natural treatment for smallpox disease in children

>>> we will request that we goup and introduce the hpv session. >> he has been, you know, anessential part of hpv basically as long as i can remember. joe has been a wonderful leaderfor this work group, so just accept the thanks and gratitude. >> i also like to point outlaurie that i worked with from the beginning. the way that this work group hasbeen so affective harrell

clearly the result of herexpertise. and we're shortened the acipmeeting that was shortened by the cdc being closed because ofthe scare of a snowstorm, and acip did vote on the majorissues related to the hpv vaccine and the changes thatwere made were then put together in a policy note which was pleabargain -- published on march 27. the one that was not consideredwas the additional vaccination for those that completed theseries.

so in review the related to thehpv vaccine and the presentations were made first onthe epidemiology of the burden of disease and the contributabledisease and it was in three separate meetings and the greatanalysis that was presented in october of 2014 and the healthanalysis of the -- the two were made one in october and one offebruary 2015 prior to the vote. discussion of the policy optionswere made in october of last year and then in february andthen the vote occurred of the vaccine recommendations and voteactually was in february.

the work group has continued tomeet subsequent to the february meeting, and have reviewedevidence for additional 900 hpv vaccinations regarding to thetypes of disease and the trial data and cost affectiveness andthe issues that have occurred since licensing and madeconsideration to have guidance on these iues for theproviders and out on the frontline. so the recommendations for todaythis is outlined of today's session is and it will discussthe background and the

transition and clinical trialdata and he is going discuss the impact and cost affectivenessand then we will review the considerations that have beenmade by the work group and open a discussion with the apip. >> last slide. i did want to thank all of themembers of the work group. this has been a ve well ranwork group that i have been with and the dc d lead. i think that we have had anumber of serious discussions

that have outlined what neededto happen to bring this information forward, so thankyou all. >> and i apologize. we have off one meeting on thedates of the last few slides. that last slide was the outlinefor today. before i start i know that therehave several mentions of the doctor's time on acip and chairof the work. i just want to mention thatagain. he is stepping down and he hasbeen chair of the work group

since 2011, but he has been amember be of the work group since 2005, and so he e reallyhas been a part of the work group. he was chair of the group forthe vote to include male in the routine recommendation for thehpv and also the vote forhpv 9. he has played a strategicleadership role. i am proud that he is goingremain the chair as a leader. thank you. so today what i am going to dois provide some background and

over view of the hpv vaccinesand a review of the recommendations from february2016 and then talk a little bit at the program to the balancevaccine and following that i will review the evidence onadditional vaccinations and the burden of disease and theclinical trial data and then administered fromadministered. there are three reviews in theskpus these are all virus by particles and it targets thecancer causing types and the balance vaccine targets 1618 aswell as 6 and 11 and the type

that cause genital warts andthen the 9 targets the vaccine and five additional cancercausing types. as it differs and the balanceand the nine balance vaccine and note about 99 percent of the hpvthat was administered in the u.s. in 2014 was hpv vaccine. whern that was licensed in theu.s. in 2014 it was recommended in 2015 and the policy was pushlish published at the end of marchand the american academy are consistent with the february aitrecommendation.

now, while it was licensedore-mails females and males nine to 26it's only censed for males age 15. it's from the time of the applyligion live case and then it's notcompleted. however, those data werepresented to acip in october of 2014 and later submitted to fdaand in february they recommended use of nine balance and thecurrtly recommended age groups for the vaccines.

however, nine use in the males16-26 is currently off label. so the february recommendationsthat are now in the policy note say that the routine isrecommended at age 11 or 12 and the vaccination is age 24 forfemales and ages 21 for males and men that have had sex withmen and compromised men to age 26. vaccination of females is withthree of the vaccines and with males it's recommended or thenine [ inaudible ]vaccine.

>> it also states that avaccination provider do not have available products administeredfor setting the transitions to nine balanced for the protectionagainst 16 and 18 and then it can be used to continue orcomplete it for the male. >> so again it was licensed indecember and it was recommended by the aic in february and thenpolicy was in march and then the concluded in april and in maythat was the first time that the vaccine was ordered of thecontrast just over 50 percent of them had placed orders thatimplaced nine vaccines.

according to june 2015 over85 percent of the care plans have covered. six months have passed for theindication and because of this the balanced vaccine is expectedto be on the market in the u.s. until mid-2016 and used ofcourse of the approval of the 16 to 26 year indication. cdc has provided somesuggestions to assist with the implementation of the balanceand nine balance vaccine. this includes the providers thatprefer the nate

their patients with nonvalentshould be able to order it. for those who choose 9 valent,those can be used to complete the series for persons whostarted the series or used in males with additional ptectionare from 9 valent vaccines will mostly benefit females. now i would like to discuss dataon the additional 9-valent hpv vaccination. it was mentioneded this was notdiscussed in february. it was not included in thepolicy note.

again, there is no indicationfor additional 9-valent vaccination in the labelalthough data are included in the label from the trial thataddresses this. additional 9-valent vaccinationhas been a common question from providers and parents. as presented last year thisslide shows a percentage of cancers at each an topic siteattributable to hpv . the percent attributable to 1618and the percent attributable to the nine additional types in thevaccine.

there is vartion in thepercent of cancers attributable to any hpv by an tomic site from63% to over 90%. the percent of cancersattributable to 16-18 ranges from 48% to 80%. in the last column is thepercent attributable to five additional types in the 9-valentvaccine ranging from a low and oral farn gilles cancers inmales. one of the less common hpvassociated cancers.pharyngeal c males.

one of the less common hpvassociated cancers. this shows -- these data are g-8generated from the last slide and the number of cases obtainedare prosecute the cancer registry. the number percent attributableto 16-18 are shown in gray. to the five additional types inblue and on the left are these feales. on the right are the males. you can see the maturity ofcancers are attributable to hpv

16 and 18 at all anatomic sitesand due to the five additional types are cervical cancers. this summarizes the data fromthe last two slides. we think 64% are attributable to16-18 in the u.s. these types account for 66% ofserve value cancers from the other types. they range from 48 to 80%. a range of 4 to 18% for theother hpv associated cannes rs. due to differences in the perevent of cancers attributable to

hpv types at the anatomic sitethere are differences by six. the five additional types ofcancer, about 14% in females and only about 4% in males. the precancer lesions, about 50%are caused by 16-18 and 25% to the five additional types. data was revieweded from theclinical development program at put pl meetings in 2014 . the 9-valent clinicaldevelopment program included males and females 16 to 26.

[ inaudible ]use trials and one trial of 9-valent vaccine among thosevaccinated previously. i will review that data today. the object tuives were to evalurecipients to evaluate the 9-valent vaccine with respect tofive additional types. there are 900 females in thestudy which was a double blind randomizedle controlled trialand the vaccine was administered on a 0, 2 and 6 month schedule. anti-body was measured atenrollment, post dose one and

three. again although the study wasconducted in the data were submitted to the manufacturer,patient among those previously vax fated for vacce. this shows the study design. there were at least 12 monthsbetween the last dose of quadrivalent vaccine and thefirst dose of 9-valent vaccine. then the green area shows withthe doses administered with a 0, 2 and 6-month schedule.

i'm going to sup vise some ofthe data among females randomized with 9-valent vaccinefor dose one. 31, 33, with 9 #%, 95%, 68%, 94%and 99%. of course these wererevaccinated. we have no information onanti-body after this dose. post dose three, over 98% ofquadrivalent vaccine recipients were 0 positive to all fivetypes. this graph shows the titres withthe gray bar being gmt enrollment.

blue being the post dose one. and purple post dose three. for the four types tar in thequadrivalent vaccine 6-11, 16-18 there was an increase inanti-body post dose one and though further increase postdose three. remember all them have receivedthree doses targeting the four types. the gmt is for the fiveadditional types appear lower than those more the fouroriginal types.

also there was an increase inanti-body after the third dose comparedo after the first doseand below the excess you can see the full difference post dosethree kpaered to post dose one. all these types, the fulldifference range from 2.3 to 6. the injection site amongrecipients of 9-valent vaccine at greater than 1% and greaterthan the saline group are shown here. there was also one adverse eventin each group. case of tonsillitis andmigraines.

both of these resolved. in order to further assessresults, data from protocol were kwused in a post hoc cross studycomparison. the objective of this analysiswere to compare the safety of 9-valent vaccine andquadrivalent vaccine recipients with 9-valent in naive femalesto compare immunogenicuty in both groups. this slide shows the the titres. for each type the geometricmeans titres quadrivalent

vaccine and those previouslyvaccinated are shown. the titres were lower for thosewith previously received quadrivalent vaccine with a ashowe between .3 and .6. this shows the injection siteadverse events following each dose in protocol 006 in 9-valentvaccine naive to vaccination in other studies. there appears a higherpercentage of erethema and swelling, 49% versus 38% the inthose who had prior quadrivalent vaccinations compared to naivewomen.

in summary, an updated pos notewas published in february. this was published at the end ofmarch. 9-valent hpv vaccine was ontrack in april. the transition vaccine in thepublic private sectorss ongoing and the manufacturerexpects quadrivalent vaccine to be in the market until mid 2015. trial eva waited 9-valentvaccine in prior quadrivalent recipients after three dosesover 98% of prior quadrivalent recipients were zero positive toall additional types.

there was an additional safetyprofile in a cross study comparison of 9-valent vaccineand quadrivalent recipients. three doses of quadrivalentvaccines results in lower anti-body titres compared tothree doses of vaccine in patients. clinical significance isunclear. there is to immune protection. the safety profile was similarexcept fo higher rates and injection site reaction.

i want to thank the work groupmembers that assisted with this. >> thank you. would you like to go on with thepresentation and take questions on both after that? >> yes. >> while he's getting the slideup people will are looking at electronic devices. the supreme court issued aruling on the health care reform 6-3 in favor of upholding it.

[ applause ]>> thank you. >> good morning. >> before addressing the impactand cost effectiveness of 9-vent i will start with areview of the health economic presentation from the februarymeeting. at that meeting we presented asummary of three models of 9-valent vaccination in the u.s. and their estimates of the costeffectiveness of roo are teen 9-valent vaccination.

we have available in the unitedstates the u.s. version of the hpv model was presented at theoctober 2014 meeting. it's based on a published9-valent canadian model calibrated with u.s. data. the merck model and simplifiedmodel are both based on podles to include the additional9-valent vaine. these models were used for thecost effectiveness of 9-valent vaccination with specificquestions addressed of what is is cost effectiveness of aroutine vaccination for both

sectors compared to a routinequadrivalent vaccination program for both sectors. this table shows the costeffective assessment in terms of the incremental cost for qualityadjusted life year or quali gain. the results are for twoscenarios with and without cross protection. the scenario of cross areprotection, the quadrivalent vaccine was assumed to providepartial protections against the

additional five and the 9-valentvaccine. the first column of results werethe no cross protection scenario. in here, all models suggest9-valent vaccination prepared to routine vaccination. in the scenario of crossprotection again the model results are similar. the cost gained is quite low. less than zero dollars.

under 10,000 dollars. to summarize the resultspresented the 9-valent vaccine compared to quadrivalent vaccinefor both sexes is likely cost savings. the cost per qui gained isless than zero dollars. most of the incremental benefitsof the 9-valent vaccination are due to vaccination of females. now we'll move on to costeffectiveness of additional same three models used toaddress routine vaccination.

the specific question weaddressed is what is the cost effectivenesof providing threedose of 9-valent vaccine to females previously vaccinatedwith three doses of quadrivalent vaccine. this table shows the age and sixof the vaccine reaccept yent. all three models assume femalesaged 13 to 18 would be eligible for additional 9-valentvaccination. all three assumed additional9-valent are vaccination would be a temporary program takingplace in the context of an

ongoing routine 9-valentvaccination program for both six s. this table shows the impact andcost for quali gained for all three models. for example, for the hpv modelit was estimated about # 1 million females would receiveadditional vaccination at a cost of $432 million with a gain inquality of 3,700. this works out to an incrementalcost of about $117,000. the results of the other modelsare consistent with the results

of the hpv model. why is routine 9-valentvaccination so much more cost effective than additional? the incremental benefits are issame for additional vaccination. are routine 9-valent vaccinationand additional vaccination both provide protection againstthese. the difference of the inkremental cost. when we are switching the inkremental cost is the difference in the cost of the two vaccines.

in contrast to po viedadditional vaccinations we incur the costs of the vaccine throughthe cost of those is over $134. the difference in incrementalcost is different from these vaccination strategies. i will present results forsensitivity analysis. that model has performed[ inaudible ] to date. the model accounts foruncertainty in the natural history.

each parameter set is runmultiple times. the results can differ from onemodel run to the next due to chance. 80% uncertainty interval aresare from the 10th and 90th percentiles. because the chance effects arelarge compared to the effects of the additional 9-valentvaccination program the uncertainty intervals houbinterpreted with caution. this shows in terms of the costper quali gained and the 80%

uncertainty intervals are shownhere. regardless of whether or notcost protection is assumed that a quadrivalent vaccine the costper quali gained ranges from 2k4r7z,000 to infinity. -- $7,000 to infinity. what's happening is chancefluctuations this the model simulations are makingadditional vaccinationlook better or worse than it is. we think the realistic estimatesare more narrow.

we haven't yet figured out how. so in summary, the cost perquali gained by three doses of 9-valent vags nation,quadrivalent is estimates are consistent across three mod leslisted here. as a reminder these are for theadditional 9-valent vax vaccinations of females age 13to 19. over 18 and for pales of any agewould be much higher. -- males. all thee three models suggest itis leek lie a cost savings.

all three models agree thatadditional 9-valent vaccination would cost more than $100,000for quali. and it could be less favorableif we were able to achieve hemoglobiner routine 9-valentvaccination for the models or if the people who receiveadditional vaccinations for the same ones who received several. why don't we entertain questionsor comments for the speakers. dr. kiren, dr. ryangold. >> i wonder about the data tosuggest three doses of the

9-valent vaccine are necessary. that's what all the economicmodels are based on. do we toe that we need three? what about two? what about one? what do we know about that? >> as we have discussed beforeat two previous petings there is an ongoing trial of two doses of9-valent vaccine. that trial is fully enrolled andi believe the data are being

analyzed over the next probablyfour to six months. that study is looking at twodoses at 0-6 pos and two at 0 and 12 months in 9 to14-year-olds. that's being compared to a threedose schedule in the age group that was in the efficacy trial. those data will be forth coming. i think you saw in the slide theanti-bodies after dose one in this trial but not after dosetwo and also there is no follow up of the individuals after theone dose.revaccinated.

they all received both dose twoand three. >> dr. ryangold? le. >> i'm curious. i know this is a contingent butis it possible to estimate how many cancerers at differentsites would be prevented with an additional three doses of9-valent to a cohort of whip who have receive ed quadrivalentvaccines? in the united states how manycervical cancers, how many other

cancers would be prevented? >> that's something we can doand get back. >> it's a little bit differentthan looking at other vaccines. the cancers occur far out and soduring that time there is going to be 9-valent vaccine use inthe routine program and there will be immunity from at. it's not as straightforward aslooking at this for other vaccines. >> dr. yamili?

>> my question was pretty muchaddressed. as you know in canada we use atwo-dose schedule in some provinces. our dilemmanow is what to do with a 9-valent vaccine. >> this is a hypotheticalquestion. i'm curious given the currentlevel of uptake of hpv-4 or hpv-9 in vaccine naive, this isfrom picking up on what was saidyesterday.

what would the effect of $400million a year being spent to enhance vaccine naive peoplegetting vaccine, ie, if we could increase the first dose from 50%to 70% growth and have a higher rate of completion, does thathave much more effect than adding in additional doses? in terms of a stable amount ofpublic expenditure. >> we could look at costeffectiveness of additional vaccination to increase coverageof routine 9-valent vaccination. i would bet you could incursubstantial program costs in the

intervention to increase9-valent coverage and still come out aanti-depressant in terms ofcost impact. >> we are still struggling toget half our population even one dose of whichever vaccine it is. my fear is that programs torevaccinate people are going to target a group that's alreadygetting the vaccine and may not get a group that needs to bevaccinated in the first place. any additional questions? if the dr. merko witz, if youcan, continue on.

>> i will end this session withconsiderations for guidance. first to summarize what waspresented today there was one randomized trial for 9-valentvaccine versus placebo. after the therd dose there wereall five additional types over 98%. there is no formalnoninferiority bridging evaluation but in an unplannedcross study comparison the gmt is for the five additional typeslower after 9-valent in vaccine naive females in the clinicalsignificance is not known.

there is no correlatedprotection. no safety concerns apparent inthe cross study comparison. there were high rates comparedto 9-valent vaccine females. the benefit of protectionagainst the five additional types would be mainly forfemales for prevention of cervical cancers and the costper quali gained is over 100,000 dollars among females 13 to 18. the cost would be higher forvales of any age. the models have shown routinevaccination for females and

males cost savings to aquadrivalent vaccination program. the work group felt the highestpriority was raising 9-valent coverage for the routine series. the variety of issueser wereconsidered as was mentioned and both members knoent the onedose was 57% and for three, 38%. this is a lot of work to be doneto raise coverage in the u.s. the economic analyses werereviewed and considerations varied if the work group.

some work group menbs placedmore weight on the health economic considerations thanothers. the work group also noted thecervical cancer screening continues to be recommendededfor women aged 21 through 65. the this is the same forvaccinated and unvaccinated women. the work group members weren'tin favor of a routine 9-valent however it was felt guidance andinformation are needed in a variety of areas.

this includes persons whostarted the series with another vaccine product and even thoughwe do have information in the policy note further guidance wasfelt to be needed. also for persons who completedthe three-dose vaccination series. it was important to clarifyrelated to additional to additional vaccination. as i mentioned before questionsabout additional vaccination have been common, both beforeand after licensure.

some providers and parents areinterested this additional protection against the fivetypes and others will be seeking information about guince andremember the 713 transition. there are a variety ofdifferences between that tran are sigs and the hpv vaccinetransition. i wanted to just review some ofthose. first of all, there is noindication for additional doses of 9-valent vaccine. an indication on the label for asupplemental dose and specific

interval ares in the label. more the p are cv 13 there weredifferent combinations evaluated. theest hated cost for qualigained for the additional 9-valent is higher than theestimated cost for supplemental dose of pcp 13. also important is slow. the manufacturer swapped outdoses of pcb with 7 for 13 during the transition.

before i discuss the guidance weare suggesting be communicated i want to mentionhere are noplans for an additional policy note since we did publish one inmarch the information would be posted on the website and therewould be a link from the acip recommendation page to thisinformation and also an announcement in the mmwr alsowith a link to the online information. i would like to show examples ofguidance for providers including basic difference scenarios.

one for thes who started withanother product. those who completed a series andthe type of information relevant to the different situations thatwould be made available. again, the suggestion is theguidance be in the form of q & as. the actual wording will changefor clarification purposes. in vaccination for those whostarted with another product, a question would be if the serieswas started with quadrivalent or bi valent vaccine can it becompleted with 9-valent?

yes. the recommendation states9-valent are vaccine may be used to complete a series startedwith a different vaccine product. this isomething that's in ourpolicy statements. our additional 9-valent hpvvaccine is is recommended after 5 valent completed with 9-valentvaccine. there is no ac are iprecommendation for additional 9-valent dose ps for a personwho started the series with kwds

or bi valent and completed withthe 9-valent vaccine. another question that has comeup is if the series was started with quadrivalent or bi valentvaccine and will be completed with 9-valent vaccine what arethe intervals for the remaining doses in the three-dose period. the current recommended hpvvaccination schedule is for the second dose to be given twomonths after the first and the third dose four months after thesecond dose or six months after the first dose.

acep doesn't state maximumintervals between hpv doses. anti-body titres haven't beenfound to be diminished after longer tan standard intervalsbetween doses. data from other hpv vaccinestudies show equal or higher anti-body titres when do twodoses are administered at an interval of six months comparedto two months. we mentioned an ongoing studyevaluating two doses of 9-valent vaccine separated by an intervalof six or 12 months. for the situation of vaccinationof persons who completed the hpv

vaccination series here are themain question is additional hpv vaccination if additionalvaccination with 9-valent hpv vaccine recommended for personwho is completed a three dose schedule with quadrivalent or bivalent vaccine. there is no acip recommendationfor routine additional 9-valent vaccination of persons whopreviously completed a quadrivalent or bi valentvaccination. if a person desires protectionagainst the five additional types prevented by the 9-valentvaccine and has completed a

three-dose series ofquadrivalent vaccine what issues should be considered? the benefit of protectionagainst five additional types targeted by 9-valent hpvvaccination is mostly limited to females. for the prevention of cervicalcancers and precancer rs only because a small rcentage ofhpv associated caers in males is due to five additional typesin the 9-valent vaccine. available data show no serioussafety concerns in persons who

are vaccinated with 9-valent hpvvaccine after having received a quadrivalent hpv vaccine. cervical cancer screening isrecommended at age 21 and continuing through age 65 forvaccinated and unvaccinated you have some of these on yourslides but i won't go over them. we'll have information toaddress the two questions. what data is available on ef kasi of 9-valent vaccination for the five additional types whenadministered after a complete three-dose series of anothervaccine product and what data

are available on the saty ofthe 9-valent vaccination. when administered after acomplete three dose series of another product. there could be otherinformational questions as well. these would, again, be posted onthe cdc website. we are not going over those. i would like tow to open it upfor acip discussion. what's your feeling about theoverall approach? are d additional questions orinformation needed?

and other comments. >> thank you very much. open it up for any comment ordiscussion. dr. middleman and dr. ornsten. >> i'm just curious to know fromour insurance quali and exp i think the big concern we have asan organization is adolescents who would like to haverevaccinations, the those who do we want to headache sure thereis no discrepancy in terms of who can afford it and whocannot.

i o with curious to know fromthe insurance arena, i assume with uses approved it would becover covered but i'm curious to knowwhat the policies might be. >> my understanding is that thiswould cover a three-dose series regardless of the combination. if the committee approves this iassume it would be the recommendation or perhaps norecommendation from what i'm understanding is it offers nosignificant advantage. that might be a patient costresponsibility.

that's what i would assume. >> that was my concern. at least the way i read this isone would have to pay out of pocket to get that. it might be preventable. i may have those numbers wrong. it looked like that from thefigures you have presented. we made a big deal about otheruses. one of the big concerns ispeople not realizing what hpv

does and to not have a categoryb recommendation raises concerns about preventable seriousdisease. i think in my opinion thereought to be least a category b reck hen days ago. >> dr. kimberland. >> to build on dr. o renstein'scomment and to tie in dr. markowitz with one of yourcomments earlier in one of your earlier slides this will be aquestion -- already is a question -- families andpediatricians are asking.

the academy will need to provideguidance. this is a situation differentperhaps than the argument i was making yesterday with thedifferent vaccines. what dr. orenstein isillustrating ties in with the doctor's comment yesterday aboutthe other vaccine considerations. if there is no recommendationand there is information out there that the vaccine is safeand adds some degree of efficacy then the people that can affordit will get it and those who

cannot will not. the category b recommendationfrom the acip would tie in those funds and equalize thatpotential discrepancy. the academy would be interestedin working with the work group to develop such language if theacip were interested. >> dr. moore? >> thanks. kelly moore. i would like to add my voice tothose suggesting that the

committee and working groupconsider a category b recommendation here, especiallyin light of the discussions and fubs we looked at yesterday. it seems like these numbers arefavorable if the cancer cases that could be presented althoughnot sudden and dramatic are are agonize deaths the for familiesof young adults. if there are those who wish toavail themselves of additional safe detection to prevent therisk more we should find ways to make the opportunity availableto them.

>> i have dr. frayhuffer and dr. harrison. >> american college ofphysicians. lorry, tank you for puttingtogether the statement. it is helpful for prak tayediggsers. when do you anticipate havingare it up on the website? >> i think it could be fairlyquickly. i haven't discussed this indetail. i think it should be fairlyquick this this the matter of

weeks on the website. it would take longer to have theannouncement in the mmwr. it would be quickly. >> dr. mar son and dr. olsen. >> did the working group discussthe pluses and pienss of the katz goir b reck men days ago? >> we did. we did grade this as well. it was discussed within the workgroup.

>> could you summarize? p.m. there were some people infavor and some people not in favor. i wanted to ask dr. shuckit ifthere are comments about that. >> i would like to. i wonder if adtional acipsmember should make comments first. i don't want to influence that. i'm happy to make commentswhen you want me to.

>> dr. alt. >> i had a question for dr. cheston. there was a publication thatsaid out of the $6 billion we spend on hpv related cancers wespend $5 billion screening for cervical cancer. is that in the model as well? it's not just cancer. it's the money on pie nor papsmear abnormalities and cervical

dysplasia and that sort of thingthing. >> the models do take intoaccount the costs associated with screening but assumecervical cancer screens will continue. >> okay. >> dr. reilly? >> with all due respect to stampout as hutch cancer as possible i think if we put all of ourenergy, money, time, interest into vaccinating more women ormore young girls and boys we

may, in fact, get much further. i feel very strongly thatspending lots of frj on that population that's already beenfully vaccinated really diverts our attention. we have tried so many things sofar only to get 50% of the eligible people vaccinated. i really think we need to putour energy into getting a much greater number of peoplevaccinated. that will, indeed, make a hugedifference.

>> dr. bolonya? >> i would like to follow upon comments made regarding theissue of equity and the fact that there is some benefit togetting additional doses with 9-valent and some people canafford that. some people can't afford that. i understand but if you take theprinciple and apply it more generally, i think you have tologically reach the conclusion that the every vaccine licensedby the fda should at least get a

categorb recommendationbecause they are safe and effective. is that where we want to go isthis. >> just keeping track i have dr. middleman, harrison, baker andsawyer. hopefully i'm catchingeverybody. dr. middleman. >> i jt want to echo again,sam really supports the immunization of one kind orother.

we want the focus on gettingeveryone immunized at least once our concern is the equityconcern. we want to make sewer there isnot a disparity when some patients want to berevaccinated. we are not suggesting the focusmove to revaccination but it be an option available tr those whodesire it. >> dr. harrison. >> is out a zero sum game? if we have a category b and irecognize we are doing poorly

with getting people vax fated. if we have a category b, not a. does that divert attention thequestion focused on getting kids imfiezed with one vaccine? i have dr. baker. >> this quick question. you mentioned you would havemore data potentially by the october meeting. i certainly understand lack ofconsensus in a work group.

sometimes it's because there isnot enough data to get therementyou anticipate that the data will help at all withthe discussion? >> i'm not 100% sure we'll havethe data in october. haven't been given an appearancein october or february. at the latest. again, i think the data will behelpful. they are not specificallyrelevant to the additional vaccination question becausethose are in vaccine naive

individuals and the anti-bodytitres were lower receiving 9-valent after quadrivalent. the other thing i want to pointout is all the data including the canadian recommendation fortwo doses are just for 9 to14-year-olds. based on the studies being doneand the regulatory agencies aren't going to be for peopleover 15 and older. they might help. they will shed light on thisthis.

>> dr.er sawyer? >> dr. are middleman's pointabout equity, i want to verify could a provider give as manyvaccines if they want if there is no recommendation? ten mmrs and have all of themcovered? >> do you have an answer? >> we run the program intennessee and don't count the number of doses. you tell us how many you need toorder.

we are not looking at individualpatients. ifyou did that all the time and someone reported you, we mighthave to have the conversation. we are not ooh teenly looking ateach patient making sure you only gave the required number ofdoses to each patient. >> you have to keep in mind dr. sutter is in california and theyhave had a problem with measles lately. there is a question.

>> dr. bennett? >> you know, i'm very sensitiveto the equity issue. it's a verymportant one, ithink. one that we always need toconsider. i just want to point out thisreminds me of the virginia slims advertisements about you havecome a long way, baby. that was about equity insmoking. it seems to me the work grouphas determined the that giving additional doses is notvaluable.

i don' think we should beworrying about equity for something we don't think is theright thing to do. >> i'm seeing a lot of interestamongst not only the menbs, but amongst the liaisons. it seems as though this might besomething best to g back to the work group for. further consideration given thatsuccinctly. there were some peopleinterested in and some people not interested in.

dr. shookit. >> yeah. i want to make a comment thatthe issue of the fda approval of the 9-valent was not for theindication of revaccination. the tran are sigs plans aregoing to be some with a prolonged compared to the pcv713 swap out. from the cdc perspective, weview implementation guidance different from the policy. implementation guidance in termsof the ordering that the states

do and so forth as somethingthat we have a bit of responsibility to take care of. so the idea of posting commonlyasked questions and answers in this transitional period wherewhere people may have got the product in the office as why weare expeing to post guidance for common questions quite soon. this isn't even an fda approvedindication. many we would like to get bothinformation out about what the evidence base is and practicalanswers out explaining what the

plan had been. >> dr. bikini. >> i want to clarify about thework group. it wasn't considered that the9-valent vaccine didn't add benefit. clear it adds benefit. the issues that have beendiscussed are the key issues. they were related to strongopinions in the work group as to whether focusing onrevaccination or allowing

revaccination would take awayfrom the primary purpose which is to get people vaccinated inthe first place. there were strong opinions onboth sides. if the february meeting wasn'ttruncated the presentation would include information aboutanalysis of one or the other. also showing the work group thatthere was differences of opinion in the work group. asking them to weigh in on itand give recommendations about a category b recommendation.

that was the original plan. we have modified that based onwhat happened. so it's reasonable for us to goback and provide additional information to help the acipmake that. >> dr. ruben? >> also the two things aren'tmutually exclusive. guidance could be provided andsubsequently a decision on a category b could be made. >> i think going forward theintent is that guidance will be

provided and to be honest as aclinician i find everything you put together very helpful. in practical terms what a lot ofus are already doing. i think taser very helpful. the question then becomes do thevotingenbs feel we should put additional effort and time intothis in terms of -- we try desperately not to use categoryb recommendations very often. but whether or not we feelstrongly that we want to invest the time further down the linefor this discussion.

do we have a consensus here? out of respect to my colleaguesi'm going to stand moot on this point. whether or not this is somethingthat is a consideration. >> this is a question onprocess. if we do nothing today,basically with a they have suggested is forced sp. >> there is good precedent here. for example with zoster vaccinewe had a no vote on the

consideration of changing theage. on tdac we had a no vote onrevaccination and by not taking a vote we affirmed our currentpolicy. by doing nothing here wewould affirm the fact that wereck emend one of the three we don't express any preferencefor any one of the vaccines but we at the same time acknowledgethat our clinician friends are really, really smart people andmake good decisions. and we also do not go beyond thelicensure in terms of pro

veeting revax thags.ydãº[ inaudible ] >> i see dr. herman's hand upand dr. harrison. >> i was going to ask if youcould show the language again regarding advice for somebodywho'ser already received three doses of another vaccine. i think i just said there is noguidance or something, no reck are men days ago. >> doesn't say they recommendagainst it. just that there is no aciprecommendation for routine

additional vvaccination. that's how we stated that. we have another question aboutwhat needs to be considered if someone thinks they do wantprotection. one of the reasons we wanted toinclude this is to really let people know that for males thereis really very little additional and with a data we have onsafety. so that was one of the reasons. again, you know -->> those are the two guidance

questions elated. the question that you areraising. >> at least it mentions benefitsfor tales. i don't know if that should bestateder more strongly. >> i think the work group did atremendous job of providing guidance. dr.er harrison? >> i guess i would favor furtherdiscussion about the possibility of a b reck men edition.

i personally would need a lot ofguidance with the question i asked before. i'm sensitive to the issue ofgetting persons vaccinated. would a category b have anegative fekt to get people vaccinated with a first series. >> dr. shookit? >> i'm not going to answer that. i wanted to raise a point. it's importanter for thecommittee to remeer with a you

do today, you are not going toget rid of hpv. in terms of the topic coming upfor you because we are expecting additional future deliberationsthis fall or winterer about the number of doses and intervalsexpected to have more data. the question of what is revaccination is probably related to what is primary vaccination. i appreciate the victoria forguidance coming out quickly. commonly asked questions beingaddressed in this unusual period we are in now where all thevaccine products are out there

and some people have one or twodoses of what's currently a three dose series. you as a committee will beprobably asked to look at alternative intervals and numbof doses and possibly differences by age. i think when you add inrevaccination more there are permutations out therer forcallyphysicians to absorb. i just say that because you willget to come back at this topic or, put another way, you have tocome back to hpv vaccination

recommendation hs the in thefuture whether y want to or not. >> there is one person at themicrophone and then dr. reilly. >> this was a question i askedmy cdc counterparts in a webinar they ga. in february, acep voted torecommend either two valent or four or 9-valent vaccination. all of the sudden we areconcerned we can't do re vax medication for 9-valent.

that would suggest to everyonethat they were inadequately vaccinated for two or fourvalent. that's a message, an indirectmessage in having the conversation. i don't know if it's right ornot. >> the current policy is wedon't express a preference. dr. hah>> actually that's similar to my comment actually. as a parent of an 11-year-oldgirl i will make sure my child

gets the 9-valent. i do feel we are in an oddposition to be talking about this. there might be people todaystarting on the 4 valent as for the current recommendations andi was wondering as far as the guidance piece would we add aquestion for a new personwalking in today since the transition do we want toemphasize children starting today other than the nonlicensedgroup.

i understand that concern. but for most young children theyshould be started on the 9-valent? are we doing what we can to makesure we don't have more children vaccinated start thing seriesnow with the quadrivalent. >> i think we are in thisawkward period of transition. quadrivalent to 9-valent. not all providers have 9-valentvaccine. i have heard stories.

a transition won't be immediate. i think program has been leeryto tell providers to delay it's a deaf cult transitionperiod because of the long delay. many share your fieldings aboutthat. the way to solve that is get9-valent into offices quicker and make sure it is available. >> if i can volume up. with flu vaccine we usedlanguage if you have both in the

office, using one in certainsituation s situations and that might be away to address it. encouraging to have 9-valentavailable for new folks walking in. something along those linescould be done, i think. >> dr. lett and dr. campo. >> i'm sure maybe the workinggroup thoughs this. i know in massachusetts we madea quick transition. but i don't know what'shappening in the country.

i have heard there is plenty of9-valent vaccine available for orders. at least i think that's true. maybe we could get clarificationif we are going to try to transition offices over to9-valent as much as possible. i don't know if anyone canaddress that. it would be more from merck ifsomebody could comment. >> my question is for them also. we went through it with 7 and13.

the manufacture er agreed toexchange, i believe. i don't know whether it and ornot. has the same arrangement beenmade here? >> i would like to comment wedon't have yushs currently with supply. the vaccine is available. we don't have currently anexchange program. with our other information thatwas desired at the time. >> i can take your questionunder advisement.

>> this is bill schaafner fromthe nfid. we don't have an exchangeprogram available. why not? >> i think our expectation is wedon't currently have an indication for males above theage of 15 that the 4 valent vaccine could be used in thisways it was begun or beginning the series with the 4 valentvax. >> and dr. reilly? >> this is a quick questionmaybe for modeling.

is there away to feger out if you did the revaccination andsaved 3,000 more cervical cancers what happens to those 3thousand if we were more successful at vaccinatingprimarily a greater percentage of the population? i'm not sure i articulated thatwell. does it make sense to peoplewith a i'm trying to get at? is it really 3,000 that we wouldbe preventing or would we be much better off by vax thatitting 70 or whatever the

numbers were elsewhere. >> i don't know where the 3,000number came from. we can certainly look atdifferent scenarios of routine vaccination coverage andadditional vaccination coverage and explore the trade off. >> dr. mereman. >> i don't see where one negatesthe other. everybody's efforts can go intogetting people vaccinated with the primary series.

for those who want to berevaccinated, to me one doesn't supplant the other. i can't imagine it would affectthe other. maybe i'm missing something. >> i thinkr. chessan can modelthis out but the,000 number may have been someone rounding upfor 2800 cancers in whip tar in the five types -- attributableto the five types. remember, that's per year. that's not among people whoreceived three doses of

quadrivalent 20 years early orsomething. that's the total universe. of course there is a lot ofother things that go into how he would end up with the modeling. i don't think 3,000 is a numberto focus on. >> dr. kemp? >> i think there are issuesabout how making a b are reck men days ago could actuallyaffect the 9-valent among those who are unimmunized.

somebody brought it up earlier. it sends a message to program,to physicians that the 9-valent is a priority. that it becomes much more of apriority to revaccinate. i think it is likely to send animportant message. you know, i think everybody istorn about this. it really comes down tocoverage, you know. these guidelines say already,yes, it's beneficial. yes, people should useindividual discretion.

what we are really talking abouthere is making sure there isn inequity on coverage. i want to be clear on that. number two, i think there isreason to think that a b recommendation does affect theway physicians, organizations will deliver the program. >> i see no additional hands up. trying to summarize thecomment -- overall especially from the liaisons, what i heardwas a lot of interest in the

possibility of a category brecommendation. i think there is a little bittermore equivocal around the table here with acip but i wouldsuggest that this go back to the hpv work group for furtherconsideration at this point in time. i i'm just looking for more of anod of heads around the table if that's something -- i have heardthree or four people who are very positive about a categoryb. some others who are much moreinterested in trying to enhance

a lot of what nvac and theoffice is doing in terms of trying to increase the uptake ofthe vaccine so -- dr. blancha. >> if i recognize it, one isequity and sort of another you were alluding to is a category breck hen days ago could potentially lead to sort of alot more focus on additional vaccinations people have alreadycompleted a primary series beyond what acip intended orwanted. but to sort of address theequity issue primarily and would

that come at the expense ofpotentially getting more people, a primary vaccination series. >> i will pick on the currentchair of the work group. is that an acceptable course? i don't want to commit you toanything that i'm not going to be herer for. >> well, again i could make thatargument. >> we'll draft you for the hpvwork group. >> i think the work group wouldbe happy to provide additional

information and work through aswe suggested the pros and cons of the b recommendation so allthe data would be beforethe acip to help make that decision. >> that sounds accept . going forward the intent isstill to provide this information on the website forguidance for the clinicians in the interrip. dr. shookit? >> since people are giving thework group more to do, as one of

the program comments mentioned,if there is -- if this is going to be taken back to the workgroup, the work group probably also needs to reassess what theywant to do about preference. there will be some intrinsicinconsistencies if there is something going forward on ifyou got all three doses or acomplete series of x thises what to do with y. y need to reassess whether youwant a preference among the licensed products.

>> good point. the in everything we have doneis if they want additional that would continue to be the focus. >> i think the strong messageneeds to be initial use of expanding the coverage. that's where the benefit lies. >> that's helpful. we'll move forward with tryingto get the guidance available on the website and bring backissues to the work group.

that's helpful discussion. now we'll is have dr. rengoldcome up. i will ask whether or not robertbenjamin is around. if you are signed up forpublic comment we can take your comments while we are waiting. we are now about 40 minuteslate. this was a topic moved to thismeeting because of the false alarm over the snowstorm. at the last meeting.

the per us the sis work grouphas been for a while . i will try to truncate my remarkares so we have time for the acual possession. basically the terms of referenceare to co-ales and update all of the statements regarding therecommendations, epidemiology, the theory. most of the focus is onpertussis, particularly around vaccination and and a number ofquestions relating to the ways to maximize the benefit we canwith the existing vaccine we owl

now recognize as limitations. we have some licensed for singleuse. the current acip recommendationsare for a single dose for all persons ages 11 and older withadministration 11 or 12. pregnant women are recommendedto receive a dose with every pregnancy and there is a boosterfor those who receive a single dose. we are generally doing prettywell at getting adolescents the doses the this inment certainlyin childhood but not well in

terms of adults. the acip has heard about theimportant question of the safety of a vaccine administered topregnant women. you may recall we have hadpresentations about the vaccine safety group about doses andreports among pregnant women. there are no safety signalsidentified at the moment this terms of ongoing monitoring. i believe the safety people arehere if people have have specific questions about that.

we did hear a presentation at aprior meeting about a possie relationship with an increasedrisk after amunitis with receipt of thevaccine. there are additional analyses inprogress. there is also a projectoing aprospective observation study of safety in pregnant women. but just to remind you in juneof 2013 information was presented at the acip suggestingthe that additional doses beyond the one booster would be alimited pub lech health impact.

that manuscript, i hope is closeto publication. that's my understanding. we are about to go into it hereat cdc. in 2014 there was no change madeto the current recommendation. the focus was on infants throughvaccination of women. the working group was asked toconsider additional doses in health care personnel and thecontext of infants. in october of 2014 basically itwas what we were presented was no supportive evidence thatadditional doses would be

beneficial in preventing diseaseand transmission in the health care setting. so no recommendation was head tochange with regard to the and today we are going to heartwo presentations. one will be by jennifer liangwho did extraordinary work with this group. she'll present data aboutvaccinations and lucy breakwell will give a presentation aboutacellular pertussis vaccine effectivenesser with regard topertactin deficient b pertussis.

as dr. liafg comes up, a commentby robert benjamin from the public health department incalifornia just asked if pertussis limitation control isa national priority. will the government incent inceare a new vaccine as they move forward. as dr. reingold noted there wasa recommendation but didn't change the currentrecommendation. the work group has consideredtdap vaccination in infants and evaluated the need for andpotential benefit and impact of

additional doses. for today's discsion i willpresent a summary of the data and the work group'sconclusions. the following slides werepresented to aci p in october2014. one reviewing consideration forhealth care personnel. as a reminder currently bothtdap vaccines are licensed only for single dose. the second, there are severalpublished trials from other

countries at five or ten yearsafter the first dose. reported adverse events weregenerally comparble to those after the first tdap. the majority of local andsubpoenaic events were mild to moderate are and self-limited. of these events none weredetermined to be reare lated to receipt of the second tdap. safety profiles were comparableat the five and ten-year interva.

after a second tdap at the timemus and diphtheria were close to 100%. for pertussis vaccine componentsresponses are comparable to historic and contemoraneousfirst dose. in t united states there areclinical trials of a second a second dose is complete andwas presented in 2013. a revaccination study in canadawill finish later this year and they plan to sub pit for fdaconsideration for label updates. gsk is conducting clinicalstudies.

one study is complete and theother began the this year. gsk plans to submit data to fdafor consideration of label updates will depend onepidemiology and acip recommendations. with regard to tdap vaccineeffectiveness previous estimates from 66% to 78%. however these studies involvedadolescents who received whole sale vaccines as part of thechildhood series. at the time the effectivenessamong adolscents who only

received acellular vaccines wasunnontone. in 2012 in collaboration withthe washington state health there was a large scale study inadolescents who only received acellular pertussis vaccines aspart of the childhood series. est hated effectiveness was 65%and is consistent with previous study. the study looked at the durationof protection. in to the 12 wisconsin looked atduration of protection in adolescent population that onlyreceived acellular vaccines.

despite the differentmethodologies both studies show tdap to be effective. for indirect protection it'sunclear what the effects of tdap vaccination is on prevent ingpertussis trance higgins. symptoms aren't as severe andpresumably less likely to transmit. an australian cocooningevaluation found a ho des decrease in the risk ofpertussis in infants whose parents were vaccinated at asufficient time to booster the

immune response rel toif to theinfant pertussis incubation period . this effect was seen in infantswhose mothers were vaccinated post partum but it is unclearwhether the lower risk for infants was attributable to ashort term impact on transmission for recentlyvaccinated mothers or lack of exposure. an animal model showed baboonswere protected against disease but not infection.

bacterial colony counts werecomparable to those in unvaccinated animals. infected but aassignment hattick baboons trance mutted pertussis to other cohousedbaboons. the results were striking but itis unclear if the animalodel represents what happens withhumans, vaccines and infection. there is currently no humanchallenge model. compared with other age groupsinfants less than 1 have substantially higher rates ofpertussis as shown here.

and the largest burden ofpertussis reare lated death. among all infant pertussiscases, infants 2 months of age and younger have the highestreported percent of hospitalizations and death. when tdap was wreck rrecommended in 2005 there was a dose of close contact forinfants. this would protect thevaccinated individual from pertussis and potentiallyprovide indirect protection to the infant.

ideally contacts would be vaxfated at least two weeks before contact with the infant andpregnant women who had never received tdap would bevaccinated post partum. this was a shift in thinking anda newer paradigm for vaccine delivery. in 2010 the united statesexperienced a resurgence of pertussis. california declared an epidemicand recommended a dose for pregnant women.

they considered shifting thetiming of the mother's tdap dose from poster partum to duringpregnancy which would provide earlier direct benefits tomothers and potentially indirect protection to the infant andhigh levels of maternal anti-bodies would likely providedirect immunity to infants. therefore in 2011 aciprecommended tdap during pregnancy for women who had notreceived tdap and if not vaccinated during pregnancy thena woman was recommended tdap post partum.

in 2012 acip expanded therecommention to every pregnancy irrespective of thepatient's prior history of receiving tdap. the reck hen days ago for thepo partum dose didn't change and limited the post partum doseto women who had not previously received tdap. for cocooning guidance onadditional doseser for close contact including the postpartum dose would be forthcoming.

successful demonstrationcocooning programs have been documented. programs have been primilyhospital based and targeting the post partum period. to achieve operation that willsuccess common strategieser were implemented for the post partumdose standing orders were in place. hospitals had clinics withconvenient hours offering free tdap.

despite the successes, cocooninghas not been implemented at the national level. the challenges the program facedare particular to vaccinating the close contact. logistically programs aretargeting close contacts during a short period of time the postpartum hospital stay. this might require additionalstaffing and administration. there is the inability to verifya person's vaccine history and not all hospitals are set up totreat outpatient and

may referfamily menbs elsewhere. financially, there are onraegsal costs to mane taning a programs with free vaccines arechallenged to offer free for programs that don't offerfree vaccines the hospital faces reimbursement and billingchallenges. these kajs make it difficult tosustain a program. in 2012 tdap coverage was 26% inadults who reported living with an infant aged less than 1 year. how complete is a cocoon aroundan infant.

published reports from cocooningprograms reported tdap up take highest in post partum motherswith limited success in vaccinating fathers or otherfamily menbs. tdap up take has been limited bythe knowledge gap about pertussis and the vaccine. household size, impacting theability to vaccinate all menbs and locating where to get vaxthat itted if no on site clinic is vaebl. for women who receive tdap postpartum in preventing infant

a california ecological studythoeted pertussis incidents in infants born in hospitals with apost partum tdap policy was lower compared to hospitalswithout tdap policies. suggesting that the vaccinatingnew mothers would protect infants from pertussis. another study comparedpreintervention to post intervention period and found noimpact of post partum tdap on infant disease. the evidence on theeffectiveness of cocooning many

in preventing infant pertussisis unclear and inconclusive. we are aware of two u.s. studiesthat attempted to look at cocooning. a hospital program observed noimpact in reduction of infant pertussis but due to the limitsof the stud results should be interpreted with caution. an mernging program study setout to conduct a case controlled study to measure effectivenessof cocooning at preventing pertussis among infants lessthan two months of age.

with limited number it is studyinstead assessed the completeness of cocooning. among infant cases and controls,a tole tall of 199 cocoons were identified. among those only nine were fullyvaccinated cocoons. five of which the mother was theonly cocoon member. the australian case controlstudy found moderate reduction in risk of pertussis in infantswhose parents were vax that itted at a sufficient tomb tobooster their immune response

relative to the infant pertussisincubation period. over the past decade with thechanging pertussis epidemiology a shift in the source ofpertussis transmission to infants has been observed. previously parents were commonlyidentified as a source of pertussis with mothers mostidentified. more recently though, siblingshave been identified as the most common source. through enhanced data over eightyears infant pertussis cas 44%

identified the source ofinfection. of those, 66% to 85% wereclassify identified as family menbs with siblings identifiedmost often. since 2011 acip recommended tdapvaccination for women during pregnancy. safety data continue os bereassuring for both women and newborns. in 2012 the united kingdomrecommended pertussis vaccination for pregnant women.

two recent publication ifs thesame program show agreement of high effectiveness of oma ternlpertussis vags nax. an observational study used thevaccine screening method. for infants less than 3 monthsof age at on set of pertussis, vaccine effectiveness was 91%for infants whose mothers were vaccinated at least 28 daysbefore birth. many contrast, effectiveness was38% for infants woes mothers were vaccinated 0 to 6 -- beforeor one to 13 days after birth. the casal control study lookedat effectiveness in infants less

than 2 months of age. the unadjusted vaccineeffectiveness was 91%. when adjusted it was 93%. the uk was able to achieve in ashort period of time which allowed for these eval waegss. here in the u.s. up take of tdapamong pregnant women has not been as successful. estimates among pregnant womenranges from 14 to 23%. after much discussion the workgroup made the following

assessments regarding pertussisand vax that itting close contacts of infants with tdap. the work group recognizes theimportance of optimizing strategies for preventingpertussis in infants and many health care programs put timeand effort in cocooning programs. after ten years implementationand sustainability remains a challenge with barrierspreventing close contact to getting vaccinated.

there is a lack of dataevaluating the effectiveness and strategy on preventing infantpertussis and the evidence is inconclusive that additionaldoses for close contacts including the post partum dosewould be beneficial in prevention of disease andtransmission. even if additional tdap dosesare recommended this would not address the observed shift forsiblings as a source of transmission to infant and putsem if a sis on the importance of providing newborns with paternalanti-bodies.

there is a strategy in place. vaccinating women duringpregnancy. close contacts of infantsincluding the post partum dose for women. if tdap vaccines are licensedfor additional dose it is acip will be asked to reconsider thevarious policy options. until then the focus houb on thecurrent pertussis vax thags maintain high levels ofcoverage. improve adult coverage andvaccinate women during pregnancy

to protect infants. before discussion i want toshare the following. in an effort to improve tdapcoverage in pregnant women cdc launched a new campaign topromote tdap immunization during after research few materialstargeting pregnant women and prenatal income professionalswere developed in collaboration with acnm and acog. these are samples of materialsthe for health care professionals.

i know copies were provided tothe committee members. i want to point out the emphasison not relying on post partum immunization in the sheet. we highlight acog's reemt burmttools and created an entire seat onowe to make a strong are referral. these are examples of theenglish and spanish language tools for pregnant women. fortunately we learned in thefocus group that preg thant

women are are very receptive togetting tdap once they learn how it can benefit the baby. a strong recommendation fromtear provider can make all the difference. >> thank you very much . ms. pelegrini is. >> great presentation. in studies looking at thesiblealings was there a question whether the siblings were up todate on their pertussis

vaccinations? >> i'm not familiar. they were not. not in that assessment, no. they weren't assessed for partof the study. >> just a follow up question tothat. do you have a sense of of theage distribution among the siblings? >> the age range is between 1and 19 with the median age about

8. >> dr. alt? >> carol hayes had to run out tocatch a plane but she wanted to compliment you on the material. i would like to second that,too. whoever is responsible nice jobwith that. the other thing i want to ask,acog made a recommendation for vaccination during pregnancy inthe spring of 2013. do you have data from this yearor last year about up take for

that recommendation? >> the most recent data is fromthe internet panel you are survey of pregnant women. that was for the 2014-15 fluseason. for that, the coverage amongwomen during that time period was 23%. so we are aware some of thecoverage do cover a period of time when we were transitioningfrom one dose for one pregnancy to every pregnancy.

>> i would like to see moreemphasis on the timing of vaccination during pregnancy. on one of the slides it says upto 36 weeks. now there are data during theweeks. the british data also suggeststhat vax thagt late in pregnancy doesn't allow time foranti-bodies. i would suggest more emphasis ontiming the vaccinations, not at the last moment in pregnancy beearlier in the third trimter. >> i want to emphasizejennifer's point that a strong

reck hen days ago does carrywell with pregnant women. this is illustrate ed by aneffort in the northern california kaiser program wherewe achieved a greater tan 80% coverage for the last threequarters in their preg thant >> from a local public healthstandpoint, a comment that in orange county i think otherlocal health departments have had the same experience i have. would we have gone to localobstetricians to talk about it is this the general push backhas not been i'm not aware of it

or it is back providing the tdapvaccine doesn't fit into my clinical model. i certainly think exortation andreminding people but to move the dial there is aeason we dowell at kaiser because kaiserer has a place to go getvaccinated. the hesitancy for many people isyou can exhort them to get vaccinated but if they don'thave a place to go, ideally the obstetrician. pharmacies aren't a good optionbecause of insurance issues and

barriers. i would love to know whichdirection to go forward here. we need a little bit more thanposters. we need clarity on where toconsistently get them back. >> dr. her man? >> just to reiterate, what wefound is it's not -- i mean the strong recommendation is great. it's having the vaccine on site. having it right there so womencan be vax that itted at that

even if there are no barrierswith insurance it's getting to the pharmacy. we know in many studies you haveto work harder. life gets in the way. it doesn't happen. toes identified in the acogstudies and others for prenatal care providers not offering onsite is real or perceived financial barriers, setting up aprogram and either real or perceived feeling they are notbeing reimbursed adequely.

i don't know how much of that'strue. but that's where we need to go. kaiserer has it right there. apparently there is drop off ifyou have to go to another building. it's important that on site. we are going to look at themed-cal data. we'll look at what our up takeis that will give us a good idea of what's happening.

we should be doing it soon. >> following up on that pointi'm curious whether there is data looking at family practicesversus obstetrical prak tes. all of the practices usuallyhave a full contingent of pediatric and adult includingtdap. based on pi sample size of theclinic, we do really well with we are probably 80 to 90% ofpregnancies receive it. dr. bakerer? >> a comment on that statement.

through cdc funding one of mycolleagues is actually the samples are being run. we will have data very precise,modern data with these vaccines of the timing by week ingestation and the amount of anti-bodies transferred. another study will look becausethe perception is 22 the to 34 weeks we don't get anti-bodies. depends how much you have. there is passive and activetransport.

in the next year we'll have moredata about timing that could do somethingment i work in ahospital. our pediatric department runsthe obstetric service with obstetricians. that may be clear. what we have is the group ofacademic prak tes people and a grup of private practice peoplewith offices in the same building with the same pharmacyso there is no barrier of access.

the vaccine is there. there is tremendous disparitybecause the blor academic group has the best practicesthey have initiated as part of the emr are and there is atremendous disparity. i agree. have it there but you have tohave the recommendation and the prak taye diggser in both groupshave been educated. >> d eli? >> the other question aboutongoing surveillance of up take.

most of us are in institutionswhere ours is 89% and it has been that way for a long time. when i see the numbers it's 22%. where do we get the data. are we going to have that? >> of the various data won itthrough pregnant women which is seasonal for each flu season. the other is through pram. there is a module where they askaboutdap coverage among

from my current understandingthat's an optional module. not required by all to answer orchoose the set of questions to answer. the last night it was at least13 states that picked up the tdap coverage module and askedthe question. they give us the information. you would have to ask someoneelse. >> i see dr. let. we need to move on.

go ahead. >> another comment aboutpertussis. from a local public healthstandpoint i think a lot. we are seeing more pertussis. biggerer waves with diseasementwhen the waves go away we are seeing a lot of these. more and more local publichealth is emphasizing, identifying high risk scenarios. ie, infants.

a lot of patients with pertussiswe call and say is there an infant. nurses in public health askthis. okay. i have a 28-year-old dad. has a 2 month old. 28-year-old dad. was supposed to get vaccinatedat 23. he got tdap.

now we know from everything wecan see the immunizations, the immunity goes away. now every adult is supposed toget the tdap coverage. everybody is supposed toment nowwe have an adult we think by all the signs we have is nonimmuneand he's now right next to a 2 month old. why would we not sax nate thatperson? i don't know if it is tococooning or whether we should be exhorting people to improveadult tdap coverage if we are

not doing repeat vaccinations. there is a logical quandary thatproviders and nurse assessments. >> dr. let? >> just a final comment. i don't understand how the pramsurvey is totally operated and funded. but i would make a plea to haveit be part of the core question. i learned by chance that it wasbeing dropped. i had to submit a brief to getit included.

i have to do a presentation andi have to come up . then they had to approve thatwithin our state. i had to provide the fundingfor my program to keep the question in an almost got lost. i don't exactly know how ithappened. it's cdc to be part of iter forcdc funded questions. if we can have dr. breakwellcome on up. >> good afternoon.

despite ieg vaccination coveragetherehas been a resurgence of disease in the united stateswith notable peaks in 2005, 2010 and 2012. in recent years reportedpertussis has significantly increased and remeans elevatedwith previous decades. there are several factors whichcould be contributing to the resurgence. surva lance bias is one explanation.

increased provider and publicawareness and improved sensitivity in tests can lead toincreased eyde caution. waning immunity could increasesusceptibleability in individuals since an increase. recent investigations have shownvaccine effectiveness like aing on children vaccinated with akreyou lar vaccine. tdap among children was 89%. although it was excellent withinone yore of receiving, 98% protection weans to 71% to fiveyears post vaccinatn.

this is consistent with otherpublished studies. waning protection was alsoobserved with tdap. in washington and wisconsinestimated by two different methodologieses was 73 to 75%within one year of tdap vaccinations. weighing to four years postvaccination. the firth krubting faker --contributing factors would be. one such example is theemergence of protack tif deficient pertussis trains.

in resistance to clearance. it is also a component of all ofthe acellular vaccines in use this the united states. our branch evaluated todetermine when pertactin deficient strains emerged in theunited states and their current national prevalence. a pertactin deficient strain wasfirst identified in 1994 but not again until 2010 when 14% lackedpertactin. by 201285% were pertactindeficient.

currently around 80%. pertactin deficiency doesn'tappear to alter clinical symptoms but may provide aselective advantage as fully vaccinated cases were morelikely to have pertussis compared to unvaccinated. the impacts of pertactin didelaware if i schenn si is unknown. here we report the firstevaluation among pertactin deficient strains.

our objective was toest pateduration of protection of the five dose tdap series among 4 to12 and tdap among 11 to the 19 and also determine amonglaboratory confirmed pertussis screens. the moment was an ideal place asit had the second highest incidence rate in 2012. its state laboratorycull temperatures all specimensreceived which is a necessary step todetermine pertactinstatus.

it had a high proportion ofpertactin deficiency from 2012 at 95%. we conducted two matched casecontrol studies of the month. cases included all probable andconfirmed cases reported during 2011 to 2013. aged 4 to 10 years for the tdapevaluation and 11 to 19 for the tdap evaluation. controls were randomly selectedfrom the same age group from the primary care home of the case ina 3-1 ratio.

cases and controls were matchedfor the tdap mall sis. demographics and history weretaken from the medical charts. the if necessary a vaccinationhistory was supplemented by parent interviews. additional regression was usedto ka cue late. accounting for matching factors. cases were clsified accordingto to the department of health deaf negligences based on thosethe council of state and territorial ep deemlologists.

probable cases were considered. confirmed cases met the clinicalcase deaf physician and had positive tests or met theclinical case definition. pertactin deficient strains werepertussis culture positive through poll lar testing,specific mutation thes and protein expression. vaccination status was con if iwered by review of medical charts or by parent interview. er for a participant to beconsidered vaccinated with a

five the dose tdap series one tothree were at less than one year of age. less than two years of age fordoser four and then five to 7 years of anyone. for tdap it was at after 11years of age. unvaccinated participants had novaccines in the chart and parental confirmation ofnonreceipt. while i present the results iwould like you to bear in mind this is preliminary data.

overall 850 cases aged 4 to 19were reported through the vermont department of healthfrom 2011 to 2013. of these, 73% were reportedduring 2012. cases came from all 12 publichelth districts in 91 premierry care homes. data was collected for # 20cases or 96% of reported cases. 30cases were excluded becausethe primary care home outside of the month decleaned toparticipate but we were unable to assign to a primary careoverwhelm.

first i will discuss the fivedose tdap series. data was collected on 380 casesand 1,113 controls aged 4 to 10. overall, 31% of cases and 35% ofcontrols were excludeded. predominantly for havingunverified vaccination history having receive ed less than fivedoses or five tdap the doses. 726 controls were included inthe analysis. 71% of cases were confirmedof which 83% were lab confirmed and 29% --[ inaudible ] cases and controls had similardemographics including six,

ethnicity, race, programeligibility and insurance status. controls shown in bluer wereselected from from across the entire age range due to thematching criteria. shown in yellow were more likewilly to be older and unvaccinated. 93% of cases were vaccinated. 99% of controls. v.e. of the five dose tdapseries wassest pateded at 84%

with 95% confidence rangingbetween 58% and 94%. we found protection waned. by 5 to 7 years post vax thagsb.e. had fallen to 68%. a reduction of 22%. this result is consistent withthe other studies mentioned earlier. moving on to the tdapevaluatn. data was collected on a 438cases and 1,256 controls, 11 to 19 years.

overall 15% of cases and 13% ofcontrols were exclud. predom fantly for havingundocumented vax first nation history or having received tdapbefore 11 years old. overall 372 cases and 1090controls were included. 80% of cases were confirmed ofwhich 90% were lab con fermed and 10% epi linked and 20%probable. paces and controls had similardemographics including ethnicity, race, insurancestatus and vaccine for children program eligiability.

as a consequence of the matchingcriteria, similar numbers of cases and controls were includedfor each age year as shown in the figurer. cases were more likely to beunvaccinated. 70% were vaccinated compared to80% of control. current recommendations the tdapanalysis was restricted to participants that received onlyacellular vaccines. following review of vaccinedistribution data provided by the department of health weassumed whole sail vaccines were

no longer available after 1997. therefore this analysis onlyincluded participants born after 1997 which would encompass allparticipants 11 to 12 shown in the red box and most aged 13 to15 years sean in the red box with the dashed line. participants that of receivedonly acellular vaccines. 95% confidence intervals rangingbetween 54 prn and 81%. as for the tdap series durationof protection waned with time. during the first year b.e. was76%.

by two to four years postvaccination it had fallen to 56%, a reduction of 20%. again the this resu wasconsistent with the other studies mentioneder earlier. lastly, i will discuss pertussisamong pertactin deficient strains. pertactin status can only be --59% were lab confirmed by pcr or cull cure or 75% were lastconfirmed for the tdap eval waegs.

both tdap cases were labconfirmed, 61% were pertussis culture positive and 90%er weretested for pertactin deficiency. of these 98% were pertactindeficient. of those cases that were labconfirmed 65%er were positive. of these 92%er were tested forpertactin deficiency. of those tested 95% werepertactin deficient. only a limited number met thedefinition of unvaccinated preventing us from looking atb.e. we were able to evaluate inpertactin deficient screensment

overall b.e. was estimated at61% with 95% confidence intervals between 5% and 75%. these intervals overlapped withthose of previous studies. in conclusion, we show that forboth vaccines initial v.e. is high but the protection wanesover time. our findings are consistent withprevious estimates. among pertactin deficientstrains we found tdap v.e. was lower but confidence intervalsoverlapped with the estimates. this implies v.e. is similar toprevious studies regardless of

the prevalence of pertactindeficiency. during the 2010 californiaoutbreak and the 2012 washington state outbreak the proportionswere 14% to 76% respectfully. our v.e. estimates arecomparable to the studies strongly suggesting thatdeficiency didn't impact disease. the control is susceptible toselection bias. cases and controls were patchedif in primary care homes to ensure exposure to similarcirculating pertussis strains

and limit provider associateddiagnostic reporting bias. another limitation if theevaluation was the low proportion of unvaccinatedparticipants with confirmed pertactin the status. since confirmation was withcompleted on 40%, the tested may not be representative. in addition if there is aselective advantage to pertactin deficiency we may expecter morethe from unvax fated cases by including them in the analysiswe may have over estimated the

vaccine effectiveness. finally, our v.e. estimates areunlikely to accounter for mild disease which may be moreprominent among vaccinated individual ares and less likelyto be reported. these evaluations suggest thatthe lack of pertactin apong currently circulating stlans ofpertussis does not substantially um pact v.e..er more forreported disease. however our evaluations didn'tcapture mild or asymptomatic cases and wasn't able toinvestigate the impact of

pertactin deficiency ontransmission given the deficiency may proride a shrekty advantage to further investigation required to betterdefine the role in transmission. that leads me to thank peoplewho made this possible. >> thank you for a clearpresentation. a number of our menbs have earlyflights if there are one or two quick questions herer orcomments. dr. reingold? >> just in reference to dr.

benjamin's question aboutincentivizing the development of better pertussis vaccines, theworking group has attempted to ascertain what types of vaccinesmay be under development. the news isn't encouraging atleast as far as i can ascertain. i don't see a better vaccinebeing available in the next few years. i think dr. benjamin's point iswell taken. >> if i other questions orcomments? thank you very much.

if we can have dr. belangy comeup to introduce the herpes zoster topic. lib brief. in 2006 sda licensed a livezoster vaccine. in 2008 the acip recommendedroutine use of the vaccine for all persons over anyone 60 withno contra indications. in 2011 the fda approved thevaccine for shingles protection for people 50 to 59 however theacip didn't make changes to the age recommendation.

since then there have been newdevelopments. gsk has investigational vaccine,sub-unit vaccine for preventing zoster in healthy adults greateror equal to 50. merck has an investigationalvaccine for immunity compromised individuals and the vaccine isbeg evaluated for a prevention of zoster in compromisedindividuals. the work group was inactive fora period of time. i just joined last year when ibecame a new acip menb. we have added new menbs withclinical expertise in

immunocompromised patients. we have been receivingrecommendations on herpes zoster activities and the status indevelopment. we have a large and highlytalented work group. i want to thank all of the menbsand particularly our cdc liaisoner for expert leadershipin helping me get up to speed on this topic. we'll have two presentationstoday. an update on herpes zosterepidemiology by dr. rarpaz and

then the sub-unit vaccine by dr. he bs ineman from gsk. >> hello. as ed mentioned this is a greatopportunity for me to update the acip about zoster. if you haven't heard about itfor a while. it's going to frame the nextpresentation. so in the next 15 minutes i willpreefly discuss the clinical manifestations of the zoster.

i will lk about theepidemiology, talk about zoster vaccine a bit. something about more recentpolicy development and then complete it with discussionabout zoster the vaccine up take. regarding clinical picture,zoster manifests as a painful unilateral rash which isgenerally affects one to three determine tomes developed overfive to seven days. it generally resolved by 25days.

the rash can sometimes causesecondary infections and scarring and the rash can infectchildren with checken pox the priepry acute problem associatedwith zoster is pain which can be excruciating at times. 90% of patients will experiencepainer or some kind of distressing sensation. in fact, these symptoms oftenwill proceed on set of rash are by four or five days which canlead -- sometimes even longer which can lead to diagnosticdilemmas and work upser for

various conditions like cardiacor abdominal etiology which itsel can lead to patientdistress. the most distressingcomplication of zoster is, of course, phn. this is the prolonged sometimesincapacitating pain that continues after the resolutionof the rash while definitions regarding duration vary phnlasts for months or years. while prompt use of anti-viralscan relieve chronic pain of zoster but treatment is at bestonly partly effective at prevent

ing phn itself. while there are guideline ps forthe treatment of phn these treatments, too, are only partlyeffective and with inconsistent benefits. taye diggs, phn treatments oftentypically involve psych tro pick medications likeanti-depressants, anti-seer sures, open yoeds, and these areoften severe side effects and they are particularly hard totolerate by the elderly who get phn.

the underlying patho physiologyisn't known. while phn clearly is contingenton zoster but the pathways that lead to the two conditions, wedon't foe to what extent they are distinct. another common importantcomplication occurs with involvement of the trigemifalnerve. it can lead to chronic oker larcomplications, reduced vision or blindness. moving on to the epidemiology isdifficult to discuss without

first talking about rex factorsand the two risk factors are many most important are agewhich is the domina risk factor and burden of zoster inany immuno suppression. the graph on the left shows datafrom markets and administrative data sets for 2000, 2001. the zoster is on the y axis. you can see how the incidence ofzoster starts to accelerate after the age of 50. basically done for epidemiologyregardless of the message.

priep ary determinant of thezoster. you can see the graph on theright with data from the county minnesota. the incidents of phn on the yaxis. the x axis starting at 59. you can see how on that theaccelerates faster than zoster. seeing ten times the risk of phnhigher in person in older parts of the 50 to 59. in fact, for every thousandpersons with zoster most severe

out. comes increase with ageespecially hospitalization and know the old est old are theones who have the hardest time tolerating phn and is are themost difficultile tolerating the treatments for phn. as i mentioned the other riskfactor is suppression. this is less common in thepopulation but because of the magnitude of the risk associatedare risk. so for instance the are risk is50 fold in people with stem cell

transpltation or hivinfection. in addition those who areimmunocompromised who experience zoster are at the greatest riskfor developing serious and life threatening or sight threateningcomplications. moving on with that backgroundon risk factors the annual rate of zoster in the united statesis 4 per thousand per year translating to over a millioncases per year and the lifetime risk for developing zoster isapproximately 30%. while age and immunocompromisedis a large portion we cannot

explain what distinguishes postmost of the 30% with the 70% who do not. finally i want to mention thatthe age adjusted rate for zoster appears to be increasing overcalendar time. let's look at that on the nextslide. the graphshows age gratified medicare data amongst people onthe y axis and time from 1992 to 2000. substantially over time for allage groups the pattern is

observed in other data from theunited states tating back as far as 1945. it's also been seen in canada,east asia and else where. we do not have a cohe sieveexplanation for this increase over time. moving onto zoster vaccine, itis licensed -- [ inaudible ]shingles study. trial involved over -- they werefollowed for about three years. subjects were randomized toreceive a placebo or the

attenuated --[ inaudible ] vaccine efficacy was foundagainst for prevention of zoster and 67% for prevention ofneuralgia. the reaction --[ inaudible ] recommended routine vaccinationwith a single dose of zoster vax. the results of the shinglesprevention study have been observational studies since thattime. here are results focused as afunction of age.

on the y axis is vaccine ef efka is he. the red corresponds and theorange is the zoster. first foet that the v.e. forzoster declines dramatically down to 18% in persons 80 andolder. second, not only is the vaccineefficacy for phn generally better, but it's also betterpreserved as a function of age with the vaccine efficacy of 39%in persons 80 and older. this graph shows singlesprevention data on vaccine efficacy at preventing phn usingdifferent definitions for phn of

progressively longer duration ofpain. the y axis shows vaccineefficacy and the x shows definition of phn and durationof pain. note the vaccine worksprogressively better at averting the most prolonged episodes ofphn and the longest episodes last for years at the mostcritical targets of the vaccine. for prevention. more recent developments. there have been several arerecent developments with policy

implications. the first was a largemultinational study conducted clinical trials in persons 50 to59. follow up lasts just about ayear. vaccine efficacy in thatpopulation was 70% . based on the results andassociated reassuring safety data on the fda issued licenseif for adults 50 to 59 in addition to the ongoing licensefor 60 and older. also subjects from the originfall trial of adults who had

then been 60 and older were if alonger follow up study that extended out about 11 yearsfollowing vaccination. there was no concurrent controlgroupin this study because the controls following sbs wereoffered zostavax. the study was unblinded and withless powers. finally they had to rely onhistoric controls to define protection and given the rapidlychanging zoster incidence over time i alluded to two slides agoit was hard to draw a clear conclusion about the waning ofprotection from the study.

there are other studies going onnow. observation al studies toaddress that further. in another development there wasa trial to look at the safety of a second dose administered toadults ten years after they receive reed the first dose ascompared to the persons who just received a first dose of thevaccine. the outcome in the two arps werecomparable. however the outcomes do notpredict protection sufficiently well to answer questions.

so with these developments theacip on october -- in october 2013 the acip reviewed thisrecommendations and left them unchanged. i.e., a routine recommendationfor one dose in adults 60 and older. this was an example of programtick conservative. given the uncertainty aboutwaning a change to vaccinated adults age 50 may leave themunprotected decades later when the burden of phn was thegreatest.

on the other hand, the degree ofadded protection conferred by a second dose of the vaccineunknown regardless of the associated program costs andcomplexities. so in the absence of adequateevidence on key issues it was felt major changes to theprogram could not be justified whether to lower the age ofvaccination of to 50 or add a revaccination recommendation. so now i will say a few wordsabout the vaccine up take. this shows national data on theup take amongst adults 60 and

rates increase from 1.9% in 2007a year after licensure to the 24% to 2013. the more recent data frommercken on doses delivered suggest a substantial jumpduring 2014 to approximately 30%. our national data suggest thethat even with modest levels of up take that ratio onneth nickdisparities have been developing. so why has up take beensluggish?

there are many reasons we couldcite. first price of 200 it is themost expensive adult vaccine on a per dose basis. not only does this make thevaccine less cost effective but results this in higher inventorycosts for providers placing them at financial risk. second there is a storage andhandling issue in the united states at least it must bestored frozen. it is the only freezer requireroing vaccine for adults.

many adult providers aren'tequipped to hand le frozen in the context of inventoryprice it is possibility of freezer failurer and so on makethe provider feel they are further at risk with theirfinancial risk. merck does have a program toshare that risk. bit's not clear that providersare aware of the prap. of program. next, between 2007 and 2011there were supply shortages due to problems of manufacturingthis live attenuated vaccine.

merck has done an outstandingjob in adding manufacturing capacity over the last couple ofyears and the problem now seems fully resolved. during that interval a lot oftime was lost since there was little promotion of the vaccineand furthermore during that time it's likely physicians andpatients became frustrated and lost interest in the vaccine. next there are barers frommedicare part d. in contrast to commercial healthinsurers obligated by provisions

of the affordable care act thatcovers it witut cost sharing medicare part d coverages itinvolves large up front costs by patients often in the range of$100. in fact, some patients have topay the cost front only to be reimbursed weeks after filing. the program is administrativelycomplex for physicians. so it is comparely seamless forpharmacies. i will detor to talk aboutpharmacies. the acip has heard a number ofpresentations over the past

couple of years on the growingrole of pharmacies and vaccination sites. this is a recent developmentaffecting all vaccines but particularly important forzostavax and a large portion of it is delivered if pharmacies. this means there need to besystems in place. back-to-back up take. it's of course affected by thesame barriers thataffect all adult vaccines.

for that matter adult preventionmatters in general. this is not to ineven tore thosebut in general they include the fact that adult providers needto juggle chronic disease management, acute care needs,administrative burdens and it leaves them with less time forprevention. furthermore adult providers haveless of a prevention piend set when it comes to ian yors whofinally there is a general fragmentation of health care forthe seener yor making prevention challenging.

that concludes my presentation. now i'd like to have dr. heineman come up. we'll answer questions after the'å†t#zlbå© session.b >> thank you very much.ã©(päq>> good afternoon. it's my pleasure to be here tothe prevent the sub-unit herpes zoster vaccine. i'm preventing it on beafter ofmany people who have worked for years and also on the externalpartners and the thousands of

individuals world with wide whovolunteered for clinical trials we have conducted as part of theprogram. from the beginning gsk conceiveda zoster vaccine program to target two particular high riskpopulations which dr. harpaz described, older adults, 50 andabove and immunocompromised adults. so with that in mind thecandidate the vaccine we call hzsu was specifically designedto elicit strong cellular immune responses in the targetpopulations in which one might

reasonably expect it may besomewhat resistant to so the vaccine contains ofcourse vaccine -- [ inaudible ]which is the purpose to target the immune responses of thevaccine to the pathogen. the target and antigen containedin the vaccine is micro are protein e which was selected fora number of reason ares but particularly because it isis abundantly expressed in theenvelope of the virus and also infected cells.

perhaps the prom nant target forspecific cellular and immune responses. in addition to the vaccinethat's specific you need a vaccine that the stimulates animmune response of sufficient magnitude to enhance thelikelihood of protection. with that in mind the antenwas combined with one of the systems. this this case we selected thesystem 01 b. this is a liposomal system withtwo immuno stimulants.

qs 21 is a fachly occurring onefrom a subsidiary. at tu any rate, this is designedspecifically to enhance kre louer lar respon whencombined. we showed in a series ofpreclinical studies in small an mas when g.e. is combined withthis it elicits strong t-cell respses. subsequent to the completion ofthe preclinical program we moved on to phase one and two clinicaltrials and have done a number of these.

they have been published. we'll highlight a few of theconclusions in particular are from the studies. first we showed two doses of thevaccine administered around two months apart induced ge specificresponses in adults 50 and we further showed th responseswere well preserved in people at the upper end of the age range. people 70 and older at the time,the immune responses were well preserved.

in older adults these responsesto the vaccine persisted well remained well above baseline atsix years following the vaccination course. we did a couple of phase onestudies in immunocompromised populations if particular stemcell recipients and hiv infected adults and showed kudos to the hhvsu vaccine comparable to those in older adults. i'm not showing a will the ofdata. i wanted to show the data in thefigurer on the right hand side.

it's informative. this graph follows a cohort ofolder adults with the hvsu vaccine over time. you see at month three which isa month after the second dose of the vaccine the immune responseand this is the kre louer lar response. the immune response to thevaccine peaked at 19 fold over the baseline level. keeping if mind all of thesubjects are zero positive to

begin with. the immune response, thecellular response in this case declined over time as one mightexpect me. they plateauafter a coup ofyears. you can see at month 72 or sixyears after the initial vaccination they were four-foldover the baseline levels. with those phase one and twodata in ha we move forward to the phase three ef ka si part ofthe program and the highlight of that part of the program arethree pifle toll studies.

two of which are being conductedthis older adults. the so-le called zoe 50 and 70study. it is an efficacy studyeingconducted in adults 50 years of age and above. the 70 is a study we conductedin adults 70 and above. these have chairvillelyidentical design s. in addition to those two olderadult studies we are conducting the so-called zoster # 002 studywhich is a true efficacy study in adult stem cell transplantrecipients.

i want to remind you today thati will be presenting the efficacy and safety resultsfthe zoe 50 study in a couple of minutes. before i do that i wanted togive you a brief overview of the other studies that we areconducting in support of the efficacy studies as part of theprogram. i won't go through them indetailment i will mention that we are doing studies, look atcoimmunization with other vaccines used in older adults.

in this case quadrivalent fluvaccine. newman cocall and tdap. and other suchs schedulecomparison studies, safety in people who previously hadzoster, safety in people who previously received the vax andvery interesting studies, i believe, in otherimmunocompromised populations. people who received solid -- hadsolid organ malignancies. or who had a recent renaltransplant. onto the zoe 50 study.

keep in mind this is an efficacystudy conducted in people 50 years are of age and above andthe primary objective is to evaluate vaccine efficacy inreducing the risk of herpes zoster in this population. there are a veert of secondaryobjectives. ones i can talk about today havebeen analyzed for the vaccine efficacy in the different anyonestrata enrolled as part of the for the enrollees werestratified into three groups, 50 to 59, 60 to 69 or 70 and above.

we have efficacy dataer forthose. of course the safety andreactiveness of the vaccine. there is a bunch of objectivesthat are part of the study. i cannot talk about them becausethey haven't been an lazed. the reason is they will beanalyzed at the time of the suser studies, the zoe 70 studyin those 70 and above is completed in order for packerspal power to draw conclusions on the data. the secondary objectives i can'ttalk about today but we look

forward to seeing the data on inthe future are efficacy if reducing phn and othercomplications of herpes zoster. efficacy and reduced mortality,morbidity, zoster associated pain. use of pain medications, impacton quality of life and important cellular. this is a brief overview of thedesign of the study. this is a randomized placebostudy that's been conducted in 18 countries around the world.

adults 50 and above. the primary seclusions arepeople with a history of zoster. people who had a previousvaccination for either varicellaer or zoster or peoplewith different compromising conditions. two groups. one group received theinvestigational vaccine. one group received a placeborandomized one to one in the the intervention was two dosesof either vacciner or placebo

given by intramuscularinjection. and the subjects were followedat various visits in addition to the vaccination visits they wereseen a month after the second vaccination and three yearsafter that. at months they didn't have avisit they were contacted by phone to solicit safety data andto prompt reporting of suspected herpes zoster cases. before i get into the resultsspecify i want to say a coup of words about the herpes zostercase confirmation pathway.

that's the primary end point ofthe study. obviously of great significance. the subjects were educated atthe beginning of the study and at every opportunity thereafterto recognize a suspected case of herpes zoster which for thepurposes of this study was the defined a new unilateral rashaccompanied by pain broadly defined and no alternativediagnosis. if they had something to meetthe definition they were asked within 48 hours.

they would be evaluated tdap bythe study investigator. if he or she thought it wasn'tzoster they were sent home. if it might be zoster thattriggered an evaluation including collection of samplesfrom the rash or pcr valuation and the digital photograph of oftherash. samples werer tested. if positive the case wasconsidered confirmeder for herpes zoster. if they were negative withappropriate controls it was not

zoster. if it was indeterminate forthink reason then it would be final adjudication was accordingto the so-called herpes zoster adjudication committee whichconsisted of five zoster experts not affiliated with gsk or thestudy otherwise for the final case determination. okay, the results of the studywere derived by the analysis of three specific cohorts for ourpurposes today. the first cohort is the totalvaccinated cohort including all

subjects who received at leastone dose of the vaccine. this included 15,000411 peoplewith a mean follow up time of three and a half years. this was a primary cohort forralses. the second cohort of majorimportance of so-le called modified cohort, this is thesame as the total vaccinated but it excluded subjects who didn'treceive the second dose or developed zoster within onemonth after receiving the second this skised of 14,759individuals with a mean follow

up time of 3.2 years. this was the primary efficacyanalysis cohort. so thegs to those we had aanother cohort. these were evaluated in moredetail for any reaction. this is a subgroup of the toletall vaccinated cohort it was a large subgroup. as you can see on the right-handside these are well distributed between the two arms. so this slide shows thedemographic characteristic this

is the study. you can see the average age ofenrollees was 62 years. the gender distribution of 61-3female to ale many. most of the subjects with mostof the remainder being even. mentioned before the study wasconducted around the world at half the subjectsen rolled ineurope. either this in asia, southamerica or north america. - bz shows the vaccinethis slide, efficacy results for the studythis the primary efficacy

analysis cohort. the modified total vaccinated tohort. recall that the primaryobjective of the stud was vaccine efficacy if people 50and above. if uh-uh you look at the topdata line you will see that the efficacy numbers for thatpopulation and what you can soo in the far right is that thevaccine efficacy in this group was 97.2% with confidenceintervals are from almost 94% to 99%.

efficacy was calculated withincident rates in the pla is he go group. the incidence rate was 9.1zoster cases per thousand person years in the vaccine group itwas 0.3 cases per thousand person years. if you want a more concreteunderstanding of the data you can look at the cases and seethere were cases con if i wered in the vaccine group. six cases confirmed.

the other secondary end point ican drooip describe are the vaccine efficacy and differentprespecified age cohorts. 50 to 59, 60 to 69 and70 plus. those are the next three rows onthe table. if you move over to the righthand column you can see the efficacy for each of the cohortswas essentially identical to efficacy from 96 1/2 to 9#%. there was almost no realdifference indicating that there was no indication from thisstudy the efficacy declined with

the anyone of the subject at thetime of initial vaccination. simply for completeness we showefficacy in people 60 and above which was 97.6% or in the samerange. just to remind you in case itwent by too quickly. that actually brings me to thenext working point which is the durability of the vaccineefficacy. what may not be entirely clearto you because it is complicated is this study is still ongoing. it's still blinded at thesubject level with the analysis

done by external blinded satstugss at the group level. because there are sofew indications in the breakthrough cases of zoster in the vaccine group we cannotactually -- the study team cannot be provided with the yearby year efficacy numbers without unblinding us at the subjectlevel. so i cannot show you thosenumbers now. i don't have them. what i can show you is the tablethat was provided by the

ex-eternal statisticians inwhich they confirmed to us that the vaccine efficacy in each ofthe four follow up years into the study was at least 90%. they further commented there isno apparent waning of efficacy during years 1 through 4 offollow up within the study. let me move to safety then. this slide shows the comparisonto the vaccine and placebo grouper for three separatesafety parameters, family sae, serious adverse events.

pimd which is potential immunemediated diseases and death. the bluer bar is vaccine group. green is placebo. on the left-hand side you seethe numbers for theuration of the study. on the right-hand side are thenumberser for the first 30 days post vaccination. without going into individualcolumn i think you can see there is no imbalance between thesafety end points between the

vaccine and placebo groupconsidered over the duration of the study or during 30 daysimmediately after vaccinationment here i have thereactive numbers for the study. this slide shows the local --solicited local reacted jenicity including pain, redness andswelling. you can see 80% of subjects havesomething within the first week after vaccination. most common local adverse eventsbeing pain. compared to 12% in the placebogroup.

of these, about nine and a halfhad grade three pain on the scale of 0 to 3. the median duration of localsymptoms overall was three days. the median duration of gradethree similar tops was one day for pain and twoer for rnessand swelling. this shows the same data forgeneral reactions. two thirds. the most common reaction in thevaccine group was mile ja, fatigue and headache.

the heed yan duration of generalreactions was two days for fatigue, gastrointestinalsymptoms, headach, mile ja and e day for fever and shivering. and the median duration of gradethree symptoms regardless of category was one day. before i conclude i want tomention a couple words about me of the things that we areexpecting and planning this this the immediate future. as i alluded to, we are stillawaiting the result ares of the

zoe 70 study in people 70 andabove. the data will be analyzed andalso analyzed in combination with the results from the zoe 50study. this will provide us withadditional information on vaccine efficacy in people over70 and with vaccine efficacy data against phn. zoster associated pain. impact on quality of life. and other stuff as well.

we are awaiting efficacy resultsin the stem cell transplants. then of course several ongoingstudies like the coadministration studies and thesafety and immunocompromised people . in addition to those thingswhich are we are waiting for directly we plan to conduct longterm post vaccination follow up with the vaccine recipients toget as good an idea as we can of the longer term efficacy. we'll do other studies such asflling up on earlier studies for

long term outcomes. we'll look eventually in thefear future at boostability of the vaccine. additional studies to assess theimpact on quality of life. just to summarize the results,the vaccine efficacy in adults 50 and above was 97.2%. the efficacy was age independentand fully preserved in people who received the vaccine at 70eror older. efficacy doesn't wane during thestudy period.

there is no imbalance in theincidence of safety end points within the study. local and systemic are reactionsto the candate vaccine are common in the first seven days. the large majority are mild tomoderate and in short draegs. -- duration. that's all for me. happy to answer questions. we can open up for questions.

yes, dr. ruben. >> that was impressive efficacy. on adverse effects was thereacceleration, worsening of adverse effects on dose one,twoer or vice versa. >> i'm sorry. that was hard to -->> the adverse effects after vax thags, worse per dose two thandose one? >> no. the incidence of adverse feintsdoesn't change.

>> dr. are romero . >> very nice study. i was struck by thepaucity of minority population in you areyour study. is there anything to increasethe number in any way? >> well, the if by minority youare referring specifically to an african-american or something,the study enrolled 2000 subjects or so in the united states andobviously the proportion of minorities who enroll are isdpen dend upon study sites and

so forth. we'd like to see more minoritiesthe future studies. >> other questions? along this line do you have aprojection in terms of submission? to the fda. >> i will defer to my colleaguehere to answer that. >> hi. it's too early to speculate onwhen we'll submit the file.

we'll eagerly submit them forreview. >> just wondered if you couldcomment on plans to look at the question of previous zostavaxreceipt patients. >> we do have plans to isvaluate this vaccine in people who previously received it. as the a specific plan ofmarketing. >> another question notcovereded at all. there is some work going down toage 18. any work be ing done if youconsider use as a pediatri

vaccine for primary protectionsfor chickenpox. >> it's an interesting question. we don't have plans to have thisvaccine as an alternative to the currently available vaccine. it is an interesting question. >> dr. moore -->> quickly, i think some of us back here just want to say, wow,that's really exciting. it seemed like we were all alittle bit blase. >> one more question for dr.

harpaz. although you said there isreally no explanationer for this increase over time, is there anyspeculation as to why we might be seeing this? is. >> speaking personally i havegiven this a lot of thoht and looked at every possibleexplanation i haver considered or heard. no, not really.

i will just highlight that itdoesn't appear to me and others at this point in time that it's associated with the varicellaand, the exterernal boosting causing the increase. in particular it startedaccuring preceding the vaccine if other countries. >> don't we have increasingpresent value dense of immunocompromised persons? the studies i'm referring tohave studies for

immunocompromised status andcontrols for chronic disease >> again as somebody who overthe last 25 year now as seen the practice age now thepediatric practice are people in their 40s. this is something we do seeroutinely in older patients. it has incredible impact onquality of life. one of the thoughts out thereand we have no control over manufacturers and price pointsbut having a more affordable vaccine would be reallydesirable.

in my practice i'm struck. i have said it before thatvirtually every one of my elderer patients and i have anethnically and racially dverse practice. they know about the vaccine. but the problem is the abilityto pay. i can assure you that there areeconomic disparities that go on every day. in our practices.

but i think what you presenthere is encouraging. dr. shuchat? >> in the graph that you showedof the incident increasing it looked like the last couple ofyears it was flattening or possibly decreasing. i wondereded if that's asignificant difference and if you have a thought about that. >> it is a fascinatingobservation. we have been exploring that tosee where it's going now.

it appears that the oldest population seems to be continuing. it depends on the age group. it's very interesting. >> any further questions? comments? correct me, i don't believeare -- natalie, are there any additional public comments? i think i can honestly sayit's time to close the meeting.

i will finish up with two linesfrom shakespeare's -- the last two lines from shakespeare'slast play. from crimes with barden b, letyour indulgence set me free. and for people sticking around. also travel safely to yourhomes. take care now. [ applause ]