natural treatment for the disease typhoid disease

it's my pleasure to introduce the meningococcal vaccinesession with this work group update.on this slide are the members of the work group, the leads ofjessica macneil and manisha patel and other representatives.you have just heard that one serogroup meningococcal vaccinewas issued yesterday. the rlp2086 for age 10 to 25years of age. a second meningococcal vaccine,4cmenb. these are distinct from theconjugate acwy vaccines because

they are based on aminoproteins. meningococcal b vaccine has beenused for outbreak response in 2013 two universitiesexperienced outbreak of serogroup b meningococcaldisease. vaccination campaigns wereconducted in response using one of the investigationalmeningococcal b vaccines obtained through an expandedaccess investigation of a new drug sponsored by cdc.in addition guidance for institutional outbreaks has beendeveloped and the link is shown

on the bottom of the slide.today's sessions will consist of the following.there will be presentations on the 4cmenb vaccine from jimwassil and a presentation on the rlp2086 and presentation ofepidemiology of serogroup b in the united states by jessicamacneil followed by an overview of serogroup b meningococcalvaccines presented for use. in terms of a timeline for thenext acip meeting in february 2015 there will be proposedrecommendations for the use of serogroup b vaccine in personswith high risk medical

conditions, laboratory workersand outbreaks. the acip meningococcal workgroup will review data on vaccines as it becomes availableand continue discussions on use and potential impacts of thevaccines and guidelines will be developed to address outbreaksdue to all serogroups. if i can call on jim wassil.>>> thank you for giving me the opportunity today to presentdata on 4cmenb for the preventi disease.earlier this year we submitted a bid with fda.the file has been accepted and

we have been granted priority ofreview status. i want to present the clinicaloverview for 4cmenb including proposed indication, estimatedstrain coverage as well as vaccine composition.i will conclude with review of clinical data in adolescents andadults i novartis is seeking indication in the u.s.based on proposed indication currently under review with fdait is indicated for prevention of meningococcal disease causedby serogroup b in individuals between 10 and 25 years of age.the vaccine is a 0 suspension

intended for intermuscularinjection. it is fully liquid and requiresrefrigeration, cannot be frozen and needs to be protected fromlight. the serogroup b capsule isimmunoogenic. the antigens are highly diverse.novart s took two approaches. the first is a process calledreverse. the second was that it developeda multi component approach. the goal was that we wouldachieve broad coverage against the circulating strains.the vaccine was formulated with

50 micrograms each.the fourth component is 25 micrograms.this is the same used in new zealand to address the outbreak.the safety and effectiveness has been demonstrated.all four of the components are absorbed.the coverage is assessed based upon the meningococcal typingsystem. it is correlated with killing astrain. the tither greater than 4 isconsidered protection against the disease.the strain exceeds a minimum

threshold value for any of thethree or geno type it is highly likely this vaccine or thisstrain would be killed and is therefore considered to becovered. in the u.s. we set coveragebased upon a representative panel of 442 strains isolatedfrom individuals between 2000 and 2008.based on that only 9% were not covered and of the 91 that werecovered, 44% were covered by one vaccine component.over half of coverage strains were covered.that is independently each

deemed sufficient to kill thestrain on its own. the difference between thisslide and the previous slide is that this is only for the subsetof strains where the disease occurred in individuals between10 and 25. it is good to see the predictedcoverage didn't change substantially.it is still 92%. it is worthy to note the numberof strains covered by multiple antigens.so now i would like to go into the summary of the 4cmenbtrials.

18,400 subjects that areadolescents and adults received at least one dose of 4cmenb.over 6,000 individuals between 2 months and 10 years of age alsoreceived the vaccine attribulating to the overalldatabase. for today i focus on thoseclinical studies that are supportive of the indication weare seeking in the u.s. 3,139 subjects between the agesof 10 and 50 received at least one dose of the vaccine in sixrandomized control clinical studies.over 50,000 received one dose at

princeton university oruniversity in california. those results have beenpresented to the committee at previous meetings.today i just want to focus on two studies in particular, phasetwo study conducted in chile in adolescents looking at differentdosing schedules. and looking at investigationaluse vaccine for different formulations of investigationalvaccine. but what is important in thatstudy was that there was one arm where individuals between 10 and25 received 4cmenb as a

comparison.before i go into that i want to give you the overall conclusionas to the results of the clinical trials to date.this includes the studies that were conducted in princeton anduniversity of california santa barbara.35 countries and over 1 million doses have been approved for thevaccine and over 1 million doses have been distributed.the results show that the vaccine is immunoogenic aftertwo doses. this has been confirmed in asmall u.s. study and has been

demonstrated up to 23 monthsafter the schedule. finally it shows thedemonstrated safety profile. this includes three recentlyconducted large scale vaccine campaigns.i mentioned two previously cht a third was conducted in theregion of quebec where over 43,000 individuals received atleast one dose of the vaccine. and what is important there isthat the ministry of health did an active safety surveillanceincluding over 12,000 subjects having been administered sevendays after vaccination.

the safety profile seen in thecampaigns were consistent with that observed in clinicalstudies. now i would like to go into thephase two b study controlled study conducted in adolescentsbetween 11 and 17. it evaluated safety of variousone, two or three dose schedules.subjects received either placebo, two doses at one, two,or six months apart or various three dose schedules.blood was drawn after each visit and safety followed up after 12months.

here are the results of theprimary end point. it shows present of subjectswith tithers greater than 4. it was measured by what of whatwe call an indicator strain. these strains were susceptibleto killing to only one component of the vaccine.in the interest of time i'm not going to show you results fromthe three arm because there was no difference between[ inaudible ] for those that receive two doses and those thatreceive three doses. the robust immune responses withseveral two dose schedules.

one month after the second doseachieved tithers greater than four.there was no difference in sero response rate.i do want to mention we did not have an indicative strainidentified at the start so analysis was done post.because of this not all analysis was conducted.in this study there were tithers to the strain.i will show you a study later on where much lower tithers.included here are the corresponding mean tithers forthe study done at baseline one

month after one dose and onemonth after two dose schedules for each component.robust responses were indicative for each component and for allthree two-dose schedules. tollerability were assessed.both were most common in both vaccine group and placebo grouprespectively. in terms of reactive.it was higher in recipients of the vaccine compared to placebobut majority were mild and moderate.there was no evident of increasing severity withsubsequent doses and tollerable.

18 months after the 0 to 6 monthschedule. 22 months after.that is shown here. you can see the percent ofsubjects greater than four and you can see the majorityretained protective levels with 75% to 95% maintaining abovefour. it did not appear to have impacton the persistence of the sero response rates.antibody persistence shown on this slide at 18 to 23 monthsafter the completion of the two dose series.you can see it did wayne however

they remained higher thancorresponding prevaccination tithers.i would like to finish up with the review of the study done tolook at different formulations of acwy vaccine in u.s. andpolish subjects between 10 and 25 years of age.in this study there was one arm where 4cmenb was used as acomparter. this is the arm i'm going toshow you data for in the next two slides.here is percent of subjects with tithers greater than 5 for eachof the corresponding and

[ inaudible ] at baseline andone month after a two dose series.you can see that baseline here compared to chile were muchlower however robust73% to93% o 5.finally, here are the mean adolescents between 10 and 25years of age. so i would just like tosummarize by saying 4cmenb has been accepted by fda andpriority review status has been granted.we believe 4cmenb generated protective immune response aftertwo doses.

this is confirmed in a smallu.s. study. persistence of antibody wasdetected two years after last dose and no difference betweensubjects receiving two doses and thrthree doses of vaccine. we have begun to collect reallife experience with this vaccine.the vaccine was approved in 35 countries.there have been over 1 million doses.from the safety data generated which includes over 30,000 dosesin princeton and uc santa

barbara we can say that overallwas identified. cerns for any thank you.>> i think we will hold questions and comments until thenext presentation. so if we can have mr. wassil --i'm sorry, dr. york. thank you.>> thank you. good morning.i'm dr. laura york, the meningococcal lead at pfizer.i'm really pleased to be here to talk with you today.dr. sun stole my thunder. we were approved yesterday.i am speaking on behalf of many

people at pfizer who work veryhard along with fda to license this product to ourmeningococcal group b vaccine. you have been introduced to itas rlp2086. i want to see if i can advancethis. so our vaccine is based onprotein 2086. this is a surface exposedprotein. you can see from the schematicaccessible to antibodies expressed at over 97% ofinvasive icelesliislips. the gene is rarely absence.they segregate into two distinct

subfamilies a and b as shown inthe fileo genetic tree. the length of the lineidentifies the similarity between the variants.you can see that the variants within a subfamily are highlyrelated and have over 84% sequence identity.the vaccine contains two lip dated variants, one from each ofthe subfamilies to give complete protection across the twosubfamilies. this vaccine design of bivalentlip dated protein was supported by data.we looked at monovalent vaccines

or bivalent vaccines.this is in rapids. and you can see that we thenlooked at the immune sera to kill diverse strains thataddress subfamily a or subfamily b as shown on the x axis.we looked at the ability to kill in terms of rabbed compliment.you can see that there are good responses across the variationin the a subfamily but not so much across the variants thatexpress b variant. similarly, you can see thepredominant subfamily specific response if inoculating animals.good responses that express the

b variants but not across the a.so very much a subfamily predominant response and only avaccine that contains both of these subfamilies provide theprotection across the strains that express either a or bsubfamilies. this data really supported usmoving into clinical trials and we opened in 2008 and began thediscussions with the fda very collaboratively to define thelicensure pathway in the u.s. a significant step was thedecision that we could use the human compliment as thecorrelate to predict protection.

in june of 2012 we came toagreement on the end point based on the measurement of responses.all of our ongoing studies were modified to provide prospectiveblind data. that length of time that it tookto come to the agreements really i think reflects the complexityof defining what the end points could be that would reallyevaluate and demonstrate a vaccine would be able to protectbroadly across the variation that we see in this protein.so these next few slides i will show you the licensure criteriaagreed upon.

we would have to have sufficientnumbers of u.s. subjects to show safety and the response.in a clinical trial there are limitations in the amount ofserum you have, to be able to test you have to have validatedstrains. and so you cannot -- you arelimited in the number of strains you will actually be able totask. however, in phase one and twoclinical studies we had data that clearly supported andconfirmed the information that we had developed in thepreclinical studies that the

immune sera following threedoses was able to demonstrate activity against strains bearingdifferent variants cht these are shown by the blue dots on thetree. we came to agreement that theresponses against four men b test strains was the end point.you have the four strains. so strains were selected in theunbiassed fashion. these strains represent theepidemiology strains in the u.s. the variants expressed are nothomologous. you can see in the orange dotand the test strains that we

have for the licensure criteriaare b 24 and b 44 are expressed a 56 and a 22.so they are not homologous to the vaccine components.the end points for our studies are -- we have five end points.the proportion of subjects achieving greater than four foldincrease from baseline to post dose 3 for each of the fourstrains. this takes into accountbackground level and defines the clear vaccine benefit.i have to point out that the minimum response is hsba titherof greater than 1 to 16 which is

higher than what has beenproposed proposed.and a fifth end point, one to 16 [ inaudible ] for all four teststrains. which is really demonstratingthe ability of the antibody elisitted in a individual torecognize across the diversity and will predict activityagainst the diversity of the antigen.there are also prespecified thresholds for the lower boundof the confidence interval for each primary end point.very stringent end points define

this vaccine will be able toprovide that broad protection. the clinical development planfor our rlp2086 was designed for implementation.you can see there were a number of different studies conductedin the u.s., europe and australia.in addition to large safety studies and clinical lotconsistency a number of studies were conducted to look atevaluating the vaccine when given with recommendedadolescent vaccines. the studies, a number of themare completed and a number are

still ongoing.at the time of the outbreak and towards the end of 2013 we had asignificant body of data available and importantly anumber of these studies, the three identified here, safetystudy evaluating administration of hpv 4, safety on dosingschedule done in the eu, the hpv study done in the u.s. and thesafety with a vaccine used in adolescents in europe.these three studies were designed for a different purposebut the data generated in those studies were done using thevalidated strain and kpreszing

those.it was possible for us to move forward and submit ourapplication to fda for accelerated approval andpriority review as was opened about this morning.we submitted that on june 15 and as you know we have approvalyesterday on october 29. we are very excited about it.the licensure was based on the clinical data from pivotaltrials involving over 4,500 subjects demonstrating safetyprofile and responses that met all of the prespecified endpoints.

because it is an acceleratedapproval there are conditions. we do have to provideconfirmatory data verifying the data in these pivotal studies.and those data will be provided from the ongoing studies thatare well underway and those would be submitted postapproval. the indication and usageindicated for active immunization to preventmeningococcal disease caused by serogroup b.the approval is based on demonstration of immuneresponses as measured against

four serogroup b strains.the effectiveness has not been confirmed.as i said in terms of the accelerated.it is administered on a 0 to 6 month schedule.these tables, the next two tables, show you the data fromthe pivotal study. study one being a study with hpvdone in the u.s. study two is the two versusthree dose schedule in the eu and another studied threelooking at administration of the vaccine with a dtap containingvaccine used in adolescents in

europe.you can see that the end point, the individuals with four foldrise 30 days post dose three on the 0 to 6 schedule, the strainsused expressing and the success criteria of the lower bound areshown with the lower bound with a 22 having to be greater than75. the compass and end point isshown in the lower bound if that is greater than 75%.very rigorous end point that will define that the vaccinewill be effective. if we focus on theadministration of the vaccine

rlp2086 and the responses youcan see it is a high proportion of individuals that respond toeach of the four strains with the four fold rise in thetither. and the response again is veryhigh. similar results were seen instudy two and you can see again a high proportion of individualsresponding with a four fold response to those indicatorstrains representative of the strains in the u.s. and the highresponse in terms of end point. the antibodies being able torecognize across all four

strains.administration of the vaccine with hpv 4 does not impact theresponse. the similar response rates interms of four fold rise and the subjects achieving greater thanone to eight for all four strains.and when given with dtap-ipv the four end points that were lookedat in this study met the four-fold rise and the lowerbound criteria for each of the four strains.you can see across all four of these three studies but fourcohorts very similar responses.

i'm showing here in this tablethe data that actually make up that composite response.the percentage of subjects achieving the tither afterreceiving the full vaccination series.the same study one in u.s. and study two and three in the eu.you can see the responses are very robust with a highproportion of individuals achieving that greater than 1 to8 tither after receiving the vaccine.in summary the responses to the bivalent, elicits responses andcompleted trials that met all of

the licensure end points andwith other regularatory agencies.the criteria designed to demonstrate responses that havepotential to provide broad protection against diversestrains. i think this is well illustratedin the exploratory analysis. it is looking at the ability ofthe immune sero against serogroup b responses to recentu.s. outbreaks. this is a small study with postdose three and presero in nine individuals from one of thestudies.

you can see there is asignificant rise presented to subjects that achieve the fourfold rise are high against the islip from university b that areexpressing a b 24 variant. that is one of the variants inour test strain so perhaps it is not unexpected.the percent response is very similar to what we had seen inthe pivotal studies. and the response against thosein university a is also similarly very high percentsubjects achieving four fold rise showing evidence ofactivity against the strains

which express a very unique hpvvariant to b 153. in terms of evaluation ofsafety, the safety data in over 4,500 subjects were submitted tofda. this is across seven clinicaltrials. demonstrated acceptable safetyprofile. majority of events were mild tomoderate in severity. the most common were pain atinjection site, fatigue, headache, muscle pain andchills. the vaccine is demonstrated whenadministered with hpv 4.

the rates of faes werecomparable 1.7% versus 1.6%. the table shows you local andadverse reactions of pain, redness and swelling withinseven days after each vaccination in the u.s. triallooking at hpv either alone or [ inaudible ] you can see ratesof adverse events are higher in those receiving the vaccine ascompared to saline. the most common was pain butmild to moderate. systemic adverse reactions areshown in this table from the same u.s. study.fever, headache and fatigue.

again, higher rates of thesesystemic reactions in those receiving rlp2086 as compared tothose receiving hpb. the rates were low and generallymild to moderate. there were no fevers over 40.you can see importantly there is no increase when rlp2086 isgiven with hpb. in summary it was designed toprovide broad protection against men b.the binding proteins one from each subfamily.it is a conserved factor which protects.it has been evaluated in

adolescents and young adults whoare at increased risk of meningococcal disease.the data met prespecified end points established with the fdapredicting protection against prevalent meningococcal bstrains. it has a favorable profile whengiven alone or with other vaccines.it is designed to provide broad protection against men b.fda licensed serogroup b vaccine will only be realized withstrategies that go beyond rate control and subjects atincreased risk of meningococcal

disease.thank you. thank you much.i think we are open for any questions.dr. karron. thank you.so i have a couple of questions for dr. york and then a coupleof questions for dr. york and mr. wassil.with respect to the pfizer vaccine, i was wondering if youhad any data on achieving protective levels after a singledose? for example in an outbreaksituation if you were to use

this vaccine.>> so i don't have data on a single dose for you.i can tell you what those data are.it's between 35% and 50% response rate after a singledose. i can show you these data in thestudy done in the eu looking at two versus three dose regimens.you can see the response of tither greater than 8.and there is a high percentage of subjects achieving thatresponse. and then we look at differentschedules of 06 and 02 you see

responses are quite significanthowever these wouldn't have met the criteria based by the fdafor licensure. so there is a very goodresponse. that was actually my secondquestion was the two versus three doses.and then the question for both of the presenters is sort oflongest data that you have on duration of protection, durationof tithers and also do you have any data on administration withacyw vaccine? we are generating persistencedata now.

we have studies where subjectswere enrolled in new protocols to extend the study.with the acceleration of the five you have to have peopleactually go through that time. you can look at the persistencebut we are generating the data and it will be available andprovided to the work group as soon as they are.acyw we have a study that is completing soon.those data will be available in the next couple of months andwill be provided to the work group.we will have a number of vacc e

vaccines.>> dr. art reingold? sorry.part two. so for novartis we demonstratedpersistence for up to 23 months. i showed that data here to thecommittee. in addition we did collect datain the uk in university students that went up for 11 months, aswell. those were similarly robust.we also plan to do studies with use of acwy vaccine.we don't have those results now. dr. art reingold.>> do we know about the effects

on carriage?>> in terms of carriage it is very difficult in a prelicensuresetting. we did try and exhibit somedemonstration of carriage reduction in the uk inuniversity students. we gave 1,000 doses to one groupwith 4cmenb. while we didn't meet our primaryend point one month after completion when we did follow itup between three months and 12 months we did see statisticalreduction in carries of around 26% in acwy and b islips.>> can i just -- since you are

asking both companies, we havenot actually looked at our vaccine in terms of being ableto impact carriage. new acquisition.so it is very difficult to actually set those up and beable to ascertain those reductions in acquisition of newcarriage. it's not getting rid of existingcarriage. so we haven't done those studiesto look at our vaccine but have been looking at the possibility.>> my questions were asked by dr. karron.>> so the parent of two

teenagers going to issue a pleahere. we are talking about anotheradolescent vaccine of three doses in less than a year whichmay or may not be aligned with recommendations for othervaccines. we are lucky to get a teenagerinto the doctor. we have to pay more attention toaligning these schedules. right now we know meningococcaland the hpv completion rates are lousy.they are not where we want or need them to be.i fear that [ inaudible ].

thank you.my question is for the novartis product.you are targeting several subcapsular proteins and i amwondering if you have data on other serogroups outside of typeb. we have limited data onprotection demonstrated for non-b serogroups.there is a publication on serogroup s where we were ableto cover there. and we have done work in the uk,germany and france as well as brazil and argentina where welooked at some strains and we do

cover them very well between 30%coverage all the way up to 95%. i know you didn't ask me thatquestion but if i could follow up and say that it is a proteinfound, a meningococcal protein. so we have preclinical orexploratory analysis. the vaccine was really developedto be used for prevention of men b.>> dr. baker. same question, a little moredetail. both of you said against othercapsular serogroups. can you say which ones or isthat too hard of a question?

well, the gene is found inall of them. we have data that shows againstw. when you remove you are stuckwith the same specific demonstration of the response.we have done testing in argentina and coveredexceptionally well. does that mean -- we don't know.we would have to do the same analysis.the reason we are hesitant to give actual information aboutwhat is pertinent in the u.s. environment is we haven't testedin the u.s.

there is an outbreak occurringin the uk right now. we cover that exceptionallywell. there are many lists that areprevalent in terms of the cause of human disease everywhere inthe world and especially in the u.s.thank you for your presentation and for your answers.>> do you have any data on immuneo compromised persons andhiv patients or any plans to do those studies?>> we have no data at this time though we have looked at thepossibility of following up with

those studies, as well.>> well, we have not looked at hiv patients.we have as a post licensure commitment to europe haveinitiated a study that is ongoing in rome and it has beencompleted. so we expect results of thatsoon. and dr. larry pickering.>> i have two questions. i couldn't find in here theadverse event which is most common in adolescents and thatis syncope. dr. karron, to follow up, wewere unpleasantly surprised with

quadrivalent vaccine we thoughtwe need one dose and found out we need two.can you give us a better projection of how long theantibodies will last for some prediction of duration ofprotection? we have not done any modelingin that context. we have done modeling in termsof looking at potential impact and estimating times ofdepletion of that antibody over time.we haven't done that to predict the actual information.since we don't have persistent

data at this point we have notactually done that. and i'm sorry your firstquestion was syncope? really the most common things wesaw were pain at the injection site.>> so similarly in the clinical studies you don't typically seesome of the reports. we distribute over 1 milliondoses, over 100,000 we know have been administered.we have seen a few cases reported in post licensuresetting. in terms of modeling we have 23months persistence in chile.

we have 11 months in the uk.so we have been able to do some modeling which depends upon, ofcourse, the protection against these indicator strains and notall of the varieties of strains circulating out there.based upon that we estimate between six to eight yearspersistence on this vaccine heavily based on modeling.>> forgive me. thank you for thispresentation. my question is to both.do you have data about safety and for how long will last inchildren when it is given with

[ inaudible ] why i'm askingthis because we introduced the quadrivalent meningococcalvaccine for children four years ago and since that time all ofthe cases of meningitis in children less than six monthsand it is type b. so as i said, we are -- thevaccine was studied in 10 to 25 year olds and we have looked atadministration with the routine immunization, the other routinevaccinations given in adolescents.we will have data very soon. i am a little confused andsort of trying to clarify.

pfizer's vaccine has been fdaapproved for general use, if i'm understanding correctly.novartis approved for special situations?were they both used? novartis has not beentechnically approved for use by fda.it was done in princeton under a cdc sponsored clinical programfor both. seeing a lack of additionalquestions, if we can have -- i'm sorry.>> i was just clarifying that it was just licensed yesterday foruse in the u.s.

if we can have ms. jessicamacneil come up and present on epidemiology of serogroup bdisease in the u.s. i will by describingcurren with focus on adolescents and adultsand college students followed by a brief review for groups athigh risk of group b meningococcal disease.the first group is the active bacterial core surveillancesystem. abcs is active surveillancesystem that collects data on culture confirmed cases in tenstates.

cases in the abc sites can beprojected to the u.s. population to estimate incidents.the surveillance system is a passive surveillance system thatall states and territories report data to.and it captures information on cases including cases confirmedhowever serogroup and outcome information has been limited.since 2005 serogroup and outcome information has beensupplemented by data from sta statehoostatehealth departments to improve quality.in the united states the

incidents of meningococcaldisease is at a historic lowism in 2013, 564 cases were reportedamong persons of all ages. declines have been observed forall serogroups including serogroup b which is notincluded in the quadrivalent meningococcal vaccine.in addition despite among adolescents much declineoccurred prior to incidents of high level of coverage.the incidents of meningococcal disease is higher among childrenless than one year of age. there is smaller peak in diseaseamong adolescents and young

adults.in that age group approximately 40% of disease is caused byserogroup b. this figure shows incidents ofmeningococcal disease for adolescents during two timeperiods. during 2005 to 2007 and solidlines are during 2010 to 2012. what you can see here is thatincidents have declined for serogroup b and serogroups c andy combined in the more recentt years but serogroup b diseasecauses about the same uz mount of disease as serogroup c and yin the age group.

the change is likely the resultof quadrivalent vaccine use in this age group.the estimated annual cases from serogroup b and serogroups c andy meningococcal disease are shown in this table.we estimate serogroup b declined from 161 per year toapproximately 48 to 56 cases annually in the recent years.the case fatality ratio from serogroup b is 12.5% which isslightly lower than for serogroups c and y combined.among adolescents and young adults the case fatality ratiois roughly half of that observed

for serogroups c and y combined.information on college attendance for meningococcalcases is collected. during 1999 through 2012, 29% ofserogroup b cases in all 18 to 23-year-olds attended college.we can apply that proportion to serogroup b cases reported inthis age group to estimate the number of cases of meningococcaldisease nationwide. in the united states in 2012approximately 61% of young adults completed high school andenrolled in college, therefore we estimate that there areapproximately 16.6 million

college students in the u.s.in 2008 to 2012 there were plksly 11 cases annually withone death in the age group. this is 37 cases and two deaths.the incidents of serogroup b disease in college studentsduring most recent years of 2008 to 2012 was 0.1% compared toincidents [ inaudible ] among all 18 to 23-year-olds.while the incidents and number of cases of serogroup bmeningococcal disease among college students has continuedto decline there have been five outbreaks.these have been described

previously but had between twoand 13 cases per outbreak and lasted from a few days to nearlytwo years. fortunately outbreaks remainrare in the united states but each cause significant anxiety.to summarize with wide spread use with vaccine serogroup bcauses 40% of meningococcal disease cases in this age group.approximately 50 cases occur among 11 to 24 year olds withone third of cases occurring in college students.serogroup b are sporadic in college students recentoutbreaks have been due to

serogroup b.i will switch gears and discuss groups at high risk formeningococcal disease. three groups are considered highrisk. first group includes medicalconditions that place them at increased risks includingfunctional and anatomic [ inaudible ] in additionmicrobiologists are at higher risk.these groups are recommended for vaccination for quadrivalentvaccine they are at risk for serogroupthe deficiencies are rare.

individuals with persistentdeficiencies often develop recurring infections.our treatment has not been previously included in therecommendations for meningococcal disease butcreates a compliment deficiency by binding and inhibiting theportion of the compliment cascade.several individuals in the clinical trial have reportedlydeveloped meningococcal infections.persons with functional or anatomic also appear to be atincreased risk.

the data are less compellingthan risk. this group includes persons withsickle cell disease and the ratio is elevated.microbiologists are also at increased risk for the disease.a high risk ratio was developed for those who developedmeningococcal infections likely because of increased exposure toorgani organisms.the majority of cases among microbiologists were not limitedto research microbiologists. an estimated 100,000 clinicalmicrobiologists and 400 research

microbiologists that work withmeningococcal in the u.s. the final high risk groupincludes people in the risk group.they only cause about 2% of the u.s. cases.as an example of the increased risk in recent serogroupoutbreak princeton university there was an increased risk formeningococcal disease and roughly 7,500 people recommendedfor vaccination. in the recently publishedguidance for serogroup b outbreaks the threshold has beendefined as two cases for less

than 5,000 persons.this table summarizes risk groups that we have gone throughand includes available data on cases that have occurred.excluding at risk population and outbreaks we estimate less than300,000 individuals who fall into the high risk groups.only a handful of cases have been documented these groups areknown to be at high risk and are currently recommended to bevaccinated but remain at risk for serogroup b disease.in summary, the incidents of meningococcal infections isdeclining.

in recent years approximately 50cases of serogroup b meningococcal disease occurredin adolescents and young adults each year.in addition persons in high risk gro recommended forvaccinations remain at risk for thank you.>> and i think we will move to dr. manisha patel's presentationand then open it up for questions thereafter. so the meningococcal workgroup has been discussing serogroup b.so for this talk i will be

providing a summary of keypoints regarding the vaccin and the work group'sconsiderations for men b vaccines in the u.s.development of men b vaccines have been challenging.the poly saccharide capsule is the vaccine target but it ispoorly imuniogenic for men b. men b vaccines that target otherantigens such as outer membrane vesicles have been [ inaudible ]these vaccines are strain specific and provide limitedcross protection with heterolog s strains and have limitedefficacy in younger children.

ideally vaccine targets wouldrequire antigens to be an essential gene, have relativelylow diversity and surface exposed.recently several outer membrane proteins found across allmeningococcal strains regardless of serogroup have beenidentified that generally meet the criteria.binding antigen ropromotes bacterial survival in the blood.although these proteins can be found on the majority of men bstrains they are antigenically diverse and can impact vaccineeffectiveness.

there are two men b vaccines forpersons 10 to 25 years of age being considered in the u.s.as mentioned in the earlier presentations rlp2086manufactured by pfizer and is a three dose series administeredat 0, 2 and 6 months and includes both subfamilies andwas licensed yesterday by fda. 4cmenb is a two dose seriescontained subfamily b variant 1, nhba, and a 1.4 which is sametype used to control the new zealand epidemic.it was licensed in europe, australia and canada and wasadministered to almost 17,000

participants under an expandedinvestigational new drug protocol to control twooutbreaks in the u.s. in light of the outbreaks it wasgranted priority review designation.because of the low incidents of meningococcal disease in theu.s. prelicensure trials using clinical outcomes require verylarge sample sizes and are not feasible.hsba has been shown to correlate with protection againstmeningococcal disease and is based on studies conducted inthe 1960s that demonstrated

bacterial antibodies wereprotective in military recruits. bacterial antibodies with peopleimmunized during various outbreaks correlated withprotection. based on these data it wasestablished as the marker to infer protection with vaccinesduring the 2011 meeting. however, there are severalchallenges in assessing with men b vaccines.first evaluating clinical efficacy in higher incidencecountries would not be appropriate for licensure in theu.s. because of molecular

epidemiology differs betweencountries. the measurement is specific andrequires validation each time a parameter is changed.and because of the antiogenic diversity bacterial activitybetween multiple strains is needed to address crossprotection. however, the number of strainsthat can be tested is limited by methodology which would requirelarge volumes of sera and a source for each strain tests.because the vaccine targets and the number of vaccine targetsdiffer between the two vaccines

selection of the four primarystrains to assess was performed differently for each vaccine.for 4cmenb it was designed individually using pooled human.for rlp2086 it was using individual human sera from arepresentative collection of circulated strains in the u.s.the differences in the strains selected and the method in whichthey were selected is important to consider when interpretingdata. a second key difference in howit was assessed for the two vaccines is the primary endpoint.

the primary end points werepresented earlier by the manufacturers.in summary 73% to 93% of adolescents demonstratedtithers. for rlp208675% to 100% ofadolescents demonstrated following three doses dependingon primary strain tested, study population and end point used.recognizing primary end points differ is important whencomparing vaccines. the poly saccharide capsule isconserved among strains. therefore vaccines that targetthe capsuletypically do not

require assessment of coverage.because the vaccine coverage are antigenically diverse withincirculating men b strains in the u.s. a multi bacterial approachcan be helpful. this includes determining thepresence or absence of the gene, level or expression of theantigen and activity by hsba. in this study the firstst twofactors were assessed. 650 men b islips were collectedand then sequenced for the three different targets.the purpose of this slide is just to show you the degree ofgenetic diversity in the

subvariant circulating in theu.s. genetic sequencing showed thatall men b islips contained it and 59% were subfamily b orvariant 1 and 41% are variant 2-3 contained only in rlp2086.because nata is found in less than 10% of islips that werevariant 2-3 which is not included in the vaccine based onthis analysis nata would increase.nhba is diverse. and then 1.4 included in 4cmenbwas found. addressing coverage can becomplicated.

for rlp2086 sequence analysisand measurement of surface expression was performed forrepresented collection of 1,200 strains of which 432 werecollected from surveillance sites.their analysis demonstrated variability between subfamiliesas well as surface expression of fhbp.in a subset of islips those with moderate or high levelexpression of fhbp was predicted whereas there was lowercorrelation with those with lower expression of fhbp.novartis used a different

approach.because there are multiple antigens contained there arelimitations on how many strains can be tested.the meningococcal antigen typing system is developed to measurecross reactivity as well as the level of expression of eachantigen to predict bacterial activity against a broad numberof strains. it was bridged in a subset ofdiverse strains and found to be greater than 80% predictive ofactivity when one antigen was expressed above a certainthreshold and greater than 90%

when at least were expressedabove a certain threshold. based on analysis 4cmenb isestimated to cover 91% of strains.differences was estimated by the manufacturers is important inunderstanding how well each vaccine will protect againstendemic disease. so in summary there are two menb vaccines available in the u.s. 4cmenb and rlp2086.demonstration of coverage against diverse strains will becritical for evaluating vaccine effectiveness.last, there could be potential

differences in coverage betweenthe twogroup considerations for men b vaccines in the u.s.jessica presented earlier rates of meningococcal disease havereached historic lows and are decreasing for all serogroups.vaccination with is recommended for adolescents with a boosterat 16 years of age. increasing coverage with thesevaccines have contributed to decreasing rates of diseaseamong adolescents, however men b disease continues to contributeto about 40% of meningococcal cases with 50 cases reportedannually among adolescents in

recent years.there are a number of challenges to keep in mind when consideringuse of men b vaccines in the u.s.coverage has only been estimated.although we have a little data for 4cmenb.the impact will be unknown until vaccines are used more broadly.the multi dose schedule makes implementation challenging.it is important to note the burden of men b disease is lowand not all cases will be prevented by vaccination.the work group has been

discussing a number of differentoptions for use of men b vaccines to address theimmediate need of protecting high risk groups.the work group is considering vaccination of persons withmedical conditions high risk of meningococcal disease.the work group has been reviewing available data anddiscussing options for routine recommendations for expandedgroups. although the vaccines werereviewed or are currently undergoing review through anaccelerated pathway there is

still additional data needed forboth vaccines to inform policy decisions including duration ofprotection, safety of vaccination high risk groups aswell as other age groups and additional safety data.a number of the studies are ongoing and will be reviewed bythe work group once the data are available.as i mentioned, the work group has prioritized considerationfor vaccination of high risk groups in persons greater thanor equal to ten years of age. as jessica presented earlierpersons with high risk medical

conditions account.based on guidelines for use of men b vaccines, vaccinationwould have been recommended for all five outbreaks reported oncollege campuses over the past five years, approximately 60,000people. the overall goal will be toalign the high risk and outbreak recommendations for bothvaccines. thus, the current plan for thefebruary acip meeting is to present language for thosegreater than or equal to 10 years of age for high riskmedical conditions,

microbiologists.for the june and october meetings we will review evidencefor expanded target groups including grade and economicimpact analysis and present guidelines for all serogroups.in conclusion, considerations regarding use of men b vaccinesin the u.s. will be complex. additional data followinglicensure will help inform policy decisions and the workgroup will continue to review data on men b vaccines as itbecomes available and engage in discussions on use of vaccinesfor expanded groups.

we were hoping to get feedbackon this two approach as well as additional data thecommittee would like presented at future meetings.that is it. thank you.>> i want to thank you both for the very nice well organizedtalks. these were just wonderful.i open it up to questions to the committee or liaisons.dr harrison. it is licensed elsewherestarting at 2 months of age. i was wondering what plans arefor licensure in the u.s. down

to that age range.>> so in terms of licensure we have decided that we madeprogress enough on acwy vaccine. that has shown two formulations.we were trying to go forward with an acwy vaccine in the u.s.but that is several years away. other questions?dr. baker? i have a question on theepidemiology and it is not relevant to the age group thatyou are targeting. so if you look at collegestudents, the current incidents is 0.01 per 100,000 yet ininfants less than 1 year of age

serogroup b specific it is 1.5per 100,000. do you have any data within thatless than 1 for the first six months and has anybody thoughtjust to raise -- it is a rhetorical question -- aboutmaternal immunization? a lot of the disease is inyounger infants. i think your question aboutmaternal immunization is a great one.>> if we say high risk, ifs is would you -- i would assume shewould be vaccinated. another question is, whattravelers to serogroup b

hyperendemic or epidemic areas?>> we haven't really considered that at this point but it issomething to discuss. so just a question, what arethe considerations for potential use in microbiologists who manyare over age 25 given that the license recommendations is 10 to25? so the granularity ofmicrobiologists recommendations we are discussing within thework group. at this point what we aresuggesting individuals greater than or equal to 10 years ofage.

the difference is as you getyounger the doses change, we expect that it is similar forthe older age groups. but this is, again, something wewill continue to discuss within the work group.>> is the work group discussing for college students a routinetype of recommendation or only consideration in outbreaksettings? i was not clear on that.>> so the outbreak, the sort of high risk recommendations thatwe are considering for february, that is the outbreak response.the routine recommendations,

college students, adolescents weare discussing that. there is a lot of data that weare still waiting to receive. we are actually reaching out tothe non-abc sites to get a better understanding of collegecases within other states that are not abc.a lot of data still to review. i'm curious at this point nowthat there is a newly licensed vaccine here.do we have a price on those two vaccines for the u.s. market?>> angela wong representing pfizer vaccines in the u.s.our priority currently has been

about securing supply which weexpect shortly. our decisions of our pricing thwhich this approval has taken place is still being finalized.as of today i do not have a price for you but we will havepricing shortly commensurate with the supply that we areadvancing as rapidly as possible.>> thank you. as our vaccine is notlicensed yet as we all know we do not discuss pricing prior tolicensure. thank you.>> i think because the vaccine

is available now the firstquestion i'm going to get in the college health world is whenwill the vaccine actually be available because our age groupis included in licensure. so we are working as quicklyas possible to add vaccine supply.we expect within the next two to three weeks for this to beavailable for pfizer. up at the microphone, please.>> i just wanted to emphasize that it was licensed to preventmen b disease. the discussion of f the coveragithink the fitree addresses

coverage and the fact that thisis a protein which is conserved and present in all men b will beused to protect that bug, its function is to protect againstthe immune system. and the other thing is that, infact, we have moved very fast to license this vaccine and i knowthe work group is working very wondering if there .is -- because the vaccine was developed actually to prevent,not to say it is not useful to using control, would the aciplike to see data on the use of this to prevent outbreaks inuniversities brought forward

sooner because of theacceleration of having a vaccine to speak about?and what information would you need for that?persistence data i can understand in terms of routinerecommendations but do you need those data to move this forwardin that risk group? gentleman at the microphone.>> i have a comment about the epidemiology which has beenshown. if i understand correctly youhave shown data up to 2013 where basically in the age group weare talking about is that 50

cases of meningococcal b with12.5% mortality. now, that data is up to 2013 butif i look at what happened in the last year we have threedeaths in that age group, one at georgetown and one in san diego.basically that means with mortality of 12.5 you will need300 cases more or less per year to justify that mortality.so i'm not challenging the data before 2013, but clearly in 2014things seem to be different because there are more deathspredicted by epidemiology. that is an observation.the other thing is that none of

this that you are proposing tolook at high risk and outbreak control in the beginning, butnone of the three deaths were going to be prevented by justrecommending outbreak control. i wonder whether -- i mean, weshould reconsider that. thank you.other comments at this point in time?at this point i would like to call steven and beverly ross andfrankie riley to the microphone. we have time for public commenton this vaccine program. and per usual, please state yourname, your association and

conflicts of interest and try tohold comments to about three minutes.>> i am president of the national meningitis association.i have no conflicts of interest. many of you are familiar of myson's story. he died in 1998 of meningococcaldisease. there was a poly saccharidevaccine available but there were no recommendations so my husbandand i did not know to have our son vaccinated.in october of 2000 acip voted to recommend that college studentsbe educated that they were at

increased risk for meningococcaldisease and that there was an available vaccine.it was the right thing to do to protect our children.in 2005 the conjugate vaccine was recommended to prevent thisdisease in adolescents and teens.again, it was the right thing to do.later on the booster dose was recommended to ensure that thesekids maintained their protection.it was the right thing to do. i have heard over and over fromparents whose children have

suffered from serogroup bdisease especially this past year.they all said the same thing, i thought my children wereprotected. they all wanted the broadestprotection possible. i was really thrilled yesterdayto hear that the fda had approved licensure of one of thevaccines and i look forward to the other vaccine being licensedsoon. we now have the tools to protectour children against all five serogroups.we need to do the right thing

and routinely recommendvaccinations. it is the right thing to do.it's what parents do. it's what society should do.we need to protect our children. i also wanted to alert you to anew activity that nma is conducting, we are going toconvene a round table that includes cross section ofmeningococcal advocates including survivors, educators,infectious disease specialists and any others who have a uniqueperspective and knowledge about meningococcal disease.our goal is to prevent the real

life impact of the disease andgive voice to the concerns and view points of those who havebeen affected. we hope to have a report toshare with the acip before the february meeting.thank you. thank you very much.>>> and then steven and beverly ross.>> my name is steven ross. this is my wife, beverly.we are here with the national meningitis association.we are the parents of stephanie ross.she was the student who died

after contracting serogroup bmeningitis. she went to bed one nightbecause she was tired and a few hours later she was fighting forher life. she was an intelligent youngwoman. she was well liked[ inaudible ]. she went on her way to assistanyone who asked for help and some who didn't.she was growing into a leadership role with her phi musorority sisters. thank you for always living yourlife the way it was supposed to

be lived, full of love, laughterand kindness, not just friends but strangers, as well.since stephanie's passing at least two more college studentshave died from the serogroup b disease.when will it stop? percentage of all students werealize these deaths represent a small number but when a studentis one of yours any number above 0 is unacceptable.it is something to think about when they send their childrenoff to college. we shouldn't have to worry aboutthis disease.

let's do the right thing to helpour children. we seem to have the means tostop spreading the disease as evidence by the fact that noadditional cases reported from the princeton campus since theuse of serogroup b vaccination there.you don't want to receive a call as we did.now that the fda licensed we hope that you will recommendthem for adolescents and young adults as you recommend it forcollege students as they seem to be largest group at risk.like us many parents and

students believed previousvaccines protected them against all the serogroups that canaffect our children. in the coming weeks severalgroups will be receiving letters supporting recommendations.some of them are from stephanie's classmates.they want to be able to win the battle over the disease thatstephanie could not conquer. we are here on their behalf andon behalf of her sister who now is an only child and a freshmanat one of the largest universities in the unitedstates.

it would be a tragedy likestephanie's death to see the vaccine approved by the fda butnot widely recommended. thank you for sharing thestory of your loss with the committee.>>> i'm frankie millie. i'm the national executivedirector of meningitis angels. you shared stats today and iwant to share a quick stat with you.my mother's twin brother died from diphtheria and her fatherfrom tetanus and cousin from influenza.as i grew one of my best friends

had polio and was in an ironlung. later he did survive and in awheelchair and very crippled for the rest of his life which wasshort. my sister had chickenpox and wasin the hospital for three weeks. we almost lost her.she had serious infections and pneumonia from that disease.my mother died from pneumonia a few years ago.as you know ryan died from meningococcal.it went from perfect health to blood coming from every orificeof his body.

my only child i watched him dieneedlessly. and i don't share this with alot of people, but i have been married to my current husbandfor 41 years. before that i was married for ayear to show my mother i could. unfortunately, i blew ascholarship to college. i came away with half thealphabet. i had tmj from being slappedaround and i had hpv which ultimately led to a hysterectomywhich took the part of my body that carried ryan.it was like losing him all over.

we now have ebola.we don't have a vaccination. i want to commend these peoplein this room and everybody at this cdc who has worked so hardagainst this disease to protect us all.you are doing a great job and keep it up.i know you don't hear that. i'm here to tell you you do.if you look at meningococcal disease and you compare it toebola, it is really similar. only sometimes meningococcaldisease works much faster. and when they survive they areless d

left devastated.as you move forward there are things i want you to consider.in our organization we have hundreds of families across thecountry. we just took in a new family.their 17-year-old son died in march of this year frommeningococcal b. i talked to scott yesterday andhe was on the way to canada today to take his other son toget vaccinated against this disease.he can't go through this again. many parents don't have thatopportunity to go to another

country and get their kidsimmunized. so we need to be protective ofthat. i also want you to consider wehad an outbreak in 2000 in our school district of 6,500.we had 15 cases of meningococcal disease.when i called the health department at the state and toldthem and asked if they knew about it they didn't and theyhadn't had any reports. they came down and we immunized45,000 people in three days in that outbreak.the problem was when i went to

the hospital to find out whythey weren't reporting they said it cost money to send thespecimens and we are just not going to do it even though it isrequired. i want you to consider that thecase rate may be higher than we think it is because a lot oftimes when the kids are brought to the e.r. they have symptomsand bum bombarded with antibiotics.we know that ryan's death was caused by meningococcal.i am afraid we are missing the actual rate of this disease inthis country because we are good

at our jobs or because we arenot good at our jobs, either way, that can go either way.finally, i just think that in a country as great as ours and thework that you have all done and the work that industry does tobring these vaccines to us, it takes years of research,development, money. some people research and neversee, never live long enough to see their research come to pass.we can prevent this disease. we can't prevent ebola right nowbut we can prevent this disease. nobody in this country shoulddie from a vaccine-preventable

disease.so moving forward -- and i know you have a lot of work to dowith this and a lot of unanswered questions but i havefaith in this committee right here that at the end of the dayyou're going to do the right thing and recommend this for age15 through 25. please, i beg you, let's don'tgo back to the day when we only vaccinate those kids living indorms. meningitis doesn't stop at thedorm room door. thank you so much for your workand your kindness.

thank you for your comment.>>> so i have absolutely no conflict of interest withrespect to pfizer or novartis. i just want to make that clear.to one specific point and one general point.the specific point is as was said, 29% of disease inadolescents occurs in college students.obviously, that means 71% occurs in non-college students who aresmoking or going to bars, et cetera.so a recommendation for college students is in a sensediscriminatory.

the more general point is onethat is obvious or sort of a 400-pound gorilla.i want to bring it out publically.the two companies have spent millions of dollars to developvaccines against what might be called a minor disease in termsof incidents. and if these vaccines are notrecommended then this puts a poll on vaccine development fordiseases that are less prevalent.i hope you will keep that in mind for the future, becausethis has great implications for

future vaccine development.>> thank you. dr. baker?>> just to add to that, what vaccine preventable disease inthe united states causes a mortality?and i would second the comment about age group as opposed tocollege. finally something i strugglewith as chair of meningococcal work group when quadrivalent wasrecommended. i still struggle with it and idon't have an answer. i know you are in the hot seatin february it sounds like.

it is very difficult to know howmuch money we should spend for prevention of rare diseases.and i think that this will increasingly trouble the cdc,acip members, the aap if it is a childhood disease, acp if it isan adult disease. it is very, very difficult giventhe past history. it's not so long ago, really, alittle more than a decade when vaccines were cheap for theprevention of childhood diseases.it is just a comment. thank you.>> i felt like i have lived

through this once before when iwas on the acip and head of the polio vaccine working group inthe late 1990s we made a decision to move from the oralpolio vaccine to the inactivated vaccine.we hadn't eliminated vaccine associated polio.to do that cost roughly $4 million per case of batchprevented. we believed we could afford it.six to eight cases there. roughly 50 cases here.i think narrowing this to a high risk recommendation or collegerecommendation will cover 15 to

50 cases occurring.if we want to prevent the disease that we can prevent weneed to make a broader recommendation.>> i really appreciate the last three comments.and just reflecting back on slide number 10 from thepresentation, the rates in college students was 0.01 caseper 100,000 and three times that for age 18 through 23.are there further comments? if none, i think we move on tothe typhoid vaccines. if we can have dr. barbara mahoncome up and introduce the topic.

goodmor talking about typhodand typhoid vaccines now. the current acip recommendationfor typhoid vaccination was published in december of 1994.and so the objective has bee update this recommendationbecause it is so long out of date.an acip work group on typhoid vaccines was not convenedbecause the statement doesn't include substantive changes tothe recommendations. in 1994 three vaccines wereincluded in the statement, the live attenuated vaccine, thesubunit vaccine and phenyl

vaccine.the first two are still marketed and available in the unitedstates. the third was discontinued in2000. and one of the major changes inthe update is the removal of that vaccine that is no longeravailable in this country. in the 1994 recommendation thestatement that either oral ty 21 a or parenteral is preferable ismade because of the highly reactoogenic nature of the heatphenyl. the vaccination is indicated forthree groups, travelers to

endemic countries which continueto be the major group which receives vaccine, householdcontacts of chronic typhoid carriers and laboratory workerswho work with cultures or specimens.these groups have not been changed.in today's session dr. brendan jackson is going to presentinformation on typhoid fever and typhoid vaccines, a summary ofproposed updates to the typhoid vaccination statement.there will be time for discussion and vote.the statement is outdated.

we are proposing no substantivechanges in recommendations. the updated statement reflectschanges in vaccine availability with removal of whole veilvaccine that is no longer available, new data onepidemiology and efficacy and effectiveness.i will turn dr. jackson now.>>> good morning. so i will provide briefbackground on typhoid fever. typhoid fever is caused bysalmonella. as opposed to most -- infectionis acquired through contaminated

food or water.incubation period from 6 to 30 days and illness has insidiouson set including increasing fever, malaise, headache andanorexia. it can result in septic shockand intestinal hemorrhage and perforation.it can be treated with one of several agents.antibiotic resistance is common. case fatality ratio wasreported. less than 1% the current caserate less than 1% with early treatment.enteric fever is broader term.

typhoid fever is caused by threesero types. the most common cause of typhoidfever is type a. this cause is indistinguishablefrom typhoid fever. it is important to note currentvaccines provide little or no protection against para typhoidfever. there are estimated 20 millioncases annually resulting in about 200,000 deaths per year.in comparison there are estimated 5 million cases eachyear. para typhoid fever caused bytype a responsible for growing

proportion accounting for halfof cases in some areas. multi drug resist anance is comfor type b. growing rates of drug resistanceincreases importance of vaccination as preventivemeasure. in the u.s. there were about 400cases of typhoid fever reported each year from 2007 to 2011 and90% of these about were travel associated.among the travel associated cases 80% to 85% involved travelto three countries, bangladesh, india and pakistan.one study finding that about 20%

of travelers had receivedvaccine. the most up to date vaccinerecommendations for travel can be found at cdc.gov/travel.currently it is recommended for travel to africa, asia and latinamerica. travel to eastern europe.i will now provide background on the typhoid vaccines.there are two available. the live attenuated vaccineadministered in oral capsules over one week.the poly saccharide vaccine is given as a single dose.it is approved for persons age 6

years and older.if continued exposure is expected repeat dosing isrecommended every five years currently and the polysaccharide vaccine re-administered every two yearsif continued exposure is expected.no booster effect is observed for either vaccine.conjugate vaccines are available in a few countries.both available vaccines have moderate efficacy in emdemiccountries. the ty 21 a vaccine had effcaseof 48%.

two excluded trials and may haveoverestimated the protective effect, efficacy was 79% at 5years and 62% at 7 years. the same systematic review theefficacy of the poly saccharide was 59% at year two.no efficacy studies have been conducted among u.s. travelersbut a study found 80% effectiveness of typhoidtolerated with low rates of adverse eventsbased on data from trials. the field trials, two eventswere more common than among placebo and this was fever and acombined measure of any mild

adverse events with risk ratioof 1.7. in an analysis of post marketingdata there were an estimated 0.6 events reported for 100,000doses distributed. serious adverse events definedas death, hospitalization, permanent disability, lifethreatening illness. the poly saccharide vaccine painand swelling at injection site were more common with risk ratiopoint estimates at 8 and 6. in the various post marketingstudy the vaccine was associated with a similarly low rate ofserious events.

contraindications includehypersensitivity to components of the vaccine.and then acip's general recommendations suggest livebacterial vaccines are generally contraindicated in pregnantwomen. the vaccine is contraindicatedand should not be admitted. because of the vaccinecontaining live bacteria persons should avoid three days beforeand after administration of the vaccine.however, certain prophylaxis medications can be taken at thesame time as vaccine.

also, ty 21 a can beadministered with other vaccines including yellowvac polyshould be tot women onl clearly needed.we will show minor updates. the first group for whom vaccineis indicated if you have heard are travelers to areas withrecognized risk. there is no substantive changesto this one and direct to current cdc website for mostupdated guidance. this includes risk is greatestto travelers to developing countries including latinamerica, asia and africa and

those who have prolongedexposure to possibly contaminated food and drink.the text notes multi drug resistant strains have becomecommon in many regions and cases of typhoid fever treated withdrugs to which organism is resistant can be fatal.the recommendation reminds clinicians that typhoid vaccinesare not a substitute and the protection can be overwhelmed.no substantive changes here. so it is also indicated forpersons with intimate exposure. household contact to documentedtype e chronic carrier.

chronic carrier is defined as[ inaudible ] the change here to the 1994 guidelines are thatcarriers are specified using the word chronic.the purpose of this change is so the recommendation is notconstrued and not just chronic carriers.the final group for whom vaccine is recommended aremicrobiologists and laboratory workers who work with culturesof salmonella type e or who work in laboratory environments.this text was suggested by laboratory colleagues to clarifythe recommendations which was

microbiology laboratoryworkers. so regarding choice of vaccinewe have no substantive changes. no preference is given betweenthe poly saccharide and oral vaccines.both are acceptable forms of immunization.in choosing a vaccine clinicians should consider approved agesfor use, dosing and contraindications andprecautions. the inactivated wholesalevaccine that is no longer available has been removed.the current statement is

updated.no substantive changes are proposed.and the updated statement is presented today for acip vote.it reflects change in availability, new data ontyphoid epidemiology and newer data on efficacy and safety.thank you. i would like to thank the twopresenters for a very good presentation.acip strives to on an every five year basis review and renew,reaffirm, retire or revise statements.this is now a 20-year-old

statement.and, again, the biggest change has been the loss of one of thevaccines and some minor wording changes.we did have a little bit of a discussion as dr. jackson knowsin terms of whether or not this should be subjected to a formalgrade review. a couple of things, there hasbeen kind of a shortage of excess time around cdc over thelast few months or so rumor has it.the other thing is that really nothing has changed from theoriginal.

there have been systematicreviews that have basically suggested strongly that there isefficacy as previously stated and the safety has not changedat all. i wanted to make the comments.>> thank you. i note that 90% of the cases oftravel associated and of 80% to 85% are travel tobangladesh, india or pakistan. i was curious as to who thesetravelers are. i'm thinking analogous tomalaria. are these people born in theunited states and traveling to

the countries or are thesepeople born in those countries and come to the united states tolive and have gone back to be with family and visit?this is very important because if the latter, perhaps asentence or two might emphasize that those are also individualsat risk because we see those folks often not taking malariaprophylaxis when they go back to their home of origin?>> i'm not familiar with the statistics of those visitingfriends and relatives from there.>> most of the travelers are

people visiting friends andrelatively and not necessarily born in those countries butvisiting friends and relatives. perhaps a sentence or two toinclude those folks or highlight the fact that those folks alsoare at risk. in your attempt to clarifylaboratory workers you confused me.are you talking about workers who work with the organism or alaboratory where they may get a patient returning traveler andtherefore come to their laboratories specimen.have you quantified how many

people may be in contact withthe organism? we were just revisiting thatrecently. i think it is a concern havingthat broad recommendation that it may apply to more people thaninitially intended. there are cases that continue tooccur among laboratory workers but they are few and farbetween. so one thing we might considerdoing is adding the word frequently.and we could consider revising that in general about thehandling of specimens.

quick question.does the oral vaccine still need to be refrigerated?>> yes, it does. thank you.>> and dr. pickering. to follow up.this is not a group that need to be immunized but we see childrenexposed to people who travelled to these areas of the world andcome back. the children who are exposed tothose individuals who have travelled develop typhoid fever.>> another follow up. there seems to be relativelyfew, small proportion of cases

from latin america.has the risk decreased there? that goes for the question.i don't recall the precise percentages but we see travelassociated cases from latin america.i think i read overall incidents has been decreasing in latinamerica. we see cases.we see a number of cases from the caribbean.those areas are still recommended to receive vaccine.>> dr. smith? thank you.this is gene smith, cdc.

i have a question i don't knowif you can answer it but i was struck by only 20% of travelersreceiving vaccine. my daughter went to india lastsummer so i paid for the oral typhoid series.it was about $50. is this a cost issue or lack ofawareness? maybe you don't have thatinformation. we really don't have thatinformation. we would like to get it.but i think that the issue that was brought up i suspect isreally central to the low rates

of vaccination which is thatmany of the travelers who are at risk for exposure are people whoare visiting friends and relatives and who simply don'tthink about it, just doesn't -- it feels like going home andthey are not thinking about vaccination for travel.so i think that efforts to reach those groups would really be themost effective way of decreasing rates of typhoid in thiscountry. so mean they are likenonresident indians? how do you have thatinformation?

so we know whether people aretraveling to visit friends and relatives because it is reportedas part of the enhanced surveillance for typhoid.i can give you an anecdote from a colleague who is of indiandissent. he kind of got a startled lookin his eye and said my father is visiting india right now and itnever occurred to me to get vaccinated.>> it probably has the same rules of 28 days away from otherlive attenuated vaccines such as measles?is that true?

if it is you may want to pointthat out in the statement. sure, i will definitelyreview the information again. as i recall from the 2011general recommendations i believe the language said therewas not a contraindication to administering these livevaccines together with typhoid. simultaneously is fine.if you give one you need 28 days between another live attenuated.>> thanks for the comment. we will need to check.i think because it is orally administered that may be thedifference.

the biology is different.>> thank you. i was puzzling a little bit overthe precaution that the vaccine should only be given to pregnantwomen if clearly needed. i was trying to figure out caseswhere it might be indicated but not clearly needed.are you thinking for instance going on a cruise and it has aport or two in central america but you are not going to havethat prolonged contact? that the sort of circumstancewhere maybe pregnant women maybe shouldn't be vaccinated?>> that statement comes directly

from the current vaccine label.there was no change from that. we definitely could discuss thatmore but i don't think we have given exact thought to how itshould be interpreted. it is based on the fda approvedlabel. i think the kind of situationthat you are bringing up would be exactly the sort of situationthat this would apply to. so someone who is clearly goingto be in a setting with very limited access to clean food andwater for a prolonged period of time during pregnancy but therisk benefit balance would be

shifted from someone like thehypothetical person you just raised.>> we may have an answer in terms of spacing.>> with respect to the 28-day rule it is injectable vaccinesbut not oral vaccines so would not apply in this case.>> that goes for that clarification.dr. decker? with respect to questionabout pregnancy language, that is regulatory languageprescribed by code. other comment?as this is a recommendation for

a vote and withstanding -- notwithstanding the changes that we have suggested to betterdescribe the frequency of exposure for microbiologists andnuances in terms of pregnancy including the language in termsof the spacing not being an issue and in terms of a liveoral vaccine there was one other that is escaping me at thispoint in time, but if that's the case with these minor changes wehave mentioned, do we have a motion for approval?and do we have a second? further discussion?wonderful.

and to your left we will move todr. riley. yes.>> yes. >> yes. yes.>> and the motion passes 13 for, 0 against and 2 absent fromvoting. and i can't say the work groupfor their efforts, but i do thank dr. barbara mahon and dr.brendan jackson for putting this together.let's have dr. tom shimabukuro for proposed changed to thevaers reporting form.

portingy i will give you anoveri will give brief on vaers, go over the form andthen activities and next steps. so vaers is national spontaneousreporting. we have received about 30,000reports annually. signs and symptoms of adverseevent are coded using medical dictionary for regulatoryactivities. it was authorized by nationalchildhood vaccine injury act of 1986.as far as submitting a vaers report there is a process andthat is roughly 30% of reports

in recent years.most reports come in as mailed hard copies or faxed hard copiesof the paper form and then rare instances via telephone througha vaers customer service representsive.the rough break down is about a third are vaccine providers,about a third are manufacturers and about a third are patients,parents or other. there are variability amongindividual vaccines. so this is a miniaturizedversion of the current vaers form, been in use since 1990.it must be completed by hand.

you have to download it, printit. forms are mailed or faxed to thevaers contractor and it requires manual processing and data entryprocedures which are fairly resource intensive and timeconsuming. hard copies are scanned anduploaded into the vaers image database.there is a database of traditional research-typedatabase and then an image database of the actual report.i just want to show you this. these are a couple of screenshots of the vaers online

reporting tool.we prefer that vaers reports get submitted online.even after we implement the new electronic form we prefer theonline reporting tool. it has the same field of thevaers-1 form. the disadvantage of the onlinereporting tool which is a barrier that the interface willtime-out. for security reasons you mustcomplete the report in a single setting.if you leave the report for a certain period of time it willtime out and you will lose the

report.so the objectives for the vaers 2.0 form proposed was to createa fillable, savable electronic reporting form, update datafields to address current vaccine safety information needsand changes in vaccine practices over time, modernize theappearance and format of the vaers form, modernize reportingprocedures specifically to implement electronic documentupload capability. i will discuss that a little bitfurther, ensure data collected on the vaers 2.0 form allowscomparisons.

we want to make historicalcomparison between the data. so why are we doing thisrevision of the vaers form? some fields on the current vaersform have limited public health and/or regulatory value.we determined that through meeting with our own iso staffthat work are vaers data on a daily basis and colleagues thatuse vaers data for regulatory purposes and other importantinformation isn't being collected.some fields are no longer relevant due to changes in theimmunization program.

the language in some fields isconfusing and needs clarification.fields used in paper reporting are for manual processes will nolonger be necessary. so certain fields like themanufacturer's use or the vaers contractors use will no longerbe necessary and the manufacturers are moving to adifferent reporting process. and also new fields such aspregnancy are needed because of new recommendations and patternsof vaccine uptake. we heard this from otherstakeholders that make

recommendations for new fields.so continuing on. so why revise the vaers form.hand written, mailed and fax paper reporting is aninefficient way to conduct vaccine safety surveillance.paperless reporting would eliminate most manual processingand much data entry. it would mitigate problems withpoor hand writing and nonstandard reporting, takeadvantage of smart features such as auto population where if wehave a valid data birth and vaccination we can populate theage of the patient and

incorporate drop down menus, popup instructions and logic checks which are important because wecan address the issue of illogical answers like on setdate being before the vaccine being administered or before thedate of birth. it will allow forstandardization of data elements and address the complaint ofgetting timed out. the vaers form is an electronicfillable savable form and can be completed in stages and multiplepeople can work on it and it avoids the problem of losing anelectronic report if you can't

complete it in a single setting.and then manufacturers are transitioning to fullyelectronic reporting using the message standard.and so it made sense to transition nonmanufacturerreporting to electronic. so actions that have alreadyoccurred, there has been initial internal development review andrevision. revision is ongoing.there is external review by immunization partners at cdcwithin the federal government and outside the federalgovernment, cognitive interviews

with potential reporters toinclude physicians, pharmacists, parents and patients andrevisions based on results of cognitive interviews.cognitive interviews are commonly used to validatequestions in surveys. we presented to the task force,conducted follow up interviews with sample of individuals thatcompleted the initial cognitive interviews.we presented to the advisory commission on childhood vaccinesand national vaccine advisory committee.our contractor conducted

computer testing of the smartform with potential reporters and we made revisions based onthe results of the computer testing.and we recently presented at the fda electronic post marketsafety reporting updates meeting.so our proposed reporting method would be that for thiselectronic form the reporter would download the vaers formfrom the vaers website. currently you have to downloadthe vaers-1 form in order to print it.downloading the form from the

website.completing the form on a computer, saving the vaers 2.0report as an electronic document in a local environment and thenuploading the report to the vaers contractor through thevaers website. the contractor extractathizedata into the vaers data by passing much of the manual dataentry and manual processing and would do reviewing and redactionon the data. the vaers contractor wouldgenerate an individual report for the vaers image database.we won't be scanning reports.

we will be creating a reportbased on the extracted data and post it on the image database.i will say when we do implement reporting we will still haveoptions for manual reporting like faxing and mailing at leastin the short term, maybe until some of the technology andconnectivity catches up. so this is miniaturized versionof the current vaers form which is available online at thatlink. and then this is the vaers 2.0form proposed. and you have a full scaleversion of this in your binder

or there were handouts for thisparticular presentation. so the changes to the vaers formcan really be summarized by three categories.there are tweaks. there are revisions and then newquestions. so tweaks are reallyclarifications or saying things more plain language or minoradditions to certain questions or data elements.some of the data elements stayed the same so there was no change.a revision would be a change in the language to get at the sameinformation.

so an example of a revision onvaers-1 form there is a question that says responsible physician.and when we tested that question a lot of the physicians feltthat they had a problem with the way it was answered because aresponsible physician implied responsibility for the event ofthe outcome, possible liable. they recommended we make changesto that. our change was to change thequestion responsible physician or best health care professionalto contact about the patient. that is an example of therevision.

the overwhelming majority ofchanges are tweaks or revisions. there are several new dataelements. there is a question aboutpregnancy status and questions about race and ethnicity andthere are several other new questions that if you look atthe vaers form and compared side to side the 2.0 with the 1 youcan see there are new questions. so next steps i will present toacip which we are doing today. public comments solicitationthrough federal register. we have one minor change to makeon the current draft of the form

and that will get posted on thefederal register for 60 days. we will make final revisions anddevelop the platform to accept the electronic vaers 2.0submission and update the online reporting tool to reflect thenew data elements. once we finalize the newquestions we will update the online reporting tool with thenew questions and implement the vaers 2.0 forms and evaluate thecompleteness and quality of vaers data, really a pre-postcomparison. so that's my presentation.i will be happy to answer any

questions.>> thank you very much, tom. i have two really quickquestions. first, will there be any forestanswers in the new form? no.there will be pop up reminders. if a person puts in an illogicalanswer there will be a pop up reminder cautioning them thatthat answer may be wrong. i don't know what the exactlanguage is. the person always has the optionto override that or leave anything blank that they wantto.

if there are answers left blankthere will be reminders saying you left these fields blank butyou never get a hard stop on the form.>> the other question is it sounds like this is going to begoing to an ex ternal contractor for extraction and then thequestion is whether or not there will be verification of theincoming information and then what do you have after it comesback from the contractor. currently the vaers reportintake processing and data entry is done by a contractor.so there is really no difference

in the way things are happeningnow except instead of paper reports getting mailed or faxedto contractor we hope most of the forms will getelectronically uploaded to contractor.>> so the likelihood is actually less variablity going from formsto final data. we hope so.>> thank you for now including pregnancy specific informationin this, but just as one plea. it says if you are pregnant, yesand then it says in the parenthesis that is where youput the pregnancy information

and goes into box 18.the biggest problem with the form and sort of then trying tofigure out what to do with the information is we almost knoweither the due date or gestational age.you can't time when the vaccination was given.so i think you have to force people to put due date downhere. you mentioned that it should bedone and then in 18 and then on the back under item 18 it nevercomes up again to put the pregnancy information in there.it is such an important critical

element that i feel like itneeds to be sort of bolded somehow.it makes pregnancy information from this useless.we keep trying to draw conclusions about vaccines andpregnancy and the vaccines given in third trimester didn't causea birth defect. until we get the due date orgestational age we are stuck. we are always going to have sortof this bad data that no one knows what to do with.>> so in previous iterations of the form we had much more detailon pregnancy.

and we actually -- i think threeof the physicians we did interviews with were obgyns.the feedback we got was not just with pregnancy but with the formin general was simplify it and have people fill in informationin the text box. we thought that by putting checkboxes in or specific questions for specific informationinitially we thought that was a good thing and that would help,but when we got to the cognitive testing which actuallychallenged a lot of our assumptions, the feedback we gotwas direct people to put that

information in the text box.so i think -- i'm not suggesting that youput in like birth defect and miscarriage -- they can writethat in if they want, but i think the one critical piece ofinformation you need to know is edc, estimated due date.however you want to call it. you can't draw anything from itotherwise. we have some instructionsbelow the question on box 8. would you suggest puttingsomething in there to highlight? we can maybe -- maybe we canwork to figure out what are the

most important things and putthem in the front of thoseions. either that or on thatwhere it says if you checked off pregnancy yes then put a littlebox saying you are forced to put in the gestational age.that is it. the rest of the pregnancy stuffif you want to write it down you can put it in the box under 18.it is such a critical element. that is a common thing that obswrite down all the time, the one box we do fill out, honestly.>> i think we have some of the -- i will say just as ageneral statement there are

probably a lot of people in thisroom who have seen versions of this and made great suggestionsand suggestions that are perfectly reasonable.if you don't see them reflerefl on here, number one a pure spaceconsideration. and number two, it may not havetested well when we actually went out and tested it.i think we can -- i think there is probably enough space in thatto work with you to address that concern.>> so two suggestions there. one would be in 18 just add asimple question, if pregnant,

due date.on the electronic version you can say if 8 is marked yes whenyou get to 18 you simply give another question under 18 ifpregnant, due date. so it is just a positive only ifmarked number 8 yes. and just to follow up onthat, as i understand it this is a nice improvement.it is essentially you are filling out a form completelyjust online instead of hard copy and maybe for version 3 when youget to that you can take advantage of computer technologythat allows branching points so

not everybody has to see theentire form but whatever is relevant for what they arefiguring out so a different pathway for people who ispregnant where you collect information but other folksdon't see those variables. for the online reporting toolthat may be an option. i talked about like the smartform. it is actually not that smartlike the online version we can build a lot of things into it.but the pdf smart form is actually limited in itssmartness.

comment up at the microphone.>> thank you. new york city immunizationprogram. so we happen to have a fairlyrobust registry in what we do now is we have an adverse eventreporting module that takes the information from the vaccineevent that was reported so it automatically pulls out the lotnumber, vaccine information and we generate a vaers form and faxit. so i think having the electroniconline system will be great because we will transition toactually be able to

electronically submit it pullingall of the information demographics that we have on achild, vaccines, lot numbers, et cetera that they receive thatday and pull it and send it to vaers.it is more a comment about the stakeholders that you mentionedand not to forget about program managers because we take therecommendations from the online form and build that into ourregistries to try to improve reporting of adverse events aswell as quality of the data that you are getting.so thank you.

and one more comment.>> american college of nurse mid wives.we would whole heartedly support the statement that without anactual estimated date of delivery your data is useless.please add that. thank you.>> i assume that pertains only to pregnant patients.thank you very much. i will say one problem withputting the pregnancy into the box 18 is you would be amazedwhat people will write if you tip them off to write aboutsomething.

i think we used to have muchmore descriptive language in box 18.in the cognitive interviews a lot of physicians were sayingjust say describe the event and leave it to us to just report itin there. so sometimes you can -- from ourresearch doing this -- sometimes the more detail you ask the moreproblems you potentially create or unintended consequences.>> i just want to make the comment that our data gatheringdoesn't stop when we receive the form and in particular forpregnancy that has been a high

priority for our officeobviously for a few years now. when we get reports of pregnancywe have gone on to get additional detailed informationabout the pregnancy, the delivery, et cetera.we do get the information about birth outcomes and date ofdelivery, expected date of conception and such.we do get those if they are deemed important and follow updata gathering. thank you for that comment.>>> other comments? seeing none, we can have abreak.

you guys have done wonderfullyfor a three-hour stretch. we have a ten minute break and resume at about 10 after 11:00. we have a ten minute break andresume at about 10 after 11:00.