERY QUICKLY AND WENT VERY NICELY SO I GUESS WE CAN GO FOR A VOTE AND WE’LL START TO THE RIGHT YES >> YES YES >> YES YES >> YES YES >> YES YES >> YES YES >> YES YES >> YES SO THE MOTION IS APPROVED UNANIMOUSLY WE THANK, AGAIN, THE HPV WORK GROUP FOR THIS BEFORE YOU STEP DOWN, LAURI, I’M WONDERING IF THERE’S ANY COMMENT OR QUESTION FOR THE WORK GROUP REGARDING KIND OF THE NEXT STEPS? I’M JUST REFLECTING ON THE DISCUSSION YESTERDAY ABOUT HOW DIFFICULT IT IS TO CONSIDER MAKING A CHANGE OR ESTABLISH A VERY SUCCESSFUL VACCINE PROGRAM TRYING TO REDUCE DOSES I’M CURIOUS AS TO WHAT TYPE OF INFORMATION WE’RE GOING TO SEE ON, YOU KNOW, POTENTIAL REVIEW SCHEDULES IN THE NEXT COMING MONTHS WE’VE BEEN WATCHING VERY CLOSELY THESE DISCUSSIONS FOR THE VACCINE BUT WE DON’T HAVE ANYTHING TO BRING FORWARD TO ACIP WE’RE KEEPING ABREAST AND WHAT’S HAPPENING AND WE’RE AWARE THERE’S A LOT OF INTEREST IN THIS AREA I UNFORTUNATE WANTED TO MAKE THAT POINT AND THAT’S WHY I RAISED IT BECAUSE THERE’S A LOT OF INFORMATION, THERE WILL BE MORE INFORMATION COMING ONE

WE’RE HAPPY TO PRESENT THOSE DATA BUT WE’RE NOT REALLY READY TO CRITIC AT THIS TIME ANY TYPE OF A MOTION OR CONSIDERATION BY ACIP >> THANKS FOR CONSOLIDATING THESE RECOMMENDATIONS AS WE ALL KNOW, HAVING GUIDANCE OUT THERE VERY USE FOWL PROVIDE TOWERS STRONGLY RECOMMEND THIS VACCINE AND I WANT TO TAKE THIS OPPORTUNITY IN LYING OF WHAT YOU JUST VOTED ON TO POINT OUT THE YOU A DEAR COLLEAGUE LETTER THAT’S NOW IN FRONT OF YOU ALONG WITH A PRESS RELEASE TO MARKET THE LETTER, ESSENTIALLY URGING PROVIDERS TO NOT JUST GAVE RECOMMENDATION FOR HPV VACCINATION BUT THE RECOMMENDATION ACTUALLY HAS TO BE A VERY STRONG RECOMMENDATION THE TAG LINE FOR THIS DEAR COLLEAGUE LETTER ESSENTIALLY IS WHAT YOU SAY MATTERS BUT HOW YOU SAY IT MATTERS EVEN MORE AND IT’S BEEN A DELIGHT TO COLLABORATE WITH THE AMERICAN ACADEMY OF PEDIATRICS AND AMERICAN ACADEMY OF FAMILY PHYSICIANS, AND WITH THE CDC TO CREATE THIS DEAR COLLEAGUE LETTER THAT YOU NOW SEE IN FRONT OF YOU THIS DEAR COLLEAGUE LETTER WAS LAUNCHED TWO DAYS AFTER THE CANCER PANEL AND WE’RE INDEED FORTUNATE TO BE COLLABORATING WITH THE PANEL TO MARKET THEIR REPORT AND THIS LETTER HAS BEEN VERY FAVORABLE RECEIVED IN THE MEDIA I WANT TO DRAW YOUR ATTENTION TO THAT IF THERE’S ANY QUESTIONS YOU CAN DIRECT HOME TO ME THANK YOU VERY MUCH >> THANK YOU THIS IS JEAN SMITH MEDICAL OFFICER WITH ACIP IN THE LAST TWO DAYS WE HEARD MENTION OF TWO NERVES, THE 50 YEAR ANNIVERSARY OF ACIP, AND THEN THE 20 YEAR ANNIVERSARY OF THE IMPLEMENTATION OF THE AFC THIS IS THE TEN YEAR ANNIVERSARY OF LAURI MARKOWITZ SERVING AS THE WORK GROUP LEAD [ APPLAUSE ] SHE HAS WORKED WITH SEVERAL ACIP MEMBERS SERVING AS WORK GROUP CHAIR AND I CAN PERSONALLY SAY THAT I’M ASTONISHED AT HER FORTITUDE AS PROBLEMS AND ISSUES ARE THROWN UP AGAIN AND AGAIN AND SHE ALWAYS MARCHES FORWARD WITH ABSOLUTE CALM THANK YOU, LAURI [ APPLAUSE ] >> THAT WAS A NICE WAY TO END THE SESSION