natural treatment for the disease jaundice

>> thank you all and thankyou for your flexibility. i know taking a break earlyis not the greatest hardship, but now we're backfor the long haul. so once again, i wouldlike to ask who would like to make a motionabout meningitis. is jessica going to putup some language for us? >> so there's a revised motion. >> dr. stephens. >> after some consultation.

jessica, you want toput it on the board? >> so before i go through therevised language, i just wanted to provide this context which will come beforethe actual language in a policy note. so basically we will statethat there are two vaccines that are licensed for peopleage 10-25 years in the us and there's no vaccinepreference. we could also go through thecurrent acip recommendations

so it's clear we have a categorya recommendation for one and a category b for the other. okay, so this is therevised language. so for persons at increasedrisk for meningococcal disease and for use in serogroupb outbreaks, three doses of menb fhbpshould be administered at zero, 1-2 and six months. when given to healthyadolescents who are not at increased risk formeningococcal disease,

two doses of menb fhbpshould be administered at zero and six months. and then the followingguidance could be provided. if a second dose is givenat an interval of less than six months, a thirddose should be given at least six monthsafter the first dose. >> is there a second? dr. romero? >> i second.

>> discussion? this is what's being proposed. this is the motion. >> i'm sorry, this is labelledoption a. which i was wondering if that meant there'sa b or a c. >> sorry, no. >> okay. [ laughter ] >> that's all you get.

[laughs]. yes, dr. atmar? >> i have a questionabout the number two for the footnote rather. if their second dose is givenat less than six months, let's say it's given at five anda half months, is there going to be a minimum interval? >> we can work on that, yes. >> dr. kemp? >> i'm just wondering aboutthe need for number two

since it's a categoryb individual recommendation anyway. i'm just thinking this through. i mean, number one is clear thatit's related to a category a, therefore a firm recommendationmakes sense to me. i'm just wondering ifeveryone feels the need to have number two since it'swithin the category b slot. >> yeah, let me respond to that. you know, at first i suggestedthat we say something like

"when a physician chooses togive to a healthy adolescent." but i think "when given to healthy adolescents"sort of sums that up. it implies that this is not -- you know, it's notgoing to be given to every healthy adolescent, because it is a categoryb recommendation. and it will be in thecontext of the statement. other questions?

yes, dr. moore? >> it's not so much aquestion but just a comment about future directionswith the working group. on the working group we would like to have furtherconversations, and obviously thoseare warranted. if an otherwise healthyadolescent is immunized during a low-risk period of timeand later finds him or herself involvedin an outbreak setting

or at high risk, thenwe'll be looking later at booster dose recommendations or what should be donein those situations. where they then move intoa new category of risk. >> thank you. ms. stinchfield? >> patsy stinchfield from napnap. to your point, i think asyou guys proceed and talk about that, separating riskrather than lumping it.

for me, as i've beenlistening, one of the things that seems complicating isthat we're lumping risks. and so a person withan immune deficiency or complement deficiency, and ithink we need to be very clear by what we mean by your innaterisk, versus the immediate risk that there's a college outbreak. those are two different risks. they could have twodifferent products, two different schedules.

and it would be helpful to keepthose separate for clinicians, which might be even in a clinicsetting they have one product and college and public healthhas a different product. >> my understanding is thatwill be covered in the statement by creating the context. >> that's correct. and we'll list eachof the groups that are at increased riskin a statement. >> dr. hunter?

>> paul hunter. i assume there willbe some cdc guidance about if you get the two-doseseries when you're healthy and then later you'reat a college or wherever there's an outbreakand exactly how to handle that. i'm just assuming that's goingto be covered in the guidance and we don't need to bother totalk about the details of that. >> right, i think that'ssomething we could talk about in the future.

i think the next topicthat we wanted to talk about as a workgroupwas booster doses for people at an increased risk. and this would fitinto that category. >> dr. weber? >> just again, obviouslyincreased risk could be increased risk of exposure or increased risk dueto immune deficiency. so my particular interestis in the microbiologists

in the hospital who are atincreased risk of exposure but normal immunologically. so would they be -- and againthey're not at immediate risk. it's really long-term risk. so again, some clarificationwhether the two- or three-dose scheduleis recommended for those would be helpful. >> right. i mean it would depend on when their exposurewould occur.

but also the three-dose scheduledoes maximize immune response a little bit, so if theyare at increased risk, it may still make sense for them to receive a three-doseschedule. >> dr. kimberlin? >> david kimberlin,aap red book. just to clarify, ithink i'm satisfied with what dr. kempe was askingabout it being category b for the second portionor the second sentence.

for the first sentence, this isnot a recommendation of trememba over the other product. this is simply thepart of the statement that deals with trememba. this is the languagethat would be used. >> that is correct. we'll be very clear. there's no product preference. >> other questions?

okay. is there anyone who wouldcare to make public comment? ms. hildebrand? christina hildebrand froma voice for choice advocacy. one second. sorry. i had three comments. one of them is thatyou're recommending this. i know you're notsaying it should be given to all healthy adolescents,but you're recommending it for healthy adolescents.

yet the advocacy of it thatwas shown in the slides showed that it had severe wearoff after 12 months. so if it's not efficaciousor that efficacious after 12 months, i wonderwhy you're recommending it at that point. especially when you look atthe number of side effects and the deaths that comefrom the actual vaccine versus the number of deaths frommeningococcal, which if you look at those numbers,the number of deaths

from the vaccine are higherthan the number of deaths that we had from meningococcal. the other thing that i wanted tosay is that as a public person and as a statistician, itreally surprises me the data that you use. so the base sizes of12, 25, 60, 71 that were up on the screen earlier. you know, i don't know if theworkgroup uses different numbers or sees more information.

but to me those numbers areextremely small for studies that you're projecting ontothe general population, even if it's the generalpopulation of adolescents. similarly, the larger studythat you showed was pfizer data, which is one of the companiesthat makes the vaccine. of course they're going tosay good stuff about it. you know, we've gotethics issues in the cdc. we know that. so sitting here andwatching this data,

it really surprises methat this is the data that you're working off tomake vaccine recommendations. thank you. again, i would recommendthat you speak to some of our subject matter experts because i think thereare a few things that we could clarify for you. but thank you for your comments. any other comment?

then i'd like to take a vote. dr. walter? and to your left. >> walter votes yes. >> belongia, yes. >> riley, yes. >> lee, yes. i technically agree withthat recommendation. >> pellegrini, yes.

>> hunter, yes. >> moore, yes. >> ezeanolue, yes. >> romero, yes. >> bennett, yes. >> atmar, yes. >> stephens, yes. >> kempe, yes. >> and szilagyi, yes.

>> thank you very much. and thank you especiallyto the meningitis workgroup and to all of you who presented. it was very, very helpful. okay, so now we aremoving on to herpes zoster and for once there's-- no, we're not. we're dong vfc. >> we have a vfc vote. >> dr. santoli?

>> so the purposeof this resolution, this revision rather, is to update the recommendedvaccination schedule and intervals for serogroupb meningococcal vaccine. the resolution has two parts andthere are no proposed changes to the meningococcalconjugate vaccine section of the resolution. in the serogroup bmeningococcal section of the resolution there's nochange to the eligible groups.

that includes the listing ofthe high-risk groups as well as the statement thatchildren age 16-18 years without high risk conditionsmay also be vaccinated. in the recommended scheduleand intervals, there's a table that summarizes therecommendation that was just approved. showing the information interms of the dosing schedule for the bexsero and the dosingschedule for menb by trememba, which is divided into twoparts, versus an increased risk

for meningococcal disease and for use duringserogroup b outbreaks. the three-dose schedule forhealthy adolescents who are not at increased risk for meningococcaldisease, two-dose schedule. the first footnoteis to just make sure that there's a disclaimer thatbrand names here aren't meant to limit other licensedcomparable vaccines. the second is thefootnote that was approved

with the recommendationjust a moment ago. for the recommended dosagesand the contraindications and precautions, the reader isreferred to the package insert. and again, a publishedrecommendation would be incorporated by referenceinto the resolution. is there a motion for vfcresolution or revision rather? >> motion. any discussion? so let's go to a vote.

dr. riley, would youstart and go to your left? >> yes. >> szilagyi, yes. >> walter, yes. thank you again. okay, we are now ready tomove on to herpes zoster. dr. belongia is going tostart this session off. and thank you again tothe meningococcal group. >> hey, good afternoon.

it's my pleasure to introducethis informational session on the herpes zosterworkgroup activities. before i do that, i would just like to thank everybody who'scontributed to the workgroup. kelly moore who'sthe other acip member and all the liaison members. and our invited expertconsultants who have provided a greatdeal of useful input. and particularly our cdcliaisons, kathleen dooling

and rafael harpaz for providingreally tremendous support and help on a complex workgroupthat's been ramping up to deal with a number of new issues. so there are currently twodifferent investigational vaccines that are on the radar. one vaccine, the herpeszoster subunit vaccine hzsu from gsk has been evaluated in both non-immunocompromisedpopulations and is currently being evaluated

in immunocompromisedpopulations. as well as a vaccine from merck, inactivated vaccine v212that's being assessed so recently the workgroup has received updates from the currentlylicensed vaccines, zostavax, as well as presentationsfrom manufacturers of these prelicensure vaccines that i just mentionedregarding their current status and future plans.

acip received a presentationin june of 2015 on zoster epidemiology with intro phase threeefficacy study results based on the hz/su vaccinein adults over 50. and recently within the pastmonth results were published for the same vaccinein adults over 70. and today we're goingto have an update on herpes zoster epidemiology and vaccine coveragefrom dr. dooling.

and then a report on the finalphase three efficacy study of the hz/su vaccine from gsk. in the coming year the workgroupwill be considering the policy options in anticipation offuture licensed products. so with that i'll turnit over to kathleen. >> good afternoon, everyone. my name is kathleen doolingand i am a cdc liaison for the herpes zosterworking group of the acip. the objective ofthis presentation is

to provide backgroundon herpes zoster disease and current vaccineprogram for the purpose of information and discussion. first, i'll review theclinical manifestations, then discuss theevolving epidemiology and finally discuss theprevention of herpes zoster. as you know, there is a licensedvaccine for the prevention of herpes zoster in adults. and there are alsoas we just heard,

two investigationalvaccines in development for the preventionof this disease. the varicella zoster viruscan cause two distinct forms of disease. primary infectionleads to chicken pox or varicella, depictedon the left. following primary infection, the virus establisheslatent infection in the dorsal root ganglianear the spinal cord.

reactivation of the virus leadsto shingles or herpes zoster, depicted on the right. the reactivated virustravels up the nerve root to discrete dermatomes to produce the characteristicshingles rash. as you can see in thesephotos, reactivation of virus may affect anydermatome of the body to produce vesicular rash. the rash is usually unilateraland may involve as many

as three adjacent dermatomes. it typically arisesover a 5-7-day period with resolution in 5-25 days. occasional consequences of the rash may includesecondary bacterial infection or transmission of thevaricella zoster virus to susceptible individualsresulting in chicken pox. about 90% of herpes zosterepisodes are associated with pain or discomfort.

the pain is variable incharacter and intensity. and it precedes rash onsetin about 84% of cases. pain without rashtypically lasts 1-5 days, but it can be weeks. localized pain in theabsence of rash can lead to diagnostic dilemmas, suchas unnecessary investigation, treatment or even surgery. another severe manifestationof herpes zoster is involvement of the ophthalmic divisionof the trigeminal nerve.

this happens in approximately15% of cases. ophthalmic involvement cancause chronic complications and in some casesloss of vision. many people thinkof herpes zoster as a self-limited illness. on the contrary,post-herpetic neuralgia, which is a commoncomplication of herpes zoster, can be a devastating illnessand may persist for years. postherpetic neuralgia isprolonged pain which lasts

for at least 90 days followingthe resolution of rash. approximately 10-18%of patients will go on to have post-herpeticneuralgia, and the pain may persistfor months to years and may be incapacitating. postherpetic neuralgiaprevention, antivirals and steroids have beenshown to shorten duration of herpes zoster, but have notconclusively reduced the risk of phn.

multiple modalities have beenused for treatment with partial or inconsistent efficacy,and have many side effects, especially in the elderly. this is from an email werecently received at cdc from a patient withpost-herpetic neuralgia. "my shingles post-herpeticneuralgia is still painful seven years after my shingles episode. my phn is worse than mycancer and chemotherapy. it has made me depressedand suicidal in the past."

and now to discuss theepidemiology of herpes zoster. herpes zoster has an annual rate of approximately fourcases per 1,000 population. that translates intoabout a million cases of disease in the us annually. your lifetime risk ofdeveloping herpes zoster is about one in three. and the age adjusted ratesappear to be increasing. age appears to be the dominantfactor driving incidents,

with incidents in 80-year-oldsabout ten times more than incidents in children. immunosuppression isalso a risk factor. blood malignancies,bone marrow transplant, hiv have all been shownto increase the risk of herpes zoster up to 50-fold. in addition to beingmore common, herpes zoster is more severe in the immunocompromisedpopulation,

resulting in moredisseminated disease and more hospitalizations. ultimately, the underlyingbiologic mechanism appears to be related to reducedcell mediated immunity, which allows varicellazoster virus to reactivate or progress to herpes zoster. this graph demonstrateshow the incidence of herpes zosterincreases with age. the vertical axisis the incidence

of herpes zoster casesper 1,000 person-years. and the horizontal axishas increasing age groups. the data are derived from a large healthcareadministrative database called market scan which containsrecords for hundreds of thousands of insured people. as you can see, in theyoungest age group the rate of herpes zoster is about onecase per 1,000 population. the incidence increases withage even more sharply after 50.

similarly, this graphdemonstrates how the incidence of post-herpetic neuralgiaincreases with age. in this case data are derivedfrom a population-based cohort in ohmstead county, minnesota. recall that only afraction of individuals with herpes zoster will go onto get post-herpetic neuralgia. in fact, post-herpetic neuralgiais rare in individuals younger than 50, but risk increasessteeply after age 60. an 80-year-old is approximately10 times more likely

to get post-herpeticneuralgia than a 50-year-old. over time, the incidence ofherpes zoster has increased for almost all age groups. this graph shows theincreasing incidence by year from 1993 to 2014. for adults 65 and older, whichis the top line on the graph, the incidence plateauedaround 2007. for all other adultsthe incidence seems to be increasing.

for children, displayedon the bottom, there has been a downwardtrend since about 2005. we do not fully understand thereasons for this increasing or plateauing incidencein adults, but it has been confirmedby numerous data sources. if we look specifically inchildren, precipitous drops of herpes zoster incidencehave occurred during the same time period. this is likely due to thedirect effects of vaccination

with varivax as wellas a decrease in circulating varicellazoster virus which has resulted in some children not everhaving had a primary infection, thus they are not atrisk for herpes zoster. next, to discuss prevention. zostavax was licensedby the fda in 2006. phase three clinicaltrials involved more than 38,000non-immunocompromised adults age 60 and older with a medianfollow up of 3.1 years.

the vaccine consists of a liveattenuated oca strain varicella zoster virus, which is about 14times the concentration found in varivax. vaccine efficacy was 51%against herpes zoster, and 67% against post-herpeticneuralgia. serious adverse eventswere not more common in the vaccinated group,however local reactions were more common. these are the resultsfor the vaccine efficacy

in the phase threeclinical trial. overall, the vaccine was 51%effective for the prevention of herpes zoster, and 67%effective for the prevention of post-herpetic neuralgia. the efficacy decreaseswith increasing age. the protection againstherpes zoster ranges from 64% for recipients intheir 60's down to 18% for recipients 80years and older. from the same phasethree clinical trial,

we see that efficacy againstpost-herpetic neuralgia was maintained againstdisease of longer duration. on the horizontal axis, post-herpetic neuralgiais categorized according to how long the episode lasts, ranging from 30 daysto 180 days. zostavax providedover 70% protection against post-herpetic neuralgiathat lasted for 180 days. in 2008, zostavax wasrecommended by acip to be given

as one dose in adults60 years and older. as a live vaccine,it is contraindicated in immunocompromised persons. in 2011, there was no change to the acip recommendationfollowing an fda age expansion of the license to50- to 59-year-olds. there were severalreasons for this decision. first, there were vaccineshortages at the time that left people inthe recommended group

without access to the vaccine. this, combined with thefact that the burden of herpes zoster increasesin people over 60 resulted in maintaining therecommendation as it stood. after vaccine supplyissues were resolved, acip revisited the issue in 2013and affirmed the recommendation for 60 years and older. this was based on data thatshowed waning of immunity that i will show you next.

this graph shows the duration ofprotection provided by zostavaz. it shows vaccine efficacy by year followingvaccine administration. the first four years ofdata were contributed by the phase three efficacytrial previously discussed. years 5-7 are contributed by afollow on study, and years 8-11 by following a subsetof the vaccinated cohort and a modelled control group. as you can see, theefficacy drops every year

in the five yearsfollowing vaccine receipt. and the vaccine may not provideany significant protection after eight years. as the risk of herpes zoster andpost-herpetic neuralgia increase with age, a higher burdenof disease can be prevented with administrationafter 60 years old, or at 60 years and above. this graph also shows waningof immunity protection from zostavax, butthe data comes

from an observationalstudy in a large hmo. protection among allvaccines started at 69%, but by year seven toeight post-vaccination, vaccine protectiondecreased to 4% and was not statisticallysignificant. zostavax uptake has shown slowand steady progress since 2007. by 2014, 28% of adults60 years and older in the us reportedprior zostavax receipt. so why has uptake been sluggish?

first, the price is high andthere may be significant copays. the storage and handlingrequires freezing and reconstitution and thismay dissuade some providers from carrying the vaccine. also, supply shortages werea problem in the early years but have since been resolved. for medicare recipients,the vaccine is only covered by part d and reimbursementcan be complicated. finally, the lowerprioritization

of adult vaccinescertainly as compared to the pediatric program andthe general fragmentation of preventive care forsenior may contribute to the low uptake. the first three factors listedhere are vaccine-specific and may be amelioratedby modification of the existing vaccine orintroduction of a new vaccine. the second three on theother hand are system factors and must be addressed ona broader scale if we are

to see meaningful increasesin zostavax vaccination. and there are newvaccines on the horizon. herpes zoster subunit vaccineor hz/su, developed by gsk, is a vaccine consisting of a varicella zoster virusglycoprotein e as well as an adjuvant system. it is administered in twodoses two months apart and it is refrigerator stable. it was tested in a phasethree clinical trial

in over 30,000non-immunocompromised adults 50 years and older. the primary endpoint ofthe study was prevention of herpes zoster, and secondaryendpoints were prevention of post-herpetic neuralgiaas well as evaluation of the safety andimmunogenicity. in those phase three clinicaltrials, vaccine efficacy for the prevention of herpeszoster range from 97% for 50- to 59-year-olds, to 91% forrecipients 80 years and older.

vaccine efficacy of atleast 85% was maintained for all four years after administrationin all age groups. this vaccine was foundto be highly reactogenic. and if one focuses on studyparticipants 70 years and older, 79% of vaccine recipientsreported local symptoms, compared to 30% ofplacebo recipients. and 12% of vaccine recipientsreported grade three symptoms, or in other words symptoms thatinterfere with their daily life,

compared to 2% ofplacebo recipients. following this presentation,dr. romulo colindres of glaxo smith klinewill present the results of the phase threeefficacy trials in detail. prevention of herpes zoster in the immunocompromisedpopulation remains an unmet need. there are two vaccinesin development for just this purpose.

v212, developed by merck, is an inactivatedformulation of zostavax. it is a four-dose seriesin persons 18 and older. there is an ongoing phasethree efficacy trial. next, hz/su consisting of the same formulation you justheard about, is administered in a two-dose series topersons 18 years and older. thus there are excitingdevelopments in the prevention of herpes zoster and theworkgroup anticipates

deliberating on policy issuesfor non-immunocompromised as well as immunocompromisedpersons for several years to come. in conclusion, the epidemiologyof herpes zoster is changing, and we don't fullyunderstand why. approximately 28%of adults 60 years and older have been vaccinatedwith zostavax in the us. vaccines to prevent varicella and herpes zoster arereducing the amount

of circulating varicellazoster virus in our population, and new vaccines in developmentmay further reduce the disease burden. i'd like to thank the workgroup for their contributiontowards this presentation. >> thank you, dr. dooling. we could entertain acouple of questions for dr. dooling before wego on to dr. colindres. any questions?

guess not. guess we'll go on. >> hey. so good afternoon,ladies and gentlemen, acip members and zosterworking group members. thank you very muchfor the invitation to speak with you today. my name is romulo colindres andi'm global medical affairs lead for gsk's zostervaccine program. i'm also an ex-eis officer,so really enjoying being back

in atlanta and connecting withold colleagues and friends. and it feels really good tobe back on the cdc campus. i actually feel like myslides should be in blue with yellow and white print. so today i'm going to bepresenting to you on behalf of a very large team at gsk,and also external collaborators and many study investigatorsacross the world on gsk's herpes zosteradjuvanted subunit vaccine, hz/su.

and specifically on recentclinical trial results in people 70 years and older. so to begin and to make a linkwith what kathleen presented, i'd like to highlightagain the burden of disease of herpes zoster and shingles. basically with approximately1 million cases being reported annually in the us. per cdc statistics, each one of us has a 32% estimatedlifetime risk of zoster.

and with such a high percentage,you don't have to go very far to find someone close to you who has been impactedby this disease. in my case, my motherwho is 72 years old, five years ago suffered from avery serious case of shingles which included facialnerve involvement. given her painful experience,i'm sure she'll be happy to learn about the newadvances that are being made to prevent this disease.

now the risk of shinglesalso increases with age, such that above 85 yearsof age the risk is 50%. the most important riskfactors increasing age, and again this is becauseof a natural decline in immune systemfunction, immunosenescence. and also immunosuppression,either because of disease or immunosuppressive therapy. now herpes zoster isgenerally not life-threatening. however, there can be somevery serious complications.

the most common beingpost-herpetic neuralgia or phn, which is pain lastinggreater than three months. also, herpes zoster ophthalmacuscan cause dangerous eye involvement, and there canalso be cranial nerve palsies. now to get started ontelling you the hz/su story, it's important to mentionthat the development of this vaccine beganat gsk 16 years ago. and at that time there weretwo target populations chosen. the first is adults50 years or older.

again, because of theincreased incidence of disease above that age, as waspresented by kathleen. and the second is immunecompromised adults greater than or equal to 18 years of age, again because ic is a clearrisk factor for shingles. from early in the developmentprogram, and also specifically as phase three clinicalstudies were being designed, there were several keyaspirations considered. the first one was to havehigh vaccine efficacy

in those 50 years and older. but we thought that wasn'tsufficient and we also wanted to increase the vaccine efficacy in older age groups70 years and above. again, because thoseare the most susceptible and highest risk for shinglesand shingles complications. at the core of the aspirationswas really having a safe vaccine for all. and this includes safetyand efficacy in all persons

at increased risk, includingimmunocompromised populations. the fourth aspiration wasto have prolonged duration of protection and we'll betalking about that some today. and lastly ease of manufactureand reliability of supply. so i think you'll see throughoutthe presentation that many of these aspirationshave been met. so here you see the composition of our non-live adjuvantedsubunit vaccine. on the left and in theblue you see the antigen,

which is 50 micrograms ofrecombinant glycoprotein e, the most abundant proteinfound on the envelope of varicella zoster virus. which elicits a specificcellular and humoral immune response. and on the right you see theadjuvant system which is aso1b which is a liposome-basedadjuvant system, which contains immunostimulantsmpl and qs21. now mpl enhances bothcellular and humoral immunity,

while qs21 stimulates th1cell-mediated immunity as well as cytotoxic t lymphocyteactivity. synergistically, when you puttogether mpl together with qs21, you get an enhancedpro-inflammatory response, or innate immunity,as well as cellular and humoral immuneresponse increased. such that overall youhave a faster, stronger and longer lastingimmune response. so before i get into thecore of the presentation,

which is really the phasethree study results, i wanted to just sharesome background conclusions from the early phase studies. so first on data that's notpresented on this slide, but to tell you about isthat early phase safety and immunogenicity studiesdetermined the combination of adjuvant and antigenand the dosing scheme. and that led to the compositionyou saw on the previous slide to be given as atwo-dose regimen.

what this slide shows islong-term immunogenicity in people 60 yearsof age and older. so on the y axis yousee the median frequency of ge-specific cd4 t cells, andalong the x axis you see time in months going outto six years. so the first observation isafter two doses of vaccine, there's a strong cell mediatedimmune response, 19-fold higher than baseline at one month afterdose two, which is depicted as the peak here at month three.

a second point is that theimmune response was maintained even in older populationsof 70 years and older, as depicted by the grayline which overlaps with the orange linewhich is the 60 and older. and lastly, although you seea decline in immune response after the first few years,this plateaus by year four and still remains four times above baseline sixyears post-vaccination. now here you seea general overview

of the three phase threeefficacy studies that make up the hz/su development program. zoe50 and zoe70 are studies thatevaluate herpes zoster efficacy, safety and immunogenicity inpopulations 50 years and older and 70 years andolder respectively. these studies were begun in 2010 and were just recentlycompleted. the zoe50 results wereactually presented here at acip last year, andwere also published

in the new englandjournal of medicine. and just as a reminder, i will share one slideon the results today. primary results of the zoe70as well as pooled results from zoe50 and 70 haverecently been published in the new england journalof medicine last month, and will be the primary focusof the rest of the presentation. just as mentioned,study 002 is a study with evaluates herpeszoster efficacy,

safety and immunogenicity inadults greater than or equal to 18, receivingautologous hematopoietic stem cell transplant. so in this table what you seeis the general study design and objectives forboth zoe50 and zoe70. both studies wererandomized, placebo controlled, multi-center studies runin parallel in 18 countries across north america, europe,latin america and asia pacific. the primary objectiveswere herpes zoster efficacy

in persons greater than orequal to 50, and greater than or equal to 70, respectively. since the studies wererun at the same sites, individuals who were 70 yearsor older were randomly assigned to either zoe50 or zoe70. there were also prespecifiedprimary objectives for a pooled analysis whichincluded all subjects 70 years and older from both studies. and these objectiveswere phn efficacy

and herpes zoster efficacy. there were 16,160subjects enrolled in zoe50 and approximately14,800 for zoe70. continuing a bit onthe study design, again an identicaldesign for both studies. subjects were randomizedone to one in two groups. the vaccine groupreceived two doses of hz/su at two-month intervals, and theplacebo group received normal saline again at two-monthintervals.

vaccination was given atmonth zero and month two. blood sampling was done aspictured on this diagram. and monthly calls were madethroughout the conclusion of the study. there were threeexclusion criteria. one was having aprevious episode of herpes zoster disease. two, having previous varicellaor herpes zoster vaccination. and three, having animmunocompromised condition.

so here, taking a pause just topresent the remarkable results from zoe50 which againhave been published in the new englandjournal of medicine. if you look at the firstrow highlighted in blue, you'll see the resultsof the primary objective in which six cases weredetected in the vaccine group, versus 210 in the placebo groupfor a vaccine efficacy of 97% in individuals 50years and older. if you work down the last columnin the table outlined in red,

you'll see that the 97% ismaintained independent of age, even in subjects70 years and older, with quite tightconfidence intervals. so now i'll shift for the restof the presentation to focus on zoe70 as well as thepooled zoe50 and 70 analysis. the primary objective for zoe70was to evaluate vaccine efficacy in the preventionof herpes zoster, with secondary objectivesincluding evaluating vaccine efficacy and theprevention of phn.

and also evaluating vaccinesafety and reactogenicity. the pooled analysishad two pre-specified primary objectives. the first was toevaluate vaccine efficacy in the prevention of phnin all subjects 70 years or older across both studies. and the second was toevaluate vaccine efficacy and the prevention of herpeszoster also in subjects 70 years or older across those studies.

so it's important to have a goodunderstanding of the cohorts that were used foreach of the analyses. the total vaccine cohortincluded 13,900 subjects who all receivedat least one dose. the follow up timewas four years, and this was the primary cohortused for the safety analysis. the modified total vaccinecohort excludes subjects not receiving the second dose,and also excludes those who developed zosterdisease within one month

after the second dose. there were 13,163 subjects inthis cohort and the mean follow up time was 3.7 years. this was the primary cohortused for the efficacy analysis. and lastly the diarycard cohort was a subset of the total vaccine cohort ofapproximately 1,000 subjects which was used for thereactogenicity analysis. so here you see thedemographic's results. in the first column yousee vaccine recipients.

in the second column,placebo recipients. the mean age at doseone was 75.6 years. 54% of subjects were female. and as you can see, therewere virtually no differences between vaccine andplacebo group for age, gender, region or race. approximately 20% ofsubjects were recruited from north america. so in the next few slides i'llpresent the primary vaccine

efficacy results, both of zoe70and also pooled zoe50 and 70. this slide showsthe vaccine efficacy against herpes zoster overalland by age group as derived from the modifiedtotal vaccine cohort. the primary objectiveresults are seen in the first rowhighlighted in blue, where 23 shingles cases weredissected in the vaccine group, compared to 223 inthe placebo group for a vaccine efficacyof approximately 90%.

again, as you work downthe column on the right, outlined in red, you see that this vaccine efficacywas maintained even in the older age groupof 80 years and older. now we looked at thepooled analysis result. again, the pooled analysisincludes all subjects 70 years or older from both studies. and this is an important tablebecause they're the results that we considerthe most robust,

as there were an additionalapproximately 3,400 subjects that came from the zoe 50 study. again, the primaryobjective is seen in the first row,highlighted in blue. there were 25 shinglescases in the vaccine group, versus 284 in the placebo groupfor a vaccine efficacy of 91%. and as you can see in thelast column outlined in red, if you go down even among thoseindividuals 80 years or older, the vaccine efficacy of 91%was maintained with consistent

and narrow confidence intervals. another important aspect tolook at is vaccine efficacy by year post-vaccination. so again, this is fromthe pooled analysis, so it includes allsubjects 70 years and older, looking at the efficacyby year post-vaccination. so the numbers in the firstcolumn are not cumulative. they're the number of casesthat were detected each year. for year one there wereonly two cases detected

in the vaccine group, versus83 cases in the placebo group, for a vaccine efficacyof approximately 98%. and this year seems tobe a bit of an outlier. but if you look at year four,four years post-vaccination, the vaccine efficacy isstill maintained at 88%. so although these vaccineefficacy estimates are a snapshot, there is someconsistency between years as can be seen by the overlappingconfidence intervals.

and for the last slide with theresults of vaccine efficacy, we look at the pooledresults of vaccine efficacy against post-hepaticneuralgia or phn, the most importantcomplication of shingles. again, in the top rowhighlighted in blue we can see that there were four phncases in the vaccine group, compared to 36 in the placebogroup, for a vaccine efficacy of 89% in individuals70 years and older. as you look acrossall the age groups,

going down the finalcolumn outlined in red, you can see that in general thevaccine efficacy is maintained, with the exception forthose above 80 years of age in which we simplyhad too few cases to have statisticalsignificance. of note, this is differentagain from what we saw in the above 80 group forherpes zoster, where there was quiterobust significance and quite high vaccine efficacy.

all right, now i will shiftyour attention to safety and reactogenicity asobserved in zoe50 and zoe70. so let me walk youthrough this slide. on the y axis you see thepercentage of events reported, and of note it'sonly up to 20% scale. otherwise it would have beendifficult to visualize some of the less reported events. and on the z axis you cansee the events reported, which hare seriousadverse events,

serious adverse eventsrelated to vaccine, potential immune mediateddiseases and deaths. for each event the first twocolumns depicted in green and yellow represent zoe50results for the vaccine and placebo group respectively. and the second two columnsdepicted in blue and pink or purple -- pink ithink -- represent zoe70. and again, for vaccine andplacebo group respectively. so one observation as might beexpected due to comorbidities

and also older age isthat there were more sae's and deaths reported fromzoe70 than from zoe50. however, the important takehome from this slide is that independent ofcoming from zoe50 or zoe70, there are no imbalancesbetween vaccine recipients and placebo recipientsfor any of the endpoints, sae's, pimd's or deaths. zoe50 and zoe70 also providedsome interesting information regarding reactogenicity.

what you see on this graphare solicited local symptoms reported seven dayspost-vaccination of any grade overall by subject. so this is comparing vaccinatedgroup to placebo group. and again, as a reminder, the placebo groupreceived normal saline. so on the y axis you have thepercentage of symptoms reported. on the x axis you havethe three local symptoms, pain, redness and swelling.

again, the first twocolumns depicted in green and yellow representzoe50, for vaccine and placebo groups respectively. and the second two columnsrepresent zoe70 for vaccine and what we see here isthat as may be expected with an adjuvanted vaccine, injection site reactionswere common, and they were more commonin vaccine recipients than in placebo recipients.

the median duration of thesesymptoms was between two and three days, and most weremild to moderate in intensity. now we look specificallyat reactogenicity for grade three reactions,again for local symptoms. and grade three here is definedas greater than 100 millimeters for redness and swelling,and impeding on normal activities for pain. on the y axis you can seethat this scale is up to 50%. and what we found is thatthere were around 8% or less

of grade three reactionsreported. however, these were reportedmore often in vaccine recipients and the mean duration forthese symptoms was 1-2 days. now we take a look at solicitedsystemic symptoms reported again seven days post-vaccination ofany grade overall by subject. and here what we found is that the three most commonsystemic symptoms were fatigue, headache and myalgia. and again, these weremore commonly reported

in vaccine rather thanplacebo recipients. most were mild tomoderate in intensity, and the median durationwas again 1-2 days. and for the last slide onreactogenicity, we take a look at the grade three systemicsymptoms that were reported. again, this is witha scale up to 50%. and what we found here is thatthere was 6% or less reported across the study, butthey were more frequent in vaccine recipients comparedto placebo, specifically

for headache, fatigue,myalgia and also shivering. the media duration, 1-2 days. so now taking a pausehere to answer a question that we're often asked:what is the compliance with the second dose? so here we actuallyhave an answer, at least an answerfrom zoe50 and zoe70. what you can see is thatfor zoe70 the compliance with the second dose was 96% forboth vaccine and placebo groups.

and for zoe70, it was 95 or 96%for vaccine and placebo groups. so essentially across the board, very high seconddose compliance. so i've presented quite a bit ofdata today and i would like now to summarize by giving youthe key take home messages for safety and reactogenicity. so aligned with previoushz/su studies, there has been nosafety signal detected, and there's no imbalance in theincidence of safety endpoints

between the placeboand the vaccine groups in either zoe50 or zoe70. additionally, adverse eventsand safety endpoints were as expected in thispatient population. local and systemicreactions to hz/su were common in the first sevendays after vaccination, but were largelymild and moderate in intensity in ashort duration. for efficacy, we havethe following summary

or take home messages. for zoe70 vaccineefficacy in adults 70 years and older was greater than 90%for the prevention of shingles. and this is fairly consistentwith the previous results in the same age groupfrom the zoe50 study. in the pooled analysis whichwe consider the most robust analysis, vaccineefficacy of the prevention of herpes zoster all the way up to adults 80 yearsand older was 91%.

the vaccine alsodemonstrated an efficacy of 88% through year four, and exhibitedsimilarly high efficacy of 89% in prevention of phn inindividuals 70 years and older. so with all this data, youmay be thinking what's next. and actually we have quite a bit of ongoing evidencegeneration activity, and this is just a few examples. so we have a revaccination study which is evaluatingthe immunogenicity,

safety and reactogenicity inindividuals who have a history of zostavax immunizationat least five years prior, who are subsequentlyvaccinated with hz/su. we have a series ofcoadministration studies which evaluate theimmunogenicity, safety and reactogenicity ofthe vaccine when coadministered with flu, pneumococcalor tdap vaccine. and as was alluded to before,we also have a duration of protection study in whichwe're looking at efficacy,

safety and immunogenicityover a long-term period, up to ten years post-vaccinationas an extension of the zoe50 and 70 studies. the other exciting news isthat we plan to submit bla for sieber review of our candidate hz/su vaccinebefore the end of the year with the expected indicationof prevention of herpes zoster in adults 50 years and older. so as a final conclusion i would

like to leave youwith this thought. we at gsk are very proud ofthis vaccine and consider that hz/su not onlyhas the real potential to improve the prevention ofshingles and its complications, but could also shed light on the way futurevaccines are developed to overcome the challengesof decreasing immunity in older adults and the elderly. thank you for your attention.

>> thank you very much forthat great presentation. do we have questionsfor dr. colindres? >> so very nice presentation,and wonderful data. so i have one questionand one comment. so are you planning on lookingat the use of the vaccine in individuals thathave a previous history of herpes zoster? and second, in looking at yourslide number 12, i was struck by the low number ofblack participants

in the study, only 1%. is that correct? >> so to take thefirst question, we have done a study lookingat vaccinating individuals who had a previous episodeof herpes zoster disease, and that should bepublished soon. i can tell you thatthe results were that the vaccine wasimmunogenic and also safe. with regards to yoursecond question,

i thin was regardingthe percentage of -- >> the number ofblack participants in your study is 1% overall which would be 150-someodd, roughly. >> got it. yes. so there are twoconsiderations there. one is that this studywas done worldwide. so in a lot of countries aroundthe world including europe, asia pacific and latin america.

if you looked at that numberjust for north america and the us, it wouldbe approximately 4%. so it's still less than thepercentage of african americans in the us population, butit is slightly higher. >> dr. middleman? >> hi, middleman sam. i'm just curiousto understand -- it was a fabulouspresentation, by the way. on slide -- oh gosh,i can't read these.

nine. you know, forzoe50 you have that the efficacy among greaterthan 70-year-olds is 97.9% and it has a pretty niceconfidence interval. and then for zoe70 for 70- to79-year-olds the efficacy still within a pretty tightconfidence interval, was 90%. and i'm just curious toknow if there's any thought about why the two studieswould have different efficacy findings, unless i'm notunderstanding something. >> yes, i don't have themagic answer to that,

other than it's what's cameout in the clinical study. there were some degreeof overlap in the confidence intervals, sothat accounts for some of it, but i don't have aspecific answer to that. on the pooled analysis for herpes zosterthe sample sizes were in the 8,200, 8,300 range. but for the phn, post-herpeticneuralgia pooled analyses it jumped up to 13,000for the sample sizes.

can you explain why? >> yeah. if we go to thatslide on phn, it's essentially because it also includedthe 50-year-old group. here we go. correct. so in realityyou're correct, and that was a good pickup. so for the pooled analysis, which would include the primaryobjective, the other sample size of the 8,000 or so is correct.

these sample sizes includedwhen we also include for the 50, which included allsubjects including the 50. >> that's 50-year-old,not zoe50? >> right, 50-year-old. yes. >> atmar. on the sameslide, the frequency of post-herpeticneuralgia in persons over 80 is remarkably lowerin the placebo group compared to younger age groupswhere it's about 50-60%

of people who developed zoster. do you have an explanationfor that? >> you're speaking onthis slide about -- >> so if you compare the numbers in the phn cases amongthe placebo on this slide and go back to thenumber of cases of zoster and the efficacy slide, this is7 out of about i don't remember, 30 or 40 patients who gotzoster in the placebo group. 56 patients, no.

earlier slide. anyway, the frequency was 50-60%in all the younger age groups. and it was 20%, 25%in this age group. >> no, i don't really have anexplanation of why it was lower in the 80 and above, althoughwe did observe that as well. what i can say is that inour study, the prevention of phn was clearly associatedwith decreased incidence so it was clearly onewas linked to the other. >> questions?

>> yes. in your efficacyanalysis, if i understood correctly, you only took the periodfollowing one month after the second dose,starting one month after the seconddose of vaccine. >> i'm sorry, i didn't catchthe first part of your question. >> in your efficacy analyses, it only included the period onemonth following the second dose. >> correct.

it included after30 days essentially. >> okay, so did you have anyinformation on the distribution of cases -- probablyvery small -- that occurred followingthe first dose through that time period? >> it was really ahandful of cases. you're right, it was very small. under 20. >> dr. messonnier?

>> hi. i wanted togo back to the slide about upcoming evidencegeneration. can you give us asense of the timing of when you'll have dataavailable from those studies? in a year from now? two? five? when will you have moredata on each of those? >> so the revaccination studywe're actively working on and we should haveresults probably

by about april ormay of this year. and this is something that we'reworking very closely obviously with the zoster working groupand rafael and kathleen to have that information reviewedas soon as possible. the coadmin studiesare completed and in the analysis phase. and actually a plugfor an abstract that will be presentedid week is the flu study. so the flu coad studywill be presented there.

and quite good results. and obviously the duration ofprotection is still a bit off. >> can i add to that, whatabout the vaccination in people who have previouslyhad herpes zoster? >> so that one has beencompleted and we're in the process ofwriting the manuscript. >> dr. hahn? >> yeah, i was wondering if youhad data on adverse reactions from first dose comparedto second dose?

and if the same person, if theyhad an adverse reaction the first time, say a lotof swelling and redness, did it get worse onthat second dose? or did it go on to becomesystemic, that type of thing? >> yeah. so we're actually still in the process ofanalyzing that. there does seem tobe some correlation. but we're still goingthrough that data. and as soon as it'savailable, we'll share it.

>> dr. whitley-williams? >> pat whitley-williams,national medical association. i know the questionwas already asked about the underrepresentationof blacks in the study, but also i did not see hispanicsalso in the us population. it may have beenincluded in other, but i want to make acomment and that is that certainly the studiesreally should reflect the population within the us.

i know how difficult it issometimes to do studies here. but really we should belooking at the population as it is represented in the us. particularly regardingnot only immunogenicity, but also the adverse events. can you imagine ifthis was rolled out and for whatever reason theremight have been an increase in adverse events in aparticular ethnic group? you can imagine whatthat would do

to an already challengingadult immunization system. >> yes, thank youfor your comment. and i see a colleague of minemay want to comment on that. >> yes, hi. dr. leonard friedland from gsk. thank you, dr. whitley-williams. we work extremely diligentlyto identify investigators and patients thatare representative of the us populationin our clinical trials.

and we continue andwill continue to identify thoseinvestigators and patients. and you see the challenges thatwe have in our clinical trials. these results are not different than other clinicaltrials with other vaccines. it's very difficult to identifypatients and investigators who can enroll inthese clinical studies so we can have representativepopulations. we're not giving up and wewill continue to work on this.

comments? okay. i guess we're done. thank you very much. really exciting information. okay, we're going tomove onto a brief update on yellow fever vaccine supply. this will be short but i thinkit's important information for everyone. is dr. gershman here?

he's already there. >> well, good afternoon,or good evening. thank you for having me here. and i appreciate everybodystaying for the late hour. i'm giving a brief update onyellow fever vaccine supply in the us, as mentioned. yellow fever is caused by theyellow fever virus which belongs to the genus flavivirus. this virus is transmittedpredominantly

by aedes mosquitos. yellow fever disease isendemic in sub-saharan africa and tropical south america. asymptomatic infectionoccurs in most people. when clinical diseasedose occur, it ranges from a mild fibrilillness to severe disease with jaundice andhemorrhage and can be fatal. in 2016 outbreaksoccurred in areas of africa where cases had not beenreported for decades.

the most notable being theongoing but subsiding outbreak in angola which has spread toseveral countries actually. yellow fever vaccine is alive attenuated viral vaccine produced in chick embryos. there are four who pre-qualifiedvaccines available globally. vaccine prequalification isa process established by who to ensure the quality andsafety of vaccines provided through the unitednations for use in national immunizationprograms.

there is only one yellow fevervaccine licensed and marketed in the us and that's yf vax,manufactured by sanofi pasteur. yf vax is not who pre-qualified and is therefore not partof the global supply. also yellow fever vaccine isthe only vaccine for which proof of vaccination can berequired by countries from arriving travelers under the internationalhealth regulations of 2005. regarding global yellowfever vaccine supply in 2016,

6 million doses of yellowfever vaccine are placed in a global emergencystockpile annually. this stockpile ismanaged by the icg which is the internationalcoordinating group on yellow fever vaccineprovision. the member agencies ofwhich are who, unicef, medecins sans fronteir andthe red cross red crescent. the emergency response tothe current large outbreaks in africa this year depletedthe stockpile several times.

consequently, yellow fevervaccine doses allotted for national, childhood and prevention campaignswere rerouted for these emergencyresponse efforts. also as a dose sparing measurein the face of global shortages, fractional doses of yellowfever vaccine were used in the democraticrepublic of the congo for preemptive vaccinationof residents of kinshasa. in the united states,yellow fever vaccine is used

to vaccinate peopletravelling internationally, including the military. this is for travel tocountries where there is a risk of yellow fever virustransmission, but it is also to countries which haveentry requirements for proof of yellow fever vaccinationof travelers as allowed also, yellow fevervaccine is used to vaccinate laboratory workerswho potentially might be exposed to yellow fever virus inthe line of their work.

regarding the yellow fevervaccine supply in the us, historically there have beenintermittent manufacturing issues which have led totemporary supply shortages. since the end of 2015 there hasbeen an ongoing yellow fever vaccine shortage inthe united states with ordering restrictions inplace during this whole time. and this was compoundedby the anticipation of additional demands on theus vaccine supply for travel to the brazil olympics, brazilbeing an endemic country by 90%

of its land mass, duringhis past summer by athletes, official delegationsand tourists. so concerns about the usyellow fever vaccine supply in conjunction with a largeyellow fever outbreak in africa and global supplyissues led the initiation of stakeholder discussionsin the spring of this year, spring 2016. the focus of thesediscussions was how to assure a stable yellow fevervaccine supply for travelers,

military and responsepersonnel from the us. participants in thesediscussions include cdc, sanofi pasteur, fda anddepartment of defense. options to assure the usyellow fever vaccine supply that were reviewed in thesediscussions included number one, maintaining the status quoby relying on the release of new yf vax slots currentlyin production secondly, implementing an expandedaccess investigational new drug or ind application to allowfor the importation and use

of a yellow fever vaccinelicensed outside of the us. and this vaccine would bestamaril, which is manufactured in france by sanofi pasteurand licensed and marketed in more than 70 countries. and the last option wasusing fractional dosing of yellow fever vaccineas was first done in drc during this year'slarge yellow fever outbreak in west and central africa. at present the status of theseoptions that were discussed

for the us yellowfever vaccine supply is that the yf vax slots currentlybeing produced are scheduled to be released before thecurrent inventory is exhausted. notably, the currentinventory is lasting longer than anticipated because thelevel of increased demand for the olympics did not occur. current ordering restrictionshowever for yf vax would remain in place to help modulatethe future depletion of the current inventory.

a contingency plan is beingdeveloped with submission of the ind application toimport and use stamaril, the yellow fever vaccinelicensed outside the us. and its ind applicationis presently under a 30-day reviewby the fda. the ind protocolincluding training of clinicians involvedwould be implemented to add to the adequate us yellowfever vaccine supply. and finally, fractionaldosing was not considered

to be a viable optionbecause of limited data and many uncertainties. in conclusion, in 2016limitations occurred in both the global and the usyellow fever vaccine supply. contingency plans are beingdeveloped for the us supply. and these plans will be enacted as needed based ondemand and supply. and finally this is the listof the japanese encephalitis and yellow fever vaccines.

acip working groupmembers, thank you. >> thank you, dr. gershman. are there questionsfor dr. gershman? yes, dr. belongia? can you explain a littlebit more about how it works with an ind with a vaccinelicensed in another county? and it's done under protocol. what is the protocol? is it a study?

how does that work? >> i'm probably not thebest person to answer it. i'll say a few lines and thendefer maybe to a representative from either the fdaor the manufacturer. the protocol i think isbasically the plan as to how to get that vaccinedistributed to the clinicians who will use it, and what arethe conditions of distribution, what are the conditions ofmonitoring safety and such. it's not an experimentalprotocol.

expanded access isa clinical protocol, almost like an orphan drugto supply a vaccine or drug that would not be otherwiseavailable, and is deemed to be absolutely necessary. but i'll defer to dr. sun fromthe fda or somebody from sanofi if they want to providemore details, since sanofi haswritten the protocol. >> thanks. david greenberg, medicalaffairs, sanofi pasteur.

i agree with everythingthat has been said. this is a clinicalprotocol, not a steady per se. it's not a clinicaltrial with hypotheses and specific statisticalquestions being asked. but rather a mechanismthat's reviewed and approved by the fda to import stamaril. so it's a mechanism toimport the product stamaril into the united statesand distribute it to clinicians throughout theunited states at specific sites

that use a lot ofyellow fever vaccine, and then have thoseclinicians -- either these will beclinicians who are used to administeringyellow fever vaccine if we do need to import it. and then they administerthe vaccine as they normally would yellowfever vaccine or yf vax, and then monitor safety,report safety issues both to us as the manufacturerand to the fda.

but otherwise it'sactually pretty routine use of the vaccine with someadditional safety follow up. >> just to add one more pieceof information to dr. greenberg. as far as the protocol, thedevil is in the details. and the problem with this isit's really unique vaccine in a unique situation. there are over 5,000 clinics,just civilian clinics, well non-military clinics that administer yellowfever vaccines.

so it would not bepractical nor achievable to distribute stamarilto all those clinics. i mean it would bevirtually impossible. so part of the protocolinvolves how site selection is accomplished. and we've worked out what seemsto be a reasonable situation to distribute to those who seemto be the top users by volume. so that geographicalaccess is maintained for people in all states.

but it's a delicatebalance because the amount of work involved isobviously quite a lot. but the vaccine needs tobe accessible if we want to prevent the importation ofa potentially fatal disease. >> hi, paul hunter. i'm just wondering if thesituation we're in now with the us supply beingseparate from the global supply of yellow fever vaccine, if thatwas a conscious policy decision, or if that just sort ofdeveloped historically

for market reasons, orif anybody knows that. >> i think that's developedhistorically for market reasons, because the us vaccineis strictly -- you know, vaccine is usedfor two main purposes. for international travelers, inwhich case it's really used only in -- well in this case thecountry it's produced in, and that's the verycircumscribed market. and then there are the who pre-qualifiedvaccines that can be used.

and it's a rigorous processto get that certification of pre-qualification toassure the many countries in which those vaccines are forare safe for those residents in mass vaccination campaigns. sanofi -- and i can'tspeak to this -- maybe one of thesanofi reps can. sanofi did not pursuewho pre-qualification for the us manufactured yfvax, but justifiably so, why would it need to be done?

it's a lengthy andexpensive process. their stamaril which is producedin france, which is one of the who pre-qualified vaccines iswho pre-qualified and is one of the major vaccines usedglobally and including in routine infantimmunization programs and mass vaccinationcampaigns in response and preemptively with outbreaks. >> dr. plotkin andthen ms. pellegrini. >> well i apologize at thislate hour, but i don't know

when yellow fever is goingto come up again to acip. and i am requesting cdc toreconvene the yellow fever group to reconsider itsrecommendation. so this is the day tocriticize cdc, but i have data. so in february 2016during a snowstorm, the yellow fevergroup recommended that revaccination isunnecessary for yellow fever. and they said andprinted that 92% of vaccinees are serumpositive in 10 years,

and that there's apaucity of vaccine failures and evidence of seropositivity. now recently an article waspublished by amana and slifka in which they reviewed theliterature and concluded that immunity is lostin 20-33% at 10 years, and that childrenare at greater risk for losing their seropositivity. i quote from their article, "anextensive study examining cases of yellow fever in brazil hasprovided much needed insight.

in this study patientswere not only queried about their vaccination status, but also asked whetherthey had been vaccinated within 10 years prior tocontracting yellow fever. there were 831 cases ofyellow fever identified between 1973 and 2008. vaccination status wasunavailable for 372 of the patients, but theremaining 459 cases had received prior yellow fevervaccination and

yet still contractedyellow fever. since all of the cases ofyellow fever were virologically confirmed, we believethat this is likely to be a more accuraterepresentation of vaccine failures thanthe previous estimate of only 23 worldwidevaccine failures." and then they comment that 52% of those had been vaccinatedmore than 10 years previously. i won't quote more fromthis paper, but i recommend

that the working group read it. there's also a studyfrom brazil, specifically in children, which showsseroconversion rates after the first vaccination ofonly about between 80 and 85%. and also a lack ofduration of those responses. now the paper that was usedprimarily by the group, at least quoted by thegroup, was a paper by gotuzo who reviewed the situation. and it's true inthe abstract he says

that the durationof immunity is good. but if you look at histable, for those studies in which there were morethan 100 people involved, the persistence was 76% at17 years, 81% at 30 years, 75% at 10 years, 69% at 4years, and 65%at 10 years. in addition, there is no studyof africans where yellow fever of course is epidemic. so we have no idea whatthe duration of immunity is in the african population.

so i think that durationof responses of immunity to the yellow fever vaccinehas been exaggerated. and whether i'm right or wrong, i think this should bereevaluated in light of all of the data available,not simply those that were used apparentlyby the initial group. and by the way, the snowstormwas also grossly exaggerated. >> thank you verymuch, dr. plotkin, and i remember that snowstorm.

i don't know if you cancall it a snowstorm. but thank you very muchfor those comments. and i think that theywill definitely be taken up by the workgroup, whichactually does sort of exist. i thought we had morecurrently that you showed at the end of your presentation. >> it exists in the form of a jeand yf combined working group. >> right, combinedworking group. so i think we can takethat into consideration.

>> i assure you,the data does exist. >> i thought so. other comments? ms. pellegrini, sorry. >> that's okay. dr. gershman, do wehave any explanation for why yellow fever hasreemerged so suddenly and so aggressively inthese parts of africa? just thinking that over thelast several years we seem

to have had a number of caseswhere the viruses have done this or left continentsand wreaked havoc. and so should we be worried about yellow fever perhapsspreading to additional areas or to brazil or other places? >> you're asking quitea global question for a vaccine supplypresentation. i work in travelers' health. i mean, i'll take a stab atit, but i really deal more

with the domestic side and theregulatory and policy side. and i'm not an internationaltype person regarding yellow fever. of course there's overlap. but i mean, i've seenthings and speculation. i don't think anybodyknows for sure, but i think it's a combinationof global climate change and probably el nino cycles thatare periodic and normal and what that does to the densityof mosquito vectors.

it has to do withchanging population in urban areas in africa. because this is an urban yellowfever outbreak that's been so severe. and there are differentcycles of transmission. the urban is the aeges egypti,really person to person. it's person to mosquitoto person. but it's really personto person, as opposed to the endemic,which his jungle yellow fever.

people wandering into the jungleand getting bitten randomly by mosquitos thatprefer monkeys usually. you have roads being builtand more access from people from areas where they might beexposed to the jungle cycle, to urban areas where theycan then introduce it to densely populated areas withdense levels of aedes mosquitos. so i think it's a host of allthese factors, is my best guess. and i think what you'd find ifyou start looking up articles. but i don't thinkanybody really knows.

but it's probablygoing to continue. i think that was a pretty goodanswer for not being an expert. dr. thompson and then dr. sun. >> yeah, so coming backto a supply question. in the contents of theevents that occurred, can you say a little bit about what caused theactual supply disruption? was it a manufacturing issue? was it something else?

and then also arewe doing anything to increase the safetystock to address this? it is a manufacturing issue. of course that's a broadrubric and i'll defer to the sanofi representative who can probablyprovide more detail. >> hi, julian ritchie,sanofi pasteur. yes, so this is amanufacturing issue. and for some time nowwe've been looking to move

to a new manufacturing facility. the current manufacturingfacility is an older facility, and this is the home stretch and this happenedin the home stretch. so we're currently inthe process of making that transition and looking tomake that transition seamless. dr. sun? >> dr. sun from fda. i just wanted to add one followup on pellegrini's question.

there have been casesfrom yellow fever from this recentoutbreak in africa that was imported to china. and yellow fever, eventhough the mosquito that transmits yellow feverhas been endemic in asia, it has not had yellow fever. so it's one of those reallyenigmas for planar virology. but nonetheless, traveler-associatedyellow fever importing

from outbreaks iscertainly a great concern. and then on the issue ofind, i just wanted to add that the expandedaccess ind is a mechanism by which we could makeunapproved products available for use. and in this case for wider use. the same mechanism was usedfor the use of bexsero for menb in university outbreaks. there are various versionsof the expanded access ind.

there's one for products thathave plans to be licensed. and there are ones wherethe product is not headed for licensure, and so they'redealt with somewhat differently. but the basic principle there is that it's still consideredan unapproved product and therefore the transport across state lineshas to be under ind. and in addition therehas to be some, in this case streamlinedcollection of adverse events.

in this case a very, verystreamlined approach. further comments or questions? last but not least, we wouldlike to have public comment and then we will be adjourned. is there any furtherpublic comment? dr. plotkin. >> once again, i apologizefor keeping the committee, but i just don't have any choicein the matter, so to speak. what i am now urgingon the committee is

to form a lyme diseasevaccine working group. that a lyme disease vaccineis sorely needed i think is without question. the cdc itself estimates300,000 annual cases, and another 120,000estimated in europe. carditis, neurologicalcomplications and rare deaths occur. i once spoke to this committeebefore and mentioned that one of my own sons had alife-threatening case

of lyme carditis. at any rate, the originalvaccine that was licensed in the late 90's worked quitewell in terms of its efficacy, although a booster was neededbecause of the mechanism of the ospey antigenthat was in the vaccine. unfortunately, and isay this carefully, but clearly that cdc did notsupport the original lyme disease vaccine. and that was one of the reasonswhy it was taken off the market.

another reason was that themanufacturer did not do a pediatric study untilit was too late. and then there was aquestionable safety signal which was never supportedby their analysis, was never supported bythe laboratory analysis. but was enough to decrease sales and the manufacturertook it off. i should mention as far asthe pediatrics is concerned, that the study that wasdone late in the game showed

that if anything, childrenresponded about 10 times better to the vaccine than did adults. so the question now is,can we have a new vaccine? now i've been working with potential lymevaccine developers and i should say clearly ihave no financial interest in this whatsoever. but they do not knowif acip is interested and will make a positiverecommendation.

clearly acip cannotmake a recommendation without having anactual vaccine. but it could indicateinterest in having one. i think a lyme diseaseworking group to consider the targetproduct profile and to meet with potential newvaccine manufacturers, and there are thecandidate vaccines, would be very desirable. and the situationi think is similar

to the rotavirus situation. if you recall, the originalrotavirus vaccine was taken off the market becauseof intersusception. and then the issuefor the manufacturers, and i was personallyinvolved in this, was will a new vaccinebe recommended? and it was clear at thetime that acip wanted to prevent rotavirus disease, and therefore two manufacturersundertook to make new vaccines

which ultimately were licensed. so again, and lastly i hope that the acip will considerforming a lyme disease working group to indicate thatthey have an interest in an eventual vaccine. >> thank you, dr. plotkin. i think this is an interestingproblem that you pose. i think it's probably beyondthe purview of the acip to develop a workinggroup to advocate

for the developmentof the vaccine. however, it's not beyond thepurview obviously of the cdc or the subject matterexperts at the cdc. and i think that you know, this is an overarchingproblem in the us. how do we decide whichvaccines we advocate for the development of? i think there's not a very goodsystematic approach to this. so i think you're raising avery, very important problem.

other comments. >> along those lines, i thoughtthat was something that nvac, the national vaccineadvisory council, advising the assistantsecretary of health. okay, all right. >> do you want to comment? dr. burkett. >> yeah, thanks. i think part of the nationalvaccine plan does get

at the development of newvaccines, but i'm not aware of a formal mechanism bywhich recommendations are made for vaccines thatare of interest for further development. >> there has been quitea bit of discussion. >> if i may comment onthat, in 2000 the institute of medicine did ananalysis of what vaccines -- that is what diseases forwhich we need vaccines. what are the first prioritiesfor developing vaccines?

that was a very importantdocument. that had a major effecton the manufacturers in terms of choosing targets. and that sort ofanalysis is really needed. nvac should do it,but they won't. and the acip could do itby various mechanisms, but again has notundertaken to do that. >> dr. thompson, doyou want to comment? >> yeah, thank you verymuch for the comment

and the opportunityto comment on it. i think nvac has been veryinterested in recent meetings in the area of vaccineinnovation. and i think this fallsinto that category. it would be a new vaccine, andwe certainly are looking at all of the incentives that thewhole system faces with respect to innovation inthe vaccine area. so i think this is somethingwe can take up as a question. but in the contextof the broader theme,

and i think one topic orone issue that you've raised that has been raised by othersto the committee is the fact that manufacturers ordevelopers in general would like some assurance that therewould be a market for a product. and that is very hard for anyadvisory committee to give. but i think the concept of target profiles is aninteresting one that's worthy of exploration andcertainly something that we could consider.

and maybe acip couldin some way consider that as well at some point. i don't know. i don't know where we'll land, but i think it's aninteresting concept. any further comment? we have one last public comment. >> thank you, my name ischristina hildebrand and i am with a voice forchoice advocacy.

to finish off the evening,i wanted to come back to a few comments that i madeearlier and just expand on them. the first one is you know,looking at all the data that was presented today, it waseither really small base sizes or it was by thepharmaceutical companies, which is not independentresearch by any means. and i really urge the cdcto do independent research, that is not the cdc or the pharmaceuticalcompanies doing research.

because both of youget money out of this. and so we need an independentresearch body doing research. we've got 12 cdcresearchers that came out today questioningthe ethics of the cdc. and the infiltrationof money into the cdc and into our government. and we know that thepharmaceutical companies are the largest lobbyingforce out there. we also have onecdc whistleblower,

dr. william thompsonwho has shown that there's beenfraud in the cdc. he's shown that there'sbeen fraud on mmr studies. there's also you know,efficacy research in the mmr. there's a lawsuit right nowquestioning the efficacy of the mmr. and you know, i lookat this data and i look at what you're doing hereat the acip and at the cdc, and i just ask thatindependent research is done

or that you use the independentresearch that is out there. because using paid for research or your own researchjust isn't good enough. any further comments? i think we are adjournedfor the day. thank you all for yourattention and hard work and we'll see youin the morning.