Cervical Cancer Vaccine

>> thank you, and welcomeback to our morning session. next up is hpv vaccine. and to introduce this session,we're going to wait a minute because i don't think -- oh no. dr. kempe is thereand ready to go. >> good morning. it is my great privilegeto begin discussion of hpv vaccines today. since 2006, as you know, hpvvaccination has been recommended

as a three-dose series. the acip hpv vaccineworking group and acip have revieweddata on to those schedules over the last year and a voteis scheduled for this meeting. so just to remindus, in february, we presented backgroundon to two-dose schedules, both in the u.s. andnationally, internationally. we also discussedthe nine-valent, two-dose immunogenicitytrial data,

and we further discussed data,two-dose data from the two, two-valent and four-valenthpv vaccine. in june, we had a updateon hpv vaccine supply. we discussed the durationhpv vac protection after the three-doseseries for the two- and four-valent hpv vaccines. we presented data on the impactand cost-effectiveness modeling for two-dose schedules. we also discussed post-licensurevaccine effectiveness studies

for the two- andfour-valent hpv vaccines. we presented grade andwe made recommendation, we discussed recommendationsand considerations. since june, we have heldmonthly conference calls. we have reviewed further data from the nine-valent two-dosetrial including follow-up data through month 12, and thatwill be presented today. and discussed further issuesabout intervals between doses. we have discussedpolicy options,

and drafted recommendations. in october, the fdaapproved a two-dose series for persons age 9 to 14years and provided an update, updated nine-valent hpv label,including immunogenicity data from the, from trials. and updated dosage and administrationinformation, as you see here. and we'll be discussingthese in, in more depth. there are a couple of issuesthat arose relatively recently

that we are going to suggestthat we table right now, but that we expect the workinggroup would like to come back and discuss with youat future meetings. one is potentiallyrevisiting the wording for the routine recommendedage groups. there's some people that feelstrongly this should move earlier, and we wouldlike to bring back that, that topic at a later date. there's also some people inthe working group and some

of our liaisons whofeel strongly about revisiting the upperage recommendation for males as opposed to females. those issues we feltwould require more data and more discussion thanwe have time for today. and therefore, we welcomediscussion but would like to proceed withthe primary goal today of discussing thetwo-dose schedule. so today, first lauri markowitzwill review the evidence

for the two-dose schedules. elissa meiteswill discuss our proposed recommendations for atwo-dose hpv vaccination. we will then havepublic comment, a vote, and hopefully a vfc vote. thanks so much. >> okay, good morning. in this presentation, i'mgoing to provide an overview of evidence for two-doseschedules and i will start

with some backgroundon hpv vaccines and our recommendations. and then provide a summaryof evidence focusing on data presented to acipover the last two meetings, and also present some new dataon the nine-valent vaccine from the two-dose trial. and i'll end with some data onvaccine coverage in the u.s. and some programmaticconsiderations. by way of review there arethree hpv vaccines licensed

in the u.s.: bivalent,quadrivalent and nine-valent. and these vaccines are allvirus-like particle vaccines composed of the l1capsid protein. the bivalent's produced bygsk and the quadrivalent and nine-valent by merck. and while all of these arevirus-like particle vaccines, they differ in thetypes that they target, in the production systems,and in their adjuvants. the first vaccinewas licensed in 2006.

that was quadrivalent, and themost recent nine-valent in 2014. this slide shows changes inour vaccine recommendations since the beginningof our program. in 2006, the quadrivalentvaccine was licensed and recommended for females. in 2009, the bivalentvaccine was licensed, and it was includedas one of the vaccines that was also recommendedfor females. also in that year,

the quadrivalent vaccinewas licensed for males, and acip made a statement that the vaccine maybe given to males. and then in 2011, quadrivalentvaccine was recommended for routine vaccinationof males. and then in 2015,after licensure of the nine-valent vaccine, thatvaccine was recommended as one of three vaccines thatcould be used in females, and one of two for males.

and since the beginningof the program, a three-dose schedule has beenrecommended for all vaccines. this is our currentrecommendation. acip recommends routinevaccination age 11 or 12. the vaccination seriescan be started beginning at age nine years. vaccinations recommendedthrough age 26 for females, through age 21 for malesnot vaccinated previously. three-dose series, and again,the vaccines for males,

for females and males. vaccine use and availability inthe united states is changing. through 2014, almostall vaccine used in the united states wasquadrivalent vaccine. this year, almost allvaccine, over 90%, is nine-valent vaccine. gsk has made a decision tostop supplying bivalent vaccine in the u.s. due tolow market demand. and u.s. supplies of thebivalent vaccine are expected

to be used up by november 2016. only nine-valentvaccine has been on the cdc contractssince april 2016. and merck has decided to distribute onlynine-valent vaccine in the u.s. after the end of this month. bivalent and quadrivalentvaccine will continue to be available outside the u.s.now i'll start on the review of evidence on thetwo-dose schedules.

as background, i justwant to remind everyone that for the initiallicensure of the hpv vaccines as a three-dose schedule,data were obtained on efficacy and immunogenicity,and these included data from large randomized,controlled trials in nine to -- in 15 to 26 year olds withthe end points being cervical pre-cancer lesions, aswell as other pre-cancers and genital warts forthe quadrivalent vaccine. and data from bridgingimmunogenicity trials

in 9 to 15 year olds. and licensure in thisyounger age group was based on non-inferior antibodyresponse compared to the young adult womenin the efficacy trials. the three-dose schedule for which the vaccines wereoriginally tested and licensed, the zero, one to two,and six month interval, can be considered aprime-prime-boost schedule with the first twodoses being the primes,

and the last dosebeing the boost. and the two-dose schedulesthat are being studied, such as the zero-six monthschedule can be considered a prime-boost with the secondprime being eliminated. memory b cells require aboutfour to six months to mature and differentiate intohigh-affinity b cells, and the approximate six-monthinterval between the first and the last doseallows the last dose to efficiently reactivatememory b cells.

so the evidence reviewedfor two-dose schedules by the work group and byacip include immunogenicity, post hoc analysis of efficacy, post-licensure effectivenessstudies, health economic models, and data on durationand protection. and i'll go through eachof these very briefly. most of the dataused for evidence on two-dose schedulesare immunogenicity data, and this slide summarizessome of these data.

i'll show in more detailsin the following slides. immunogenicity trialscomparing two and three doses havebeen conducted for all three hpv vaccines. and the main analysesand those considered by regulatory authoritiesare comparisons of the antibody responseafter two doses and the young adolescents,about 9 to 14 years of age with three doses on theadult women, 16 to 26.

again, this comparisongroup is the age group and the vaccine schedule forwhich efficacy was demonstrated in the large randomizedcontrol trials. immuno bridging analysesare used because the basis of protection, whileit's felt to be due to neutralizing antibodyafter vaccination, there's no establishedminimum protective threshold for protection. trials of all three ofthese vaccines found

that the antibodyresponse after two doses, given at either zero-sixor zero-twelve months in 9 to 14 year olds is not inferiorto the antibody response after three doses inthe older age group. some trials also comparedtwo and three doses in the same age group, 9 --about 9 to 14 years of age, and the results vary by trial. and antibody titers arelower after two doses versus three doses for some ofthese, some of the hpv types

in some of the trials. based on data from theimmunogenicity trials, regulatory authorities haveapproved two-dose vaccination schedules, and theseare being used, these schedules arebeing used in, in multiple countries worldwide. now i want to spend a littlebit of time reviewing data from the nine-valent trial. this shows the study designof the trial which lead

to fda approval of the two-doseschedule earlier this month. there are five studyarms in the trial. three study arms at9 to 14 years of age. a group of girls receivedvaccine at zero-six, a group of boys receivedvaccine at zero-six, and a combined group of girls and boys received vaccineat zero to12 months. and then there were two groupsreceived a three-dose schedule, females 16 to 26 years,considered the control group,

and females 9 to14 that were used as an exploratorycomparison group. and the primary analyses ofthose that were submitted to fda for review were the results ofone month after the last dose. and these are the data reviewedby fda, by fda as well as by cdc and acip in february 2016. and follow-up to assessantibody persistence is planned at month 12, 24, and 36. and just a very brief review,you've seen these data before.

one month after the last dose, there were non-inferiorgeometric mean antibody titers in girls received two doses atzero-six, shown here in blue. compared with women who receivedthree doses shown in yellow. and the gmts were in facthigher in the younger age group. and the geometric mean titerratios are shown below the graph, and they rangefrom 1.6 to 2.96. for the differenttypes of the lower band above of the [inaudible]above 1 for all types.

and results for thecomparison with the boys who received the vaccine atzero-six months are similar. and this slide shows the results in a two-dose zero-12month group. again, there were non-inferiorgmts in the two-dose group shown in blue compared to women who received threedoses, shown in yellow. and again, the gmts werenot only non-inferior but significantly higherin the younger age group

who received two doses,and the gmt rations range from 1.96 to 6.31. at the time of presentationto acip in february, only data from one month afterlast dose were available, and recently the work groupreviewed data from six months after the last dose, andthese are shown on this and the following slides. this slide shows data fromboth one and six months after the last dose,labeled on the x axis

as month seven and month 12. and the bars in thetwo different shades of blue are the zero-sixmonth girls and the zero-six month boys. and the yellow bars arethe three-dose women, and the gmt ratios shown inthe table below the graph are for the comparison ofthe girls with the women. and data from the zero-12 montharm are [inaudible] six month follow-up data are not yetavailable from that group.

just looking at hpv6 as an example, you can see the gmtsdecreased in all groups between these two time points, consistent with whathas been seen for other hpv vaccinationfollow-up studies. and at 12 months, the groupsthat received two doses at six months were stillnon-inferior and higher than women who receivedthree doses. the gmt ratios of girlscompared to women was 2.15

at month seven, and1.69 at month 12. and there were similarfindings for hpv 11 and 16, shown on this slide. i'm sorry, that's the 12 month. and on this slide is shown,shows months 7 and month 12 for hpv 18, hpv 31, and hpv 8 -- 33, again with geometricmean titers being higher in the two-dose groups at[inaudible] time points. and finally for hpv 45,52, and 58, and again,

for all nine types, the geometric mean titer ratioscomparing the two-dose nine to 14 year olds with thethree-dose women were not inferior. they did decrease betweenmonth one and month seven, as has been seen for othertrials of two-dose schedules. now additional datareviewed by the work group from the nine-valent two-dosetrial included data on geometric meantiters by the interval

between dose one and dose two. and this was to inform decisionsabout minimum intervals. in the two-dose trial, theinterval between the two doses in the zero-six month groupwas plus or minus four weeks. and as you can see here,over half of the vaccines, vaccinees received dosetwo between five and less than six months after dose one. and this table shows thegeometric mean titers for four of the types by intervalbetween dose one and dose two

in this two-dose group. and as you can seein the blue columns, geometric mean titers weresimilar if administered at five to less than six months andgrown equal to six months to seven months after dose one. and for all types andfor both intervals, the geometric mean titers werehigher, numerically higher than in women whoreceived three doses that are shown inthe last column.

for the two-dose schedule, the updated nine-valent labelindicates a two-dose series at zero and six-to 12 months, and it also states a minimalinterval between dose one and dose two of five months. so in summary, in thenine-valent two-dose trial, immunogenicity was 97- to 100% for all nine types onemonth after the last dose. compared with three dosesin 16 to 26 year olds,

antibody titers werenon-inferior and significantly higher onemonth after the last dose. and two doses in 9 to 14year olds [inaudible] at the, in the zero-six monthgroup remain non-inferior and higher six monthsafter the last dose. gmts by intervalbetween two doses and the two-dose zero-sixmonth group supports a minimum interval of five monthsbetween the two doses, and follow-up will continue inthis study through 36 months.

and just a reminder again, [inaudible] showed [inaudible]the fda did approve a two-dose schedule in october. the label includes dataas well as updated dosing and administration sectionwhich does state the zero, six to 12 month regimenand schedule, and the minimum intervalbetween doses. now acip also revieweddata on immunogenicity of two-dose vaccinationsfor the bivalent

and quadrivalent vaccines. as we just discussed, in alltrials two doses at zero-six and zero-twelve months in 9 to14 year olds were non-inferior to three doses inthe older age group. these trials provideimportant information because there's longerfollow-up than in the trial of the nine-valent vaccine. and while there are differencesbetween the vaccines, there studies do providerelevant data on persistence

of antibody after vaccination. the longest follow-up for thebivalent vaccine is 60 months, for the quadrivalentvaccine is 36 months, and for the nine-valent vaccine which i just presentedis 12 months. another reason that thesedata were reviewed is that although quadrivalentwill not be marketed anymore in the united statesafter this month, many individuals have receivedquadrivalent vaccine in the u.s.

and some have not completedthe three-dose series and recommendations will need tobe made for those individuals. and data for the bivalent, quadrivalent vaccineimmunogenicity trials were included in our gradeevaluation. i'm just going to show a fewslides on data from the bivalent and quadrivalenttrials that are of note. this slide shows geometricmean titers through 60 months of follow up from oneof the bivalent trials.

shown here are two groups,one that received two doses at zero-six monthsat age 9 to 14, and a group that receivedthree doses at age 15 to 25. and as you can see, theantibody kinetics were identical in the two groups withpeak titers one month after the last dose, adecline and then a plateau at about 18 to 24 months. and this basic curve of theantibody kinetic has been seen in all the hpv vaccine trials.

and this slide shows thegeometric mean titers through 36 monthsin follow up of one of the quadrivalentvaccine trials. there were three groups here: atwo-dose group at age 9 to 13, and a three-dosegroup at 9 to 13; and a three-dosegroup at 16 to 26. and again, you can see basicallythe same antibody kinetics in all three groups. the two-dose group, which isshown in black, remains higher

than three-dose womenshown in green. as discussed at past acipmeetings, there are no data from randomized control trialsof two versus three doses of hpv vaccines evaluatingefficacy against infectionor disease outcomes. for the bivalentvaccine, there are data from a post hoc analysis ofa three-dose efficacy trial. and there were also some -- these were some of the firstdata that stimulated interest

in reduced-dose schedules. and for the bi -- quadrivalentvaccine, there are data from an interruptedstudy of a two-dose versus three-dose efficacytrial that was analyzed as an observational study. and data from these analysesdo suggest efficacy with less than a three-dose schedule. post-licensure effectivenessstudies have been used to evaluate other vaccines.

however, these arechallenging -- these types of studies arechallenging for hpv vaccines at this point in our program. there are ten published studies that have evaluatedpost-licensure effectiveness by number of dosesin the setting of a recommendedthree-dose schedule for hpv vaccine bivalentor quadrivalent. all of these foundthat two doses were not

as effective as three doses. however, there ismany limitations for post-licensure effectivenessstudies at this time in our vaccination program. first of all, most two-dosevaccinees received vaccine at zero-one month orzero-two month schedule, and because these weredone in the setting of the three-doserecommendation, and persons received onlytwo doses were people

who didn't completethe schedule. persons received only two dosesdiffered from those completing. some studies they were older, they were lower socioeconomicstatus, or had earlier cervical cancerscreening suggesting differences to exposure priorto vaccination. one study did evaluate differentintervals between doses and did find that effectivenessincreased as the interval between doses increased.

well, our conclusion is thatthere are many challenges for vaccine effectivenessevaluation even in the context of three-dose program. and data from theseeffectiveness studies may not be directly applicable to ourcurrent policy question of a two-dose recommendation dueto the differences in the age of vaccination, the intervalbetween the two doses, and differences in thepopulations receiving two and three doses inthese studies.

and we did not includepost-licensure effectiveness evaluations in ourgrade evaluation. to examine different aspects ofshifting to a two-dose schedule, we did consider resultsfrom health economic models. the model we used was anindividual-based transmission dynamic model, andthis model takes into account herdimmunity protects -- effects, as well as directeffects of vaccination. the model uses avariety of inputs

and six different components,as shown on the slide. and the objective was to evaluate the populationlevel effectiveness and cost effectivenessof a three dose versus a two dosenine-valent vaccination program in the united states. and we had a verynice presentation at the last meeting, and i'mjust going to try to summarize that here on this one slide.

the conclusions were logicallythat if efficacy and duration of protection aftertwo doses are similar, that two doses will becost savings compared with three doses. exploration of differentimportant parameters show that the incremental costbenefits and cost effective ness of the third dose dependmost on the relative duration of efficacy providedby a two-dose schedule versus three-dose schedule.

vaccination is protectedto reduce hpv burden of disease substantiallyafter any schedule if protection isat least 20 years. a two-dose vaccination programwill provide similar population health benefits to a three-dosevaccination program unless two doses provide shorterduration of protection and do not enable highervaccination coverage. two-dose -- three-dosevaccination is predicted to have a high incrementalcost per quality gained

of over $118,000 compareto two doses except when two-dose protectionis less than 20 years and a three-dose protectionis assumed to be lifelong. because duration ofprotection is found in the model to be the most importantparameter influencing population impact, we reviewed dataon duration of protection with acip at the last meeting. most of these data come fromfollow-up of clinical trials. in summary, and whatwe presented in june,

there's no evidence ofwaning of protection after a three-doseschedule to date. and data through about tenyears after both the bivalent and quadrivalentvaccines are available. and longer follow-up throughabout 14 years is ongoing in some of these studies. antibody responses aremaintained over time after a three-dose schedule. again, data are availablefor about ten years

for the bivalentand the we vaccines. and longer follow-up isongoing in some studies. for the we vaccine, waning ofprotective antibody to hpv 18 by the assay used in themerck trials was found but not associated withloss of protection. now for two-dose schedules, long-term protectiondata are not available. however, the antibodykinetics which i showed in some earlier slidesare similar between two-

and three-dose schedulesfor the bivalent and the quadrivalent vaccines. and this suggest duration ofprotection will be very similar for two- and three-doseschedule. just a brief review of grade that was also presentedat the acip in june. the main quest -- policyquestion is should two doses of any hpv vaccinebe recommended for 9 to 14 year olds?

the population, intervention,and comparison groups are shown. the outcome was immunogenicity. this is the grade summary. again, i'm -- just anabbreviation version of grade. for the grade summary for twodoses hpv vaccine in girls about 9 to 14 years comparedwith three doses in women about 15 to 26, 26years, the age group in which clinical efficacy wasdemonstrated, data are available on immunogenicity outcomesfor the nine-valent vaccine

for one study, for thequadrivalent vaccine for two studies, andfor the bivalent vaccine from four studies. all these were found to not -- not, non-inferiorimmunogenicity was found in all of these studies. these were observational trialsbecause it's not possible to randomize in differentage groups. and the overall evidencetype is three.

and for the summaryof the considerations for formulating recommendations,for balances between benefits and harms. if balances are expectedto be the same and potential adverse eventslower, then the balance of benefits overharms is greater. again, the evidencetype was three. for values, therewas high value placed on programmatic considerationsas well as prevention

of outcomes due tohpv vaccine types. and two-dose schedulesare likely to be cost-effectivecompared to three doses. the proposed recommendationis a category a. and dr. meites will reviewspecific recommendation language in the next, next presentation. now i want to mentionbriefly some programmatic considerations. shown here is coverage for threevaccines that are recommended

for adolescents in theu.s. from 2006 to 2015. i think you're familiarwith some of these data. in spite of hpv recommendationsfor females being published around the same timeas those for tdap and meningococcalconjugate vaccine, hpv vaccination coveragehas increased at a comparatively slow pace. coverage for at least one andthree doses has reached 62% for one dose, and42% for three doses.

and coverage for malesbegan to increase after 2011 when the routine recommendationwas made for males. and in 2015, was about, itwas 50% for at least one dose, and 42% for three doses. a variety of efforts areongoing to increase coverage. and these have been reviewedwith acip in the past. it is unknown how a two-doserecommendation would impact vaccination initiationor series completion in the u.s. althoughit's generally thought

that a two-dose schedulewould be easier to implement and would be more acceptable. many other countries haveswitched to a two-dose schedule. most of these have hadschool-based vaccination, and many alreadyhad high coverage. and so the information from these countries may reallynot inform what we would see in the u.s. however, in theu.s. the two-dose schedule at zero-six to 12 monthswould allow flexibility,

and vaccinations could coincide with preventive healthcarevisits. finally, i want tomention that examination of current coverage datacan provide information on the impact of a potentialchange in recommendation on our current coverageestimates and also on the need for recommendations thataddress incomplete schedules. this slide shows thepercentage of boys and girls who received three,three-two and one doses

as determined in nist in 2015. and you can see that about 10to 11% received only two doses, and about 10 to 11% additionallyonly received one dose. and recommendations, ofcourse, would need to be made for these individuals. because the intervalbetween doses is important for a two-dose schedule, welooked at the interval in months between the first andsecond dose among teens who had started the vaccinationseries before 15 years of age

in the u.s. you can seein this graph that most of these teens did receivethe second dose close to the recommendedinterval of two months in our current three-doseschedule. now these data include persons who completed a three-doseschedule as well as those who did not completea three-dose schedule. and when looking only atteens who completed two doses, we see a slightlydifferent picture.

this slide looks at the teenswho received only two doses and the percent whoreceived only two doses, both at least five months apart and started the seriesbefore age 15. ten point six percent of 13 to 17 year olds onlyreceived two doses. five point four percentreceived two doses at least five months apart if acip votes to accepta two-dose schedule,

these individuals wouldpotentially be considered fully vaccinated. and the other two-dosevaccinees would be recommended to receive a thirddose in this age group. so in summary, today ireviewed a variety of issues to set the stage for the nexttalk on proposed recommendation. although three vaccines arelicensed for use in the u.s., after the end of 2016, only nine-valent vaccinewill be available.

in october 2016, fdaapproved nine-valent vaccine as a two-dose series forperson aged 9 through 14 years. during the past year, acip hasbeen reviewing data related to dose schedulesincluding immunogenicity, post-hoc analysisof efficacy trials, post-licensure effectiveness,health and economic models of duration and protection. and importantly aswe reviewed today, all trials of these vaccinesfound the antibody response

after two doses at zero-sixor zero-12 interval in 9 to 14 year olds isnon-inferior to the response after three dosesin the age group in which efficacywas demonstrated. post-licensure examiningvaccine effectiveness by number of doses are difficultto interpret at this time and data from follow-up of three-dose vaccinetrials showed the duration of protection after hpvvaccination is long-lasting.

of immunogenicity trials suggestduration of protection the same after two- and three-doseschedules. acip used grade toevaluate evidence on two-dose vaccinationschedules. and the work group proposesa category a recommendation for two-dose schedule forpersons initiating the series at 9 through 14 years. and a two-dose vaccinationschedule might facilitate vaccine initiation seriescompletion in the united states.

i'd like to thank many peopleon the work group as well as cdc contributors who haveparticipated in this process. thank you. >> thank you, dr. markowitz. should we go directlyon to dr. meites? as you've heard, threehpv vaccines are licensed for use in the united states. nine-valent, quadrivalent,and bivalent hpv vaccine. recently on october 7th,

nine-valent hpv vaccinewas approved for fda -- approved by fda for use ina two-dose series for girls and boys at ages 9through 14 years. current acip recommendationsare shown here. hpv vaccine is recommendedfor routine vaccination at age 11 or 12 years. at age 9 years. acip also recommends hpvvaccination for females age 13 through 26 years notvaccinated previously.

males 13 through 21 yearsnot vaccinated previously, and immunocompromisedpersons including those with hiv infection andmen who have sex with men through age 26 years ifnot vaccinated previously. in addition, males age 22 through 26 yearsmay be vaccinated. the rationale for a vote todayis that hpv vaccines are known to be highly effective and safe,and a powerful prevention tool for reducing theburden of hpv infections

and associated disease. evidence suggests that atwo-dose schedule administered at zero and six to 12 monthswill have efficacy equivalent to a three-dose scheduleadministered at zero, one to two, and six months. if the hpv vaccination seriesis initiated before the 15th birthday. here are the proposedrecommendations. this outline shows the sections

that would be includedin a policy note. no changes are proposedto the routine and catch-up age groupsfor hpv vaccination. major additions are proposedon sections on dosing schedules and persons withprior vaccination. clarifying language isproposed for the sections on interrupted schedules,special populations, and medical conditions. for contraindicationsand precautions, again,

no changes are proposed. and finally, the summaryincludes the proposed recommendation category. the routine and catch-upage groups for whom hpv vaccination isrecommended would not change. the text of this sectionwould continue to emphasize that acip recommends routine hpvvaccination for girls and boys vaccination can be givenstarting at age 9 years. acip also recommends vaccinationfor females through age 26 years

and for males throughage 21 years who are not adequatelyvaccinated previously. males age 22 through 26years may be vaccinated. additional details will bepresented in the sections on special populationsand medical conditions. beginning in this section, underlined text indicatesnew information or changes to the current recommendations. based on the evidencepreviously presented to acip

on two-dose immunogenicity,efficacy, cost-effectiveness, duration of protection,grade evaluation and additional considerations,the proposed dosing schedules for hpv vaccination are: for person initiatingvaccination before the 15th birthday, the recommendedimmunization schedule is two doses of hpv vaccine. the second dose shouldbe administered six to twelve months afterthe first dose for a zero,

six- to 12-month schedule. for persons initiatingvaccination on or after the 15thbirthday, the recommendation for a three-dose schedulewill remain in place. the recommended immunizationschedule is three doses of hpv vaccine. the second dose shouldbe administered one to two months afterthe first dose. and the third dose shouldbe administered six months

after the first dosefor a zero, one to two, and six month schedule. text of a footnote definingminimum intervals will be presented on later slides. the next sectionwith major changes is about evaluating personswith prior vaccination. this [inaudible] new sectionproposed to address questions about persons who've receivedany hpv vaccine in the past. the proposed text is: personswho initiated vaccination

with nine-valent, quadrivalent, or bivalent hpv vaccinebefore the 15th birthday and received two doses at therecommended dosing schedule or three doses of the recommended dosingschedule are considered adequately vaccinated. persons who initiatedvaccination with nine-valent, quadrivalent, orbivalent hpv vaccine on or after the 15th birthdayand received three doses

at the recommended dosingschedule are considered in addition, this sectioncould formalize current cdc supplemental guidancefor vaccination providers which appears atthe link shown here. this states that nine-valentvaccine may be used to continue or complete a series started with quadrivalentor bivalent vaccine. furthermore, thework group would like to include an explicitstatement that for persons

who have been adequatelyvaccinated with bivalent or quadrivalent vaccine, there'scurrently no acip recommendation regarding additional vaccinationwith nine-valent vaccine. in the section on interruptedschedules, to the acip statement that if the vaccineschedule is interrupted, the vaccination series doesnot need to be restarted. it is proposed thatadditional text be added stating that the number of recommendeddoses is based on age at administrationof the first dose.

before presenting theproposed minimum intervals, i would like to review thecurrent recommendations and evidence consideredon this topic. in current guideline,the current interval between the first and third dosein a three-dose series is given as 24 weeks, slightlyless than six months. the work group noted thatin both the new two-dose and the originalthree-dose trials of nine-valent hpv vaccine,

doses given at a targetsix-month interval were scheduled for 180 daysafter their first dose which is equivalent to 26 weeks. however, participantswere included if they received vaccine fourweeks within this target date. and many participants in the two-dose trial didreceive their second dose within this window. therefore, the nine-valentvaccine trial data support a

minimum interval of five monthswhich is equivalent to 22 weeks. furthermore, the updatedfda-approved label for nine-valent vaccine states aminimum interval of five months between doses ina two-dose series. for these reasons, the workgroup proposes a footnote defining the minimum intervalsinclude the following change. in a two-dose seriesof hpv vaccine, the minimum intervalis five months between the firstand second dose.

for consistency, anda three-dose series of hpv vaccine, the minimumintervals are one month between the first andsecond dose, three months between the second andthird dose, and five months between the firstand third dose. a vaccine dose administered at a shorter intervalshould be re-administered at the recommended interval. the section on specialpopulations is

largely unchanged. currently, for children witha history of sexual abuse or assault, acip recommendsroutine hpv vaccination beginning at age 9 years. in addition, acip recommendsan extended catch-up age range for men who have sex with menand immunocompromised persons. the work group proposesto add clarifying text to our current guidance that defines thesepopulations more clearly.

to the current recommendationfor men who have sex with men, the proposed clarificationwould add terms that are used elsewhere torecognize diversity in sexuality and gender identity and expression among menwhose behavior may include sex with men. the proposed text is forgay, bisexual, or other men who have sex with men, acip recommends routine hpvvaccinations for all adolescents

and initiation of vaccinationthrough age 26 years for those who were not adequatelyvaccinated previously. for transgender persons, aciprecommends hpv vaccination through age 26 years for those for immunocompromised persons,the work group did not feel that a two-dose scheduleshould be required for all types ofimmunocompromised. the purpose of thisaddition is to clarify which immunocompromisingconditions should continue

to receive three doses based onexpert opinion and consistent with the [inaudible] practiceguidelines for vaccination of the immunocompromised[inaudible]. the current recommendation isacip recommends hpv vaccination for immunocompromised femalesand males age 9 through 26 years with three doses of hpvvaccine administered at zero, the proposed addition is persons who should receive threedoses are those with primary or secondary immunocompromisedconditions

that might reduce cell-mediatedor humoral immunity such as hiv infection andother conditions listed here. since immune response tovaccination may be attenuated. a separate footnotecould clarify that the blanket recommendationfor three doses does not apply to children agedless than 15 years with other common conditions that could be consideredimmunocompromising such as asthma, diabetes,and others also listed here.

finally, there are noproposed changes to the section on contraindicationsand precautions. the proposed text hereis that contraindications and precautions includingthose related to pregnancy are unchangedfrom previous recommendations. standard language is included on the vaccine adverseevent reporting system. and before we breakfor public comment, i'd like to acknowledgethe members

of the hpv vaccine's workgroup and the cdc staff who contributed tothe development of these proposedrecommendations. >> thank you. what i'd like to do now is to have some discussionparticularly among the committee and liaisons and,and anyone else. and then we'll have amotion, further discussion, and then public comment.

so are there any initialquestions or concerns? peter? or dr. szilagyi? >> thank you foroutstanding presentations. one thought thatliterally i just thought of as you were presenting aboutthe six to 12 month interval, and how this may playout in the real world. and, and, and my thought isnecessarily, not necessarily to change the recommendationbut education for pediatricians and family physicians.

so six to 12 months,a lot of, i suspect, many primary care practitionerswill bring adolescents back at their next well-child visit. there is one complication thati hadn't thought of before which is there is somecommercial insurance plans that will not pay for awell-child visit if it's within 12 months, and theyrequire longer than 12 months. so that doesn't include medicaidor public health insurance, so i don't know what percentage

of the u.s. populationthat includes. i think it's actuallysmall, but measurable. so there may be alot of practitioners who are actuallybringing their kids back at 13 or 14 or 15 months. and so we may just want to bevery careful about education about the six to 12 months, ifthat's the final recommendation, to bring the adolescentback for a second dose, even if that's not duringthe well-child visit.

that's a great point. others? dr. hunter, did youhave a question? >> yes. i'm sorry, i wasprocessing what he was saying. i have a question aboutwhat the current rates of one-dose vaccination isamongst n9 to 14 year olds, and especially in comparisonto whether that is higher than the current rates of three-dose vaccinationamongst 15 to 26 year olds

to get at the how much we'regoing to bump up rates here. >> alright, looks like someonefrom nis team is going to try to answer that. but could you repeatyour question? >> sure. what arethe current rates of one-dose vaccination amongst9 to 14 year olds compared to the current rates of three-dose vaccinationamongst 15 to 26 year olds? i think i'm trying to getat that same idea you had

of how much we're going to bump up potentially not immediately,but very soon after. you presented a slide about howimmediately, just by definition, we'll bump people upby about five percent. and i'm wondering, youknow, with the next shot, how much we're goingto bump things up? >> those are not our age groupsin nis team, but it looks like dr. wharton will be able to possibly pull somedata together for that.

>> she's lookingat the data now. our age groups don'texactly match what you asked, but i guess the other thing thatour program folks would say is that there may be people whoare not initiating the series because of the complicatedschedule. and so while we cananswer that question based on who's gettingthe vaccine now, our hope is that bysimplifying the regimen, more people will access it.

and also importantly, that thiswill really help providers make a stronger vaccinerecommendation which impacts acceptance. >> you ready? i gave you [inaudible]. >> yeah. well, at leastwhat's been reported in our most recent publication on the national immunizationsurvey team was three-dose coverage during, in the 13 to 15year age group which corresponds

to healthy people 2020 target. and, and coverage was pretty lowat those ages with 27% coverage in males and 37%coverage in females. i, i think the point dr.[inaudible] made is the correct -- is i would like toemphasize that point that i, i think a recommendationfor a two-dose series at these younger ages mightvery well, we might be able to get better completionthan we do with our current, our current recommendation.

miss pellegrini? >> i'd just like to follow up onsomething dr. messonnier said. the zero to six monthschedule is really hard for families with teenagers. you know, getting back tothe pediatrician three times in six months is really tough. so i think this more flexibleschedule and wider interval that allows either forthe next well-child visit or the next sports physical,

or even in some casesthe next sick visit is, could make a real difference. number one, in increasingjust the completion rates in a timely fashion, but alsoin incentivizing families to begin the schedule. because there arepeople who look -- and because i know becausei've talked to them. and -- look at zero to six andsay, "i know i can't do that, so let's not evenstart right now.

let's wait a year or two." other comments, question? okay, i'm going tostart over here. dr. lett? i, i heard that you're goingto consider recommendations for the earliest age atwhich to start it later and maybe not includethat in this statement. but is there any other kind ofmore permissive use language that you can consider includingin the statement that's going

to come out now withthe two-dose schedule about starting it earlier? >> so if i couldcomment on that? we, as i think dr. kempe indicated in her opening remarks,we're really focusing today on the two-dose schedule. however, the work groupdoes intend to look at the age parameters bothgoing down and going up. so that will probably bebrought back at a later time.

>> okay. >> dr. o'leary? >> yeah, could you goback to slide nine? i just want to lookat the wording because i think it mightbe a little confusing. i just noticed this. so if you look atthat first bullet. "persons who initiatedvaccination with one of the vaccines before the 15thbirthday and received two doses

at the recommendedschedule or three doses adequately vaccinated." and that statement in and ofitself could be interpreted by the providers as theold recommended schedule, so two doses at zeroand one to two months. so we might just want toclarify that it's the zero, six to 12 month schedule orthe newly recommended schedule. >> dr. gamble? >> well thank you very much

for a very comprehensivepresentation. and i'm really glad that we'regetting to this stage now. just and as a fyi, wetook a different route. i think we're going tocome to the same position at some point in time. we went to a two-dose schedulewith a four-valent vaccine and on our agenda is the samething you're discussing today for future consideration. i just have one quick questionwhich isn't quite related

to this two-dose issue. but you did mention, i think, and i hope i didn't misinterpretit or miss it, that anybody who had had two or three doseswith any vaccine was considered to be completely immunized. but inevitably, the questionwill come up from some people who have had bivalentor quadrivalent vaccine, "i want that protection for, from the other [inaudible]strains."

is there any, going to beany permissive recommendation that allows that to take place? and if so what it is? because we're strugglingwith that a little bit. >> the current proposalwould include the language that there is no aciprecommendation at this time for additional vaccinationwith nine-valent. >> dr. walter? >> one other potential languageclarification which may come

out in additionalguidances on slide 13 and the minimal intervals. it says the vaccinedose administered and so for example, ifsomebody gave a vaccine at zero and four months, i wouldassume that would mean that if that was not following advice, you should give the nextdose at five months. but one might confusethat and say six months from the dose givenat four months.

so i think there needs tobe some clarification there. >> you're quite right. and chris, couldi have slide 27? you're right. i abbreviated on this slide thati presented, but the full text of the minimum intervalsfootnote would include additional information aboutwhat that recommended interval and the minimum intervalwould be for a re-administrationof an early dose.

i didn't want that to distractfrom the main presentation, but the proposedtext is shown here. >> miss hayes? >> yes i'm fairly certain, i hope my memory'sworking well today. i'm sorry. i'm carol hayes withthe american college of nurse midwives. that there's an icd 10 codethat you don't have to have

as a well-child visitin order to be able to just give the vaccine. and also i love theliberal language about how you're not limitedto giving the vaccine. if the child comes in late,you can still give it, and that's a big, big question. when i administered the vaccineat family planning visits at the same time igive depo-provera, all of my colleagues werelike, "oh, but it's been a year

since they got their first dose. can we give the seconddose now?" heck, yes! you can give it! so i love that, thatliberal language. dr. messonnier? >> yeah, i just wanted tocomment that there are a number of complicated clinicaldecision issues that are going tocome from this.

where it sounds fine, but youall can really find places where a clinicianmight be confused. you have our commitment thatwe're going to try to sort if work through all of those with the other professionalorganizations. melinda wharton, you know,queue up your questions to her, and we'll try to make surethat those get included with the massive healthcommunication materials that we're going tohave to develop in order

to help clinicians worktheir way through this. >> good point. dr. hahn? >> yeah, thank you. i had a similar comment. my daughter's had the first two,two months apart on slide 9, and i was just going topropose that it just read "and receive two doses atleast five months apart," would be the clearestway to put that.

dr. middleman? >> thank you, amymiddleman from the society for adolescent healthand medicine. members of the society foradolescent health and medicine, including the vaccinationcommittee and the president-elect and current president havesignificant concerns regarding the new policy's use of thelabels "gay and bisexual" as proxies for behavior.

that places men atage 22 to 26 of age at increased riskof hpv acquisition. labels that characterize sexualorientation do not necessarily characterize behavior. if a behavior puts a personat greater risk for disease and greater needfor vaccination, then it's more accurate todescribe the specific behavior. for example, men who may haveor have had sex with men. men who identify as gayor bisexual may not engage

in behaviors that place them at increased riskfor hpv acquisition. and conversely, men whodo not identify as gay or bisexual may engagein sexual behaviors that place them atincreased risk. importantly, many healthcareproviders do not routinely screen their patients ingreat detail regarding sexual orientation or sexual behaviors. the evolving nature of sexual,

sexual and gender expressionmakes generalizing with the use of labels obsoleteand inaccurate. we potentially missvaccinating many young men who should be protectedagainst disease. furthermore, we knowfrom past experiences as dr. schaffner noted earliertoday that targeting vaccination for specific risk groups hasnot been an effective public, public health strategy. the most inclusive and effectivestrategy to protect young men is

to avoid assumptionsbased on generic labels. we recommend, number one,eliminate imprecise labels from vaccination recommendations that falsely assumean equivalence between sexual orientationand risk behaviors. potentially resultingin mixed -- missed opportunitiesfor vaccination. and two, update therecommendations for young men hopefully atthe next to include catch-up

for all 22 to 26 years olds inorder to protect all young men, including those whosebehaviors defy labels. from the morbidity and mortalityassociated with hpv infection. we have an extremelyeffective vaccine that is most cost-effectivethan initially predicted. the number of vaccinesdistributed for 22- to 26-year-old males isreportedly extremely low, implying poor uptakeamong this group of men. the goal for our young menat this point should be

to use fewer labels,make fewer assumptions, have fewer restrictions, andstrive to be more inclusive, immunize more men,and save more lives. >> thank you, dr. middleman. did you want to respond? >> sure, chris -- couldi have slide 30 please? i'd like to thank dr. middlemanfor her commitment to this issue and her work withadolescent patients. i think it's certainly -- arethe intention of our proposal

to make our language inclusivehere of the populations that should receive vaccine. as far as the particularphrasing of the terms, i wanted to point out that theseterms are widely in use at cdc. this is an assortmentof websites from, from different cdc programsthat focus on lesbian and gay, transgender and bisexual health. and including, i'd liketo point out on the right, this is the language that's inour hpv admin cdc fact sheet.

so that -- let's see ifi can point this out. on the third bullet here, cdcalready says "gay, bisexual, and other men who have sex withmen" as part of the targeted, extended catch-up age range. so the intent ofproposing this today was to formalize the languagethat is already in use. but as dr. middlemansuggested, this is a -- the full age ranges in ourrecommendations are a topic that the work group wouldlike to continue discussing.

>> yeah, thank you,[inaudible] work group. we appreciate sam's concern. they're an incrediblyimportant partner in this age groupand on this vaccine. and we want to try to finda way to make this work. the work group came tothis language as you heard, but we're committed, youknow, outside of the vote, there is clinicallanguage that we use in our health communicationmaterials that derives

from the kind ofconversations you have but the wording isn't alwaysexactly what is voted on. and that we commit to sam thatwe will engage with the experts who are putting up thisinformation and try to find something thatis acceptable to sam and also meets the, thepurpose of the work group which is actually moreinclusive, not less. >> and thank you. i just appreciatethat a great deal.

sam really appreciates theopportunity to contribute. >> thank you again forraising this important issue. dr. wexler? >> hi, on slide number 13, theproposed minimum intervals? so this is a divergencefrom how cdc usually writes recommendations forspacing minimum intervals. usually acip would say instead of one month youwould say four weeks. and instead of three months,you would say 12 weeks.

and five months would be fine. and you can find the languageon the childhood schedule. it says, "for purposesof calculating intervals between doses, fourweeks equals 2 days. intervals of four months or greater are determinedby calendar months." so four months is the cutoff for when you use fourmonths terminology. thank you

and that was my understandingas well. if it's preferable, i think ourwork group would be supportive of using four weeksand 12 weeks instead of one month and three months. dr. offit? >> alright, paul offit. children's hospitalof philadelphia. i just guess want tofollow up on a question that was asked earlier.

while i understandthat there is, is no additionalrecommendation for those who have finishedeither hpv 4 or hpv 2, what i don't understand is why. i mean, you have a vaccinewith hpv 9 and it will protect against an additional severalthousand cases of cancer and presumably hundredsof deaths. you could argue that the bestmedical recommendation is for someone who's, who'scompleted either hpv 2

or hpv 4 would be to gettwo doses of hpv 9 separated by at least six months. that would save lives. so is the reason thatyou're not making that recommendationprogrammatic, or is it financial? because it certainlyseems it would be the best medical recommendation. >> laurie and i, we talkabout this all the time,

so now we get todo it in public. >> i, i believe the committeealso considered this. >> well no, this, this was notbrought before the whole acip. and i feel like this is a --we could, the work group can, you know, revisit thisand discuss it as well. but we, we -- right now it is -- for a variety of reasonsthis is not, it will -- it's not part ofour recommendations. and i think it's somethingthat we could revisit

within the work group. dr. thompson? >> i -- so going back to thepoint that was raised before. on slide 15, i didn't understandwhy there was different language used for these differentpopulations of gay, bisexual, and other men whohave sex with men, and transgender individuals. the language that's in thatactual slide is different for those in a way thatdidn't make sense to me.

and i just wondered whatthe rationale was for, for what you actually have therethat the committee is going to be voting on today. i also wondered aboutthe language for proposed medical conditions? what evidence do we haveabout the three-dose schedule in these special populationswith respect to the timing? is it actually reallybetter for these individuals to do the zero, one to two,and six month schedule?

or in fact would it be betterfor them to get a zero, six to 12 month, andthen a booster later on? i mean, do we know any of that? and if not you know, i guessthe question is are we doing any of that researchto try to figure out what the righttiming would be for those immunocompromisedpopulations? it sounds like yourfirst question, and we're on slide15, thank you.

your first question waswhether the language in these two sentencesshould be the same? is that you -- ? was that your question? >> yeah. what's the reasonwhy we are saying acip, acip recommends routinehpv vaccination for all, as for all adolescents for thefirst group but not the second? >> i see what you mean. the reason is that they wereoriginally one sentence,

and we made them into twosentences for clarity. and so repeated onlyhalf the sentence. we could certainly repeat, "acip recommendsroutine hpv vaccination as for all adolescents"in the second sentence. >> i just, i just want tointerrupt and make it clear to the committee that theproposed recommendation from the work group issolely about the two doses, and all of this clinicalguidance language

that you guys haveseen can be modified for the publication of the mmwr. >> can you comment on thesecond question though about the schedule? >> yes, as far as the secondquestion on the timing of the three-doseimmunocompromised. let's see. chris, could i please have-- actually i want 28. and i'll say thatthe, the timing --

let me just read the firstsentence here, and then talk about what we do and don'tknow about the timing. so we know hpv vaccinesare non-infectious. and for the immunocompromisedconditions we listed, the concern is that immuneresponse may be attenuated following vaccinations, soit might produce lower gmts and antibody responses. when it's cell-mediate or humoral immunity are reduced. as far as the timing, i'm notaware of any studies that looked

at the zero, one totwo, and six month versus a six to 12month schedule. but we've left the three-doserecommendation in place for these, these persons. >> dr. maldonado? >> thank you, yes. coid has met to discussthe proposed wording, and we obviouslysupport strongly the two-dose recommendation.

taking into account the otherissues that have been brought up around operational issues. miss, you know, forexample miss -- opportunities for missedsecond doses, et cetera. but in particular one of theareas that we're concerned about and would recommend somethoughtful consideration is the expanding the, to the largerage range for the purposes of including optimal vaccinationperiods for younger children. dr. -- no?

okay. any other? >> i just want to ask,could you go back? i know we keep askingyou to go back. could you go back again to theslide about the footnotes -- additional wording aboutwhat happens if the, your -- haven't gotten it atthe right interval. when do you get the? it was your footnote, itwas your slide about the -- >> dr. lett, canyou restate your question?

>> i am. sorry. >> we're having alittle problem. >> yeah, sorry. the slide isn't in the handout. and so it was one ofyour extra slides added in different language about -- >> yeah, it was. >> yes. and so, and so you'renow going to be recommending that if it was at ashorter interval,

it should be four months later? that's going to be thenew recommendation? because i think they couldhave, that could have -- >> this slide isn'tin the handout because what thedifference between this slide and the one that'sin the handout is that this slide also articulatesthe recommended intervals for what to do if the vaccine, if a vaccine dosehas been administered

at an interval thatwas too short. so in addition to therecommended intervals, if you miss the recommendedintervals, then what? and so in a two-dose schedule,the second sentence states, "if the second doseis administered at a shorter interval, an additional doseshould be administered at least four months later." >> and it, similarlyclarifies what to do

in a three-dose schedule if thevaccine dose is administered at a shorter interval, waitanother minimum interval, and then re-administer the dose. >> okay. no, i think, i think --it's just that it, it just kind of went by just a little bitfast, and i think this is going to be important for all those,those kids who, you know, really haven't hadtheir vaccines on time. so thank you. i think it's timeto move to a motion.

would someone liketo make the motion? >> i'd like to makemotion that we vote on the proposed two-dosehpv schedule. >> is there a second? dr. lee? thank you. any further comment? then we would like tomove to public comment, and i'd like to pointout to all the members that in your notebooks thereis a letter that we received.

and i hope that youwill read it. and is there anyfurther public comment? is there anyone in the roomwho would like to comment? dr. hill-- , mrs. hildebrand? christina hildebrand fromvoice of choice advocacy. i -- i agree with thedosing going down to two. my concern, and i know thisisn't your, your choice, but with the hpv 9 being theonly one available, the increase in aluminum increasesdouble for every dose.

and that's a concern,and i wonder if the safety studies havebeen done surrounding the aluminum specifically? and looking at things likepremature ovarian failure and other, otheradverse reactions that have been reported? and looking at the long term. and i know the two-dose bringsit down, although it would, it's still higher thanthe three doses

of the initial four or two variant gardasil. so i just wanted tomake, make that comment. and, and again, let us refer youto our subject matter experts and also to vaccinesafety personnel at the cdc to discuss that issue. any further comments? i think we should take a vote. dr. stephens? do you want to start?

>> stephens, yes. >> atmar, yes. >> bennett, yes. >> romero, recusedbecause of funding for non-vaccine-related support. >> ezeanolue, yes. >> moore, yes. >> hunter, yes. >> pellegrini, yes.

>> lee, yes. >> riley, yes. >> belongia, yes. >> walter, yes. >> szilagyi, yes. >> kempe, yes. i believe that's againa unanimous decision to support two dosesof hpv vaccine. thank you all foryour consideration.

we now have also apresentation for the vfc vote. >> dr. santoli. >> so i'm going to go throughwhat the updated resolution is proposed to be toreflect the discussion and vote that's justtaken place. the purpose of thisresolution is to reflect the newdosing schedule for human papillomavirusvaccine. eligible groups are allchildren age 9 through 18 years.

acip recommends routinehpv vaccination and vaccination can be givenstarting at age 9 years. acip also recommends vaccinationfor females and males age 13 through 18 years whoare not adequately vaccinated previously. in the recommended schedules andintervals, there's also a table that summarizes therecommendations that were just discussedwith the two-dose schedule for persons initiatingvaccination at age 9

through 14 years except forimmunocompromised persons. and the three-dose schedule forpersons initiating vaccination at age15 through 18 and immunocompromisedpersons initiating vaccination at 9 through 18 years. there's also informationabout the, the -- which children are consideredadequately vaccinated. taken from the previousdiscussion, the note that vaccine doseis administered at shorter

than minimum intervals should bere-administered as recommended. the, the statement that nine-valent hpv vaccinemay be used to continue or complete a series startedwith another hpv vaccine and the statement that if thevaccine schedule's interrupted, the series does notneed to be restarted. for recommended dosageand contraindications and precautions, the reader isreferred to the package inserts. and then as you saw inthe last resolution,

when there is a publishedrecommendation, that is incorporatedby reference. and that's what i'dlike to present. >> thank you, dr. santoli. can i have a motionfor the vfc vote? >> i move to acceptthe recommendation for the vfc on hpv two-dose. and a second? >> i'll second it.

>> thank you, dr. walter. and i think we can godirectly to a vote. dr. szilagyi, wouldyou like to start? >> which way are we going? >> this way? >> romero, recused forreasons previously stated. so i need to say thati misspoke previously. on our last vote it wasactually there was one recusal and otherwise unanimous.

and summarily with this vote. i need to comment that ourprevious chair used to call on someone to votefirst and then tell them to go clockwise orcounterclockwise. and we discovered thatthere were no acip members who could do clockwiseversus counterclockwise. and that's why -- so in thefuture, i will be more specific and say to your rightor to your left. i promise.

thank you all. this has been a really excellentsession on hpv vaccine, and i think this isreally a big step forward. and we thank the hpv work group and our presenterswho were terrific.