respiratory tract infection drug that is safe for pregnant women

>> so welcome to day two of thejune 2016 advisory committee on immunization practicesmeeting. this morning we'regoing to start out first with a little bit of unfinishedbusiness from yesterday. but first i wanted to mention that we will have public commentboth at the end of the day today and also before the vfc vote. so if there's anyonein the room who would like to make publiccomment, please register

in the rear of the room. in addition, i wantedto point out that for the committee members thereis a copy of some public comment from debra sullivan which has been circulatedto all of you and we wanted to be sure that you saw that. and with that, i think wewill turn to the vfc vote. is there any otherunfinished business from the committeethat i'm overlooking?

just wanted to be sure. and we will turn to dr.santoli and the vfc resolution. thank you. >> the recommendationthat was made yesterday. so the purpose ofthis resolution is to update the resolution to remove live attenuatedinfluenza vaccine or laiv from the vfc program. there's two componentsto this resolution.

there's the iiv component, whichis injectable influenza vaccine, and then there'sthe laiv component. the iiv component of theresolution will not be changed. the laiv component of the vfcresolution will be removed. and this is our standardstatement, you saw this yesterday, thatwhen their recommendations that update certain things thatare linked from the document that this we incorporatethem by reference and these are aciprecommendations regarding

influenza vaccinationthat are published in the next six months,and that is the resolution. >> thank you, dr. santoli. are there any questionsfor dr. santoli? yes, dr. thompson, >> yeah, could you just clarifywhat does that mean in terms of payments for physiciansfor vfc-ordered vaccines if they've already ordered them and potentially alreadypaid for them?

what are the implications ofthis change for physicians? and also, you know, could youjust clarify what the timing of the decision wouldmean in terms of the current fluseason or expectations? >> sure. so for vfc vaccines,providers receive those. they don't purchase those. they don't pay for those. so we actually provide contractsand make doses available to states for the vaccinesfor children program.

so this is indicating that wewill make vaccines available for children that arecovered by the vfc program and those are thevaccines that providers in the vfc program will getand will be able to administer and they, of course,don't bill for those. they do bill for theadministration fee and that will happen as normal. but this is sort of limitingwhat the formulary will be that the flu vaccinesthat we'll make available

through the vfc programthis year. >> thank you. do i have a motionfor the vfc vote? dr. kempe, i'd liketo make a motion that we pass this resolution. is there a second? >> second. >> second, dr. rubin. any further discussion?

is there any publiccomment in the room? no one signed up but ijust want to be sure. okay, i see none. let's move forwardwith the vote. how about dr. stephens,would you start? >> stephens, yes. >> rubin, yes. >> bennett, yes. >> romero, yes.

>> moore, yes. >> ezeanolue, yes. >> harriman, yes. >> reingold, yes. >> pellegrini, no. >> riley, yes. >> harrison, yes. >> belongia, abstain dueto conflict of interest. >> karron, yes.

>> walter, yes. >> kempe, yes. so we record one no and oneabstention, otherwise yes. so i believe this passes. thank you, dr. santoli. great, so we are going to move on to respiratorysyncytial virus. dr. karron is up. >> good morning, everyone.

i'm really delighted tointroduce the rsv workgroup to you, both because rsv issuch an important pathogen in young children andthe elderly and also because it's actually thatwe have accomplished so much in terms of vaccine developmentthat it's actually time to constitute an acip workgroup. so, let's see. rsv was discovered almost60 years ago in 1957. it's a major cause of lowerrespiratory tract illness

in infants, youngchildren, and older adults. in the us, there are about 150,000 hospitalizationseach year. there are about 180,000hospitalizations in the elderly, but these in the us reallyrepresent the tip of the iceberg and there's a substantialoutpatient disease burden in both populations. rsv is a global pathogenand is a leading cause of hospitalization and seriouslower respiratory tract illness

in children all over the world. despite, as i said,having been recognized as a human pathogen 59 yearsago, a vaccine doesn't exit. there is a monoclonal antibodythat many of you may be familiar with called palivizumab but thatis given as a monthly injection, is quite expensive,and is recommended for only a subset ofhigh-risk infants. so some of us have been workingon rsv vaccines for a long time, and if you think aboutwhere we were, you know,

as recently as 13 years ago, this was the rsv vaccinelandscape in 2003. there were just a coupleof companies involved in making vaccines, developingvaccines, as was the nih. you can contrast that witha current state of affairs. i would just like to saythis is what we call the rsv vaccine snapshot. it's now been updated toinclude monoclonal antibodies. it's maintained bypath vaccines,

which does a greatservice to the community. and for those of you who areinterested in this topic, i urge you to go to the websiteand look for updated versions of this snapshot which comeout about every six months. one of our workgroupmembers, who i shall not name, when we said therewere 60 vaccines and vaccine-like productsand developments, said, "oh, that can't be possible. you must be exaggerating."

we're not exaggerating. that's actually true. oops, i actually -- yeah,i think there is a little, a couple of boxesthat i meant to have on these slides thataren't here. but what i wanted to callyour attention to and i -- yeah, i do have a pointer. wow. is that thereare a couple of -- there are a few productsin phase three development,

two manufactured by novavax, onethat's currently being evaluated in mothers for maternalimmunization to protect young infants and one that has completedenrollment in the elderly. there are a number of otherproducts, but the products in particular that are meant forthe elderly are further along in clinical developmentthan the products meant to protect young children, either through maternalimmunization

or through activeimmunization of the infant. so for that reason, at this timethe workgroup was constituted to focus primarily on theelderly because we anticipate that there could be a vaccinelicensed as early as 2017/2018. so the current terms ofreference for this workgroup are to consider recommendationsfor the use of rsv vaccine in adults 60 years of ageand older and also in adults with underlying medicalconditions. the task of thisworkgroup currently is

to review the epidemiology ofrsv infection and the burden of rsv disease in olderadults, to review the efficacy, immunogenicity, safety, and costeffectiveness of rsv vaccines in older adults and adults withunderlying medical conditions as these data become available, to provide evidencerecommendations regarding the use of rsv vaccines in olderadults, and to identify areas in need of further research for informing potential futurevaccine recommendations.

because it is anticipated that over time there willalso be vaccines to consider for protection of infants andchildren, the terms of reference as well as the membershipwork may evolve over time to accommodate theseadditional needs. but currently with the exceptionof the liaison members, the workgroup was reallyconstituted with its focus on elderly adults in mind. i am chair, i think,for a little bit longer

and laura riley is alsothe other acip member. i particularly wanted to acknowledge lindsay kim, who's the workgroup lead,who you'll be hearing from in just a minuteand sue gerber at cdc, and all of my other colleagueson the workgroup as well. so today you're going to heara brief overview from lindsey of rsv and rsv vaccines,the obstacles and progress in rsv vaccine development,

issues around targetedvaccine populations and considerationsfor rsv vaccine use. in future presentations to acip,you'll hear about the burden of rsv disease in older adults,the clinical trial results as they become available, andcost effectiveness analyses. lindsey. >> so i'll just wait formy slides to come up, but while we havethis dead time, i just wanted tothank ruth karron.

this is probably my lastand only chance publically to acknowledge her leadershipand all of her mentorship as we have startedthis acip workgroup. so good morning and thank youfor the opportunity to talk to you all aboutrespiratory syncytial virus or rsv and rsv vaccines. rsv is a common cause of acuterespiratory infections or ari in infants and young children. fifty percent are infectedby their first year of life

and virtually all children areinfected by two years of age. rsv is the most common cause of lower respiratory tractinfections or lrti among infants and it frequently manifestsas bronchiolitis or pneumonia. it can present with apnea ininfants less than six weeks of age and there's aquestionable relationship between rsv infectionduring early childhood and subsequent development of reactive airwaydisease and wheezing.

in adults, rsv cancause repeat infections after adults are exposed in their early infancyand childhood to rsv. it most often causes an upperrespiratory tract illness but sometimes canbe asymptomatic. when it does causesymptoms, they are more severe than the common cold andusually they have less fever and systemic symptomscompared to influenza. lower respiratory tractillnesses can also occur,

especially among theimmunocompromised, those with underlyingcardiopulmonary disease, and the elderly. and frequently thismanifests exacerbations of chronic medicalconditions, like copd, asthma, congestive heart failure,and obviously pneumonia also. in some cases ofimmunocompromised persons that have rsv, usuallythis can manifest as pneumonia or sinusitis.

mortality rates have beenseen up to 50% or more. this is a table takenfrom an article by dr. falsey in 2014 looking at symptoms in adults 65 years and olderamong different pathogens causing ari. if you look at the red box,it's a bit small, but rsv, the most frequently reportedsymptoms included new or worsening cough at92%, headache at 82%, fatigue at about 80%, andnasal congestion at 72%.

flu and rsv commonly are kindof thought as similar pathogens but they do havedifferent symptomologies and in this slide whatwe can see here is that fever is lessfrequently reported in influenza a infectedpersons at about 52% versus fever -- i'm sorry. flu is reported fevermore at 72% versus in rsv which is 56% in adults. so the next two slides are goingto be a very brief overview

of the burden of rsv in olderadults and we will be presenting to acip later thisyear more detailed data on the burden that exist today. the importance of rsv wasfirst recognized with outbreaks in long-term healthcarefacilities in older adults in the 1970s. in a population-based study, they found that there are177,000 hospitalizations and 14,000 deaths annually,attributable to rsv in the us.

another study in 2012 found that the average annual rsvhospitalization rate was 15 per 10,000 residents. this is a prospective studyover three winter seasons and one county innashville, tennessee; however, what was striking was that thisannual rsv hospitalization rate was very similar to thehospital rate for influenza. another study in 2014 looked atmedically attended rsv episodes and found that there were154 per 10,000 persons

in adults 50 years and older. again, this was aprospective study over four respiratory seasons incommunity-dwelling older adults that were seeking care for ari. in the study, investigatorshere found that there was anincreasing incidence of [inaudible] as age increased. and lastly in a study in 2003,in adults 55 years and older with chronic lung disease,which is a high-risk group,

they found that hospitalizationrate of 18 per 1000 persons and five deaths per 1000 persons and this is usingretrospective data from tennessee medicaiddatabase. so there is a burden ofrsv in the us older adults. now i wanted to change thefocus and actually talk about the virus itself. so rsv is an envelopedrna paramyxoviridae virus, has two major subgroups, aand b, and these are based

on the surface proteins. the viral genome has tengenes that encode 11 proteins, two of which are the f andg, f standing for fusion and the g protein, whichis the attachment protein. these two surface proteinsactually are the ones that induce neutralizingantibody and so far are thetargets for vaccines. however, f is more highlyconserved between the two and, thus, is a vaccine target.

humans are the only source oftransmission and rsv is spread by direct or close contactthrough large droplets or fomites on objects andsurfaces, and these can last from 30 minutes all theway up to six hours. the incubation period is fourto six days with a range of two to eight days and viral sheddingis about three to eight days but can last up to four weeks. there are severalmethods of testing for rsv and diagnosing [inaudible].

rapid test respiratory specimensthat include midturbinate swabs, nasal swabs or nasalwashes are one way. these include antigen assays. now these are very highlysensitive in young children with reports of 80to 95%; however, they have much lower sensitivityin adults, reporting about 14 to 39% due to lowvirus shedding. so it's not the optimal wayto diagnose rsv in adults. reversed transcriptasepolymerase chain reaction

or rt-pcr assays are nowmore widely available and also very highlysensitive in adults with some reportsapproaching over 90%. viral isolation fromrespiratory specimens and cell culture is also amethod to diagnose rsv; however, it can take several days,about one to five days. it's more costly. it's also less sensitivecompared to the current methodsof rt-pcr.

additionally, sensitivityis affected by which laboratory isperforming that method. and lastly, serology is mainlyused for seroprevalence studies, not for patient care; however,the added benefit of serology is that it can actually add tocase finding when we're looking at diagnosing rsv in adults. and studies that lookedat how you diagnose rsv, if you add serology andpcr, they found more cases versus just pcr aloneor just virus isolation

from cell culture alone. the goal for rsvvaccine development is to safely induce sufficientimmunity to protect against serious rsv infections, like lower respiratorytract infection and possibly apnea in infants. the induction of sterilizingimmunity is not required and actually mightnot be feasible. in the late 1960s,

a formalin-inactivatedvaccine went to clinical trials in children two monthsto seven years. unfortunately, there weresome devastating results. it actually impactedthe development of rsv vaccines forseveral decades. and what they found was that seronegative vaccinerecipients had more severe rsv-associated lrtis thannon-recipients when infected with rsv in the subsequentseason.

about 80% of vaccine recipientswere hospitalized versus 5% of controls who neverreceived vaccine. and there were two deaths inthe vaccine-recipient group. later data looking atthe vaccine recipients with serious outcomesfrom this trial and [inaudible] studiesfound that the mechanism was that it caused avaccine-enhanced disease syndrome in rsv-naiveinfants or those that had not yet had primary infection

and that was dueto two main points. one was at the vaccine didnot induce enough neutralizing antibody and number two was itinduced a th2 cd4 biased immune response leading tomore inflammation, more cytokine release and, thus,leading to more obstruction and worse outcomes ininfants and children. so obviously thereare many implications of the formalin-inactivatedvaccine trial, including the fact thatvaccine production,

vaccine development slowed downdue to wanting to know more about the immunology of rsvdisease and immune responses, but also we learned thatbecause of enhanced disease, a nonreplicating vaccine, likethe formalin-inactivated one, was unlikely to be used inrsv- naive infants; therefore, different vaccine typesare now being used for different target populationsand those include replicating or vectored vaccines forthe active immunization of rsv-naive infants andchildren, subunit vaccines with

or without adjuvant formaternal immunization to protect the very youngestinfants, and subunit vaccines with or without adjuvantto protect the elderly and boost their alreadyexisting immunity. so dr. karron earlier presentedthis slide to you, but again, this is the pathsnapshot of rsv vaccine and monoclonal antibodydevelopment. there are 60 plusin development. the one that's circledhere is again the vaccine

that we will be focusing on asthe acip workgroup and for acip and that is novavax rsvf nanoparticle vaccine that currently just finishedphase three clinical trials. there are four vaccine prioritygroups for rsv and that's due to these are thepopulations that are at risk for severe disease. they are neonates and younginfants, older infants and children, pregnantwomen, and older adults. neonates and young infants havethe greatest potential benefit

to the high disease burden. they have the highestdisease burden, the highest mortalityrates; however, there are couple obstaclesto think about here when developing a vaccine. one is that they have animmature immune system as well as that active immunization in this age groupis challenging due to pre-existing maternalantibody

that might suppressan immune response. therefore, the mostpromising strategy for the youngest infantsis maternal vaccination or administration of an extendedhalf-life monoclonal antibody. older infants and children havesimilar issues to young infants, but they have more matureimmune systems and lower levels of maternally acquiredantibodies. so this should lead tobetter responses to vaccines. development right nowis currently focusing

on live attenuated virusand vectored vaccines and several vaccinecandidates are currently in phase one clinical trials. pregnant women are alsoa high-risk population. and the use of a maternalvaccination would include the following objectives: one,to protect the young infants by inducing high levelsof neutralizing antibodies that are transferred via theplacenta to the fetus; two, to prevent maternal-to-infanttransmission of infection;

and three, to protectthe pregnant woman from infection herself. pregnant women wouldnot be at risk for enhanced disease giventhat, as children, as infants, they're already naturallyexposed and infected. and currently rsv f subunitvaccines are in development and vaccine candidatesare in phase one, two, and three clinical trials. and lastly, this is thefocus of the acip workgroup

and for acip is older adults. again, there is substantialdisease burden in this population. an obstacle here wouldbe immunosenescence, the aging of the immune system. currently subunitvaccines are in development and vaccine candidates are inphase one through three trials. the rsv f subunitnanoparticle vaccine, again as we've alreadymentioned,

will be the first rsvvaccine to be considered for rsv fda licensureand use, and the focus of the current acip workgroup. so in the fall of 2015, news media outlets startedreporting the preliminary vaccine efficacy results fromthe novavax trial phase two and early indications reportedthat it was efficacious for rsv in older adults. and the vaccine manufactureris here today

but will also be presentingin future acip meetings, the results of boththe clinical trial two and phase three results. so, therefore, as we deliberatethe use of an rsv vaccine in older adults, there areseveral considerations: disease burden inthis population, appropriate outcomemeasures, immunogenicity, and the correlatesof protection, duration of protection, the costeffectiveness of the vaccine,

implementation issues, andeducation of stakeholders, particularly amongfamily practitioners and those other providers whowould be giving the vaccine and also to the public, whowould be receiving the vaccine. the proposed acip timeline and activities isshown on this slide. this year we hope to present theepidemiology and burden of rsv in older adults in great detail. in 2017 we will be invitingthe vaccine manufacturer

to present phase two and phasethree clinical trial results. correlates, we will discusscorrelates of protection and immunogenicity as wellas cost effectiveness. and in 2018 we will bediscussing implementation considerations, thegrade of the evidence, and have a potential vote. >> thank you, dr. kim. are there questions? i guess not.

i guess we'll move on. but thank you very muchfor that great presentation and i think we're allgoing to be looking forward to learning moreabout rsv vaccine. so next we're going tohave a report on safety of maternal tetanus, diphtheria, and acellular pertussisimmunization, and there are severalpresentations in the session. dr. moro will start us off.

>> well, good morning. so this is -- this session willprovide an update on the safety of tdap vaccinationin pregnancy. there will four presentations. i will give a verybrief background and also describingenhanced surveillance of tdap vaccine safetyin pregnancy in vaers. next, dr. lakshmi sukumaran willdiscuss the findings of study in the vaccine safety datalink

on maternal pertussisvaccination and the structural birthdefects in offspring. next, dr. kathy edwards will describe a study on the safety of tdap inpregnancy in the cisa project. dr. art reingoldwill provide an update on acip pertussisworking group activities. so there were two recentacip recommendations. the first one was in 2011and that one indicated that vaccinated pregnantwomen receive a dose of tdap

and this was to provide infants with maternal transplacentalantibody protection against pertussis duringthe early postnatal months. the next recommendationwas a year later in 2012 and that one indicated tdapshould be given during every pregnancy, irrespective ofprior history of receiving tdap. and the optimal timing foradministration is between 27 and 36 weeks' gestation. at the time of therecommendations,

limited data wasavailable on the safety now during the 2012deliberations, acip expressed the needfor enhanced monitoring and safety studiesof tdap in pregnancy. the cdc immunizationsafety office implemented a comprehensive vaccinesafety monitoring effort for maternal tdap safety and that included enhancedsurveillance of vaers, epidemiological status inthe vaccine safety datalink

on studies in the clinicalimmunization safety assessment project. in 2015, tdap vaccinationcoverage during pregnancy among women who had a live birthwas 42% versus 27% in 2014. so these are the three systems, the vaccine adverseevent reporting system, the vaccine safety datalink, and the clinical immunizationsafety assessment project that were used to monitor thesafety of tdap in pregnancy.

and these are the systemsthat are normally used to conduct surveillance ofadverse events after vaccination or conduct vaccinesafety studies. so in terms of the safety oftdap in pregnancy in vaers, surveillance in vaersfrom october 2011 through june 2015 showed no new or unexpected vaccine safetyconcerns among pregnant women who received tdapor their infants. part of these findingswere presented

at february 2014 acip meetingand have been published. so there were three studiesin the vaccine safety datalink on the safety oftdap in pregnancy. one first study inthe period from 2010 to 2012 did not find anyincreased risk of preterm birth, small for gestational age,or hypertensive disorders. there was a slight increase inthe risk of chorioamnionitis and that presentation was shownin february 2014 acip meeting. next study in the periodfrom 2007 to 2013 looked

at the safety of repeattdap in pregnancy. and there was no increasedrisk of acute adverse events or adverse birthoutcomes for women who had a previoustetanus vaccination, regardless of timingsince the prior tetanus containing vaccine. and the third study at the sameperiod looked at the safety of tdap and inactivatedinfluenza vaccines given on the same day or sequentially

and did not findany safety concerns. all of these three studieshave been published. so i'll provide abrief update on vaers on enhanced surveillance. so this is just --i'm not going to go over in detail on this slide. this just shows the strengthsand limitations of vaers. this is just to point outthat an important limitation of vaers is that vaers doesnot collect information,

does not collect data onthe number of vaccinees. there's no comparison group. and because there is nodenominator, it's not possible to calculate the incidence orprevalence of an adverse event and it's not possible to estimate any riskof an adverse event. so if you see a percentageor proportion, that should not beinterpreted as being a rate. surveillance wasinitiated on november 2012.

vaers database search for report of pregnant women after administration of tdap. that was for women vaccinated from october 2011to may 6, 2016. medical records wererequested and reviewed for all pregnancy reportsassociated with tdap. we also queried reporter or thepatient for prior administration of tetanus-containing vaccine. so vaers received a total 464pregnancy reports after tdap;

5% were serious reports. a little than 50% were themanufacturer was the reporter and the majority or 85%tdap was given alone and 6% comprised reportsof repeat tdap doses. this is just to show inthis slide that the majority of reports are about 80%tdap was given during the third trimester. here we see the pregnancyspecific adverse events reported to vaers.

and premature delivery and stillbirth were the two mostcommonly reported conditions. here we see the infant orfetal adverse events reported there was one reportof a neonatal demise that was reported to vaers. there were four majorbirth defects reported. here we see the non-pregnancyspecific adverse events. injection site reactionsor pain in extremity, systemic reactions were thetwo most commonly reported

non-pregnancy specificconditions. in terms of the reportsof repeat tdap doses in pregnant women in vaers,there were 26 of these reports and this comprised 6% ofall the pregnancy reports. the interval between the currentand previous tdap ranged widely from seven days to 9.4 yearsand the median was 1.8 years. thirteen reports not diddescribe an adverse event, adverse events and the other 13reports are shown in this slide. so in conclusion in vaers,

there were no new unexpectedvaccine safety concerns noted among pregnant women whoreceived tdap or their infants. a limited number ofpregnancy reports with repeat tdap doseswere received by vaers. and cdc will continueto monitor the safety of tdap vaccine duringpregnancy. and i would like to thankseveral collaborators from cdc for working on this project. yes.

>> carol hayes with the americancollege of nurse midwives. could you tell me what therate of guillain-barre is in the general populationthat received tdap compared to the maternal vaccinationgroup? >> that's a good questionbut i don't have the, sorry, i don't have theanswer for that. >> do you want tomto answer that? >> yes. >> could you state thatquestion one more time.

>> yes, i asked what therate of guillain-barre is in the maternal vaccinationgroup versus the generalpopulation that receives tdap. so there were four reports of guillain-barreamong an n of 172. so what's the rate inthe general population? >> i don't think we havethose specific rates. so i would say that pregnancyis a risk factor for gbs but we don't have anydata to suggest that tdap,

maternal tdap vaccinationis associated with guillain-barre syndrome. >> other questions? no? okay, i'll think we'llmove on to dr. sukumaran. >> hi. good morning. my name is lakshmi sukumaranand i'll be presenting a study from the vaccinesafety datalink entitled "maternal tdap vaccination and structural birthdefects in offspring."

and i'm presentingthis study on behalf of the health partnersinstitute vsd team. to briefly reviewsome background, the tdap vaccine has beenroutinely recommended for previously unvaccinatedpregnant women since 2010 in california and since 2011 inthe rest of the united states. as you are aware, in the fall of2012 the acip recommended tdap for every pregnancywith a preference for 27 to 36 weeks' gestation.

and many other countries havealso implemented maternal tdap immunization programs. so the objective of our studywas to evaluate the risks for structural birth defectsfollowing maternal tdap within the vsd. we had three outcomes,any birth defect, major structuraldefects, and microcephaly. microcephaly in particularwas chosen because in brazil there isa maternal tdap immunization

program and there wassome speculation initially that increases inmicrocephaly were due to the maternal tdapvaccination and not zika virus. so this slide shows the sevenvsd sites that contributed data to this study, including ourtwo largest sites in california. this is some coveragedata from the vsd that was published earlier thisyear describing the receipt of tdap vaccine duringpregnancy, by trimester. as you can see, from 2007

to 2013 there is astudy background rate of first trimestervaccinations here in purple and this usually representswomen who did not realize that they were pregnant at thetime of vaccination; however, it is an important groupfor us in this study because most birth defectsoccur in the first trimester. in 2010 there was also anincrease in vaccination due to the californiarecommendation. and in 2013 we had another largeincrease following the latest

acip recommendation. so we performed an observationalcohort study of pregnant women and their infants from sevenvsd sites and we looked at pregnancies ending in a livebirth between 2007 and 2013. we identified these pregnanciesthrough a validated algorithm that is based on administrativeelectronic health record and birth certificate data. we included pregnant women who had continuous insuranceenrollment from six months prior

to their lmp throughsix weeks postpartum. they were required to haveone outpatient visit during the pregnancy. infants were requiredto have birth weight and gestational age available. and if they survivedto 12 months of age, they were required to have fourmonths of insurance enrollment with one outpatient visitduring the first year of life. if the infant died in the firstyear of age, this insurance

and utilization criteriawas not applied. so exclusions were identified from icd-9 codesand pharmacy files. we excluded multiple-gestationbirths and exposures or conditions thatpotentially increase the risk of birth defects, includingmaternal live virus vaccines during pregnancy,pre-existing diabetes, teratogenic medications,maternal or infant torch infections,

and infant chromosomalabnormalities. maternal tdap administrationswere identified using claims and ehr data found instandardized vsd files. we had three exposurewindows that we looked at: less than 14 weeks' gestation, since this is the mostbiologically plausible time period for birthdefect to occur. we also looked at 27 to 36weeks' gestation station, which is the current acippreference for administration,

and any week during pregnancysince tdap can be given at any time during pregnancy. these are the outcomesin more detail. so any structural birth defectwas defined as an icd-9 code from 740 to 759 andan infant was required to have two of the same codes. for selected major structuralbirth defects, we had a list of over 50 defects that affectlife expectancy, health status, or physical or socialfunctioning.

these are ones thatare monitored in the us and european birth defectssurveillance systems and we developed and appliedoutcome-specific algorithms in order to increasethe specificity for identifying these defects. microcephaly was one of the selected majorstructural defects. and we had an algorithmto identify microcephaly, which i will show youin the next slide.

so these are the algorithms forcentral nervous system defects. as you can see, microcephalyis icd-9 code 742.1 and an infant was required tohave one inpatient diagnosis with this code or twooutpatient diagnoses or one outpatient diagnosisand death in the first year. for the statistical analysis, we compared baselinecharacteristics between vaccinatedand unvaccinated women and we used a logisticregression

to estimate propensity scores,which allowed us to adjust for multiple risk factorsincluding maternal demographics, healthcare utilizationduring pregnancy, and maternal comorbidities. we estimated prevalencedifferences using poisson distribution with identitylink and robust variance. and prevalence ratios wereestimated using generalized linear models withpoisson distribution. so now i will reviewthe results.

after our exclusions, wehad 324,463 pregnancies. thirteen percent ofthese were tdap exposed and 87% were unexposed. we had over 3000 women who arevaccinated before 14 weeks' gestation and over 20,000 womenwho were vaccinated between 27 this slide shows the baselinecharacteristics comparing women who received tdap duringpregnancy to unexposed women. maternal age, race, and ethnicity weresimilar between the groups.

and most women whowere vaccinated were between 25 and 34 years old. women who received tdap duringpregnancy were more likely to have adequate prenatal care and to have received anothervaccine during pregnancy. rates of smoking and hypertension weresimilar between the groups. so this slide shows the results of any structural birth defectfollowing maternal tdap.

when tdap was givenbefore 14 weeks' gestation, the rate was 6.3% comparedto 6.2% in unexposed women. for tdap between 27 and36 weeks' gestation, the rate was 7% in each group. and for tdap at anytime during pregnancy, the rate was 6.8% comparedto 6.2% in unexposed women. and these differences werenot statistically significant. now looking at major structuralbirth defects following maternal tdap.

the rate was 1.8% comparedto 1.6% in unexposed women. for tdap between27 and 36 weeks, the rate was 1.7% comparedto 1.6 in unexposed women. again, these differences arenot statistically significant. finally, looking at microcephalyfollowing maternal tdap, when tdap was givenbefore 14 weeks, the rate was 12 per10,000 in tdap exposed and 12 per 10,000 in unexposed. the rate was 10 per10,000 compared

to 12 per 10,000 in unexposed. the rate was nineper 10,000 compared and again, these differences arenot statistically significant. there are some limitationsto our study. we identified birth defects through diagnostic codes usingthe outcome-specific algorithms rather than clinical examor direct review of charts. there is a potential formissing diagnoses in infants if they had lapses intheir insurance coverage.

and also our study waslimited to live births. so we were not ableto study stillbirth, elective terminations,and spontaneous abortions. in summary, maternal tdapvaccination during pregnancy was not associated with increasedrisk of birth defects, including microcephaly,among live birth offspring. these results support the safetyof maternal tdap vaccination for the infant outcomesthat we evaluated. i would like to acknowledgethe health partners vsd team

for leading the study,the cdc collaborators, and other vsd investigatorswho helped out. >> thank you very much,really a nice presentation. dr. harrison. >> so why not do a record review for at least a subsetof your icd-9 codes? >> so we did to a record review when we were developingthe algorithms for identifying the birthdefects, to make sure

that the codes were valid, andto make sure that the rates that we found, the backgroundrates and the vsd were similar to national background rates. and then we used thatalgorithm in order to apply it to the larger dataset. >> dr. reingold. >> so that's a verynice presentation. i know the answerthat you were fine but i'm just curious why youdidn't also look at the effect

of giving vaccinein that interval between 15 and 26 weeks. it's pretty clear from looking at any exposure during pregnancyis going to be pretty much one as well, but i'm justcurious why you wouldn't look. and since we may bepotentially looking at administering thevaccine earlier in pregnancy than we currently do, it mightbe of interest at least to do that calculation and show it.

>> uh-huh. yeah. so we included thatgroup in the tdap given at any time duringpregnancy, but right, if the recommendationchanges for the timing of administration, wecan go back and look at that group more carefully. >> dr. baker. >> given the furorin the discussion about the 2011/2012recommendations

by many acip members atthat time and liaisons, i just want to congratulateyou on performing this study. and the whole second trimesteris going to be looked at and evaluated and i thinkwe'll need that kind of information as we go forward. but it is beautiful,very reassuring data. so thank you. and we definitely have thedata on the second trimester so we can look closelyinto that as well.

thank you very, very much for that wonderfulstudy and presentation. dr. edwards. >> good morning. it's nice to see old friends. so i am pleased to be ableto present our clinical study of tdap safety in pregnant women and to represent myco-collaborators geeta swamy from duke university andkaren broder from cdc

and the immunizationsafety office. the disclaimers notedhere exist. so in order to outline whatwere going discuss this morning, there basically are twocomponents to this study. first, what i'd like to dois to provide an overview of the clinical study oftdap safety during pregnancy and then i'd like to providethe preliminary results from both reactogenicity andimmunogenicity assessment. the background you'veheard several times,

so i will just remind youthat the recommendation for tdap vaccination with eachpregnancy exist and is part of comprehensive monitoringto evaluate the safety of tdap in pregnant women. this study was implemented,funded, and supported by the cdc cisa project. the primary objectives are goingto be first to compare the rates of injection site andsystemic reactions after tdap in pregnant women versusnon-pregnant women.

the secondary objective isto explore the differences in injection site and systemicreactions in pregnant women who received tdap beforethe current pregnancy versus pregnant women who arereceiving their first tdap dose. and finally exploratory studies,which were funded by the bill and melinda gates foundation, were to measure the antibodylevels to pt, fha, pertactin and fim, in additionto diphtheria and tetanus toxoids prior to andone month after administration

of the tdap in both pregnantand non-pregnant women and to compare actual cytokinelevels in women, both pregnant and non-pregnant, with severelocal or systemic reactions after tdap with those withoutreaction using measurements obtained of cytokines before,during, and after the reactions. there are additional studiesin progress to assess the rates of preterm as sga infants inthe mothers who received tdap, to assess the rates ofadditional obstetrical and infant outcomes, and todescribe the health outcomes

and growth parametersthrough six months of life. and those studies are stillongoing and were also supported in addition to the cdc by agenerous support from nvpo. the methods of ourstudy are shown here. this is a prospectiveobservational study of women aged 18 to 45 yearswho received tdap as first or repeat doses at vanderbiltor duke in their clinics. pregnant women greater than orequal to 20 weeks or less than or equal to or greater,less than the equal

to 34 weeks' gestationwere enrolled in the study and these women receiving tdapas part of the routine care. the goal of this partof this study was to enroll 375 pregnant women. non-pregnant women alsoreceiving tdap as usual care or as part of our researchprocedure and followed for one month aftervaccination were also enrolled and the goal was 225non-pregnant women. prior tdap, td or tt historywas assessed by subject report,

medical record review, orstate registry documents, to document vaccine receipt. the rates of local and systemicreaction were assessed during days zero, which was the dayvaccination, through day seven for tdap using memoryaids with severity scales. blood was collected on dayzero and 28 after tdap. and pertussis serology studieswere performed at vanderbilt. the diphtheria and tetanustoxoid serologies were performed at duke.

for those women who had severelocal or systemic reactions, blood was collectedin both those women with reactions and in controls. and cytokine analysis wasperformed on day zero, the day of the reaction,and day 28. pregnancy outcomes wereassessed via chart review and infant outcomes by phoneinterview with their parents, not the infants, andchart review at three and six months of life.

the major statistical analysiswas directed at looking at non-inferiorityanalysis for reactogenicity because the study was reallyhad the goal of looking at the safety of the vaccines. so for this purpose, we madecomparisons of the proportions with moderate severe andsevere reactions during zero to seven days post vaccinationbetween pregnant women and non-pregnant womenand between pregnant women that had receivedprior dtap and those

with no prior tdap receipt. our hypothesis was thatthe rates of moderate to severe reactions in pregnantwomen receiving tdap would be non-inferior to non-pregnantwomen receiving tdap. one-sided statisticaltests were used and the non-inferiority marginof 10% for moderate to severe and 5% for severereactions was used. the following severalslides will analyze the data and present the data thatwe obtained in this study.

as you will see, anumber of the variables on the left side indicatethat that the mean age, gestational age, gestationin weeks at delivery between both study sites,vanderbilt and duke, were indeed very comparableand very much the same as what we have seen fromthe other studies presented this morning. we also had prior tdapreceipt in about 50% of the pregnant women atvanderbilt, about 65% at duke.

and indeed, a higher percentagehad received prior tdap, td or tt. in addition, because the vaccineavailability at our pharmacies, almost all the vaccineadministered with sanofi pasteur adacelvaccine although a small proportion were boostrixvaccines, and is what you had seenin the earlier slides. by and large, these women arewomen who have participated in other vaccine studies

and received othervaccines prior to the tdap. the non-pregnant women are shownhere at vanderbilt and duke. and again, the meanage is very similar. we do see prior tdapreceipt a bit higher with 60% at vanderbilt andalmost 80% at duke. and these non-pregnantwomen were often enriched in healthcare providers, whichmay explain their higher rate of prior tdap receipt. again, you'll see that tdap,

td or tt receiptwas also very high. all of the women inthe non-pregnant group at vanderbilt received adacel and about 2/3 atduke did as well. and again, many of these womenhad received influenza vaccine the previous year. now i'm going to walk youthrough the complicated and busy slide here thatgoes over local reactions within the sevendays after pregnancy.

the local symptomsare shown on the left. the pregnant women in the left,in this left-sided box here, and non-pregnant here, thenumbers indicate those women that completed their diary cardand sent them back for analysis. the definitions of reactionsare moderate, means induration, erythema between 30 to34 millimeters, pain, tenderness interferingwith activity but did not necessitate amedical visit or absenteeism. severe is induration or erythemagreater than 35 millimeters,

and pain, tenderness whichprevented daily activity and resulted in a medicalvisit or absenteeism from work. so as you notice in themoderate severe category, which was the primaryanalysis, the rates of pain in the pregnant women and non-pregnant womenare shown here with more in the pregnant women for thisvariable, but the tenderness, the swelling and the redness didnot differ between the pregnant and non-pregnant groups.

very few severe reactions wereseen in the pregnant women or in the non-pregnant women anddid not differ in their rates. here are two pregnant womenwho had local reactions and are shown here in termsof the size of the reactions. these would indeedhave been severe, but there were a restrictednumber of such local reactions. and when we compare theproportion difference between pregnant andnon-pregnant women, you'll see that for moderateto severe pain, there were,

it did reach the 10% higherlevel in pregnant women. we are not sure exactlythe biology that would explain pregnantwomen having more pain, maybe in general justdiscomforts, but perhaps some of our obstetrical colleagueswill have biologic thoughts about that as well. in terms when we lookat systemic symptoms after vaccination, again thestudy, the slide is organized in very much the same way.

fever is defined as moderate ifit's 100.4 to less than 102.2, severe if it's greaterthan 102.2, and the rest of the symptoms aredefined in the same way, meaning that if they preventeddaily activity and they resulted in a medical visit orabsenteeism, that was severe. you'll see here that the rates of moderate-to-severesystemic reactions and for fever wereindeed very, very low. for feverishness, formalaise, for body aches,

and for headaches were quitecomparable in the pregnant and non-pregnant group. and indeed, when onelooked at the moderate and severe reactions, dependingupon whether women had received prior tdap gap in blue or noprior tdap in blue or prior tdap in yellow, there were nosignificant differences or no indication that priortdap would predispose you to more reactions, asshown on the slide. again, with the sameproportion difference,

you'll see that in this slidefor systemic reactions and also for local reactions thatwhen we compare people who had tdap before and tdap, with or without receivingprior tdap, you'll see that there were nosignificant differences in any of the reactions at the 10% formoderate or severe reaction. so again, very reassuring to us that repeated tdap vaccinationdid not appear to program you for a more severe localor systemic response.

no women sought medicalattention after the vaccine reaction and there were no seriousadverse events reported. i'm now going to outlinethe serologic studies and to compare pregnantand non-pregnant women. in this slide, you'll seethat the antigens are shown on the left: pertussis toxin, filamentous hemagglutinin,fim, and pertactin. the pregnant women areshown on the left again

and the non-pregnant here. and if one looks at day zero,which is pre-vaccination, and 28 days later, for each ofthe antigens in the pregnant and in the non-pregnant women, the antibody responseswere significantly higher with the post-vaccinationfor all of the antigens seen. now when one compares theratio of the antibody titers in the non-pregnantto the pregnant, you'll notice somedifferences do exist.

and this suggests that thenon-pregnant women indeed had higher, significantly higherantibody titers at 28 days after vaccination for pt, forfilamentous hemagglutinin. they also had significantlyhigher antibody titers at day zero for fim,which is shown here, and for pertactin,which is shown here. the reasons for thisand the fact that not consistently do wesee higher antibody titers from pregnant womenthan non-pregnant women,

but it may be that thenon-pregnant women were slightly more highly vaccinated thathad a higher antibody titer pre-vaccination and mayindeed have explained those differences. the antibody titersshown for women who received tdap previouslyand those who had not are shown in very much the sameorganizational structure. tdap before is shown here. no tdap before is shown here.

and again, for all ofthe vaccine antigens, significant antibody riseswere noted between the pre- and the post antibody titers. when one compares the ratio ofthose antibody titers to those who had not receivetdap before and those that had received tdap before,you'll notice that for all of the pre-antibody titers, the no tdap beforehad a lower ratio, meaning that the antibodytiters in no tdap before

for pre-titers wereall significantly less. again, this may have reflectedthe more highly immunized or the higher titersin the women who had received tdap beforereflected in their pre-titers. what is interesting, however, isthat not for all of the antigens but for the fim andthe pertactin, the antibody titerswere higher in those who had not had prior antibody and whether had nothad prior tdap.

whether that reflectsimmune suppression, whether that's astatistical fluke or whatever, i think it's hard to say but there were some differencesseen between these groups. but again, all of them hadsignificant antibody rises. the final segmentof the study i want to outline are thecytokine studies. there were six subjectsthat had severe reactions and they were seen at thetime of the severe reactions.

they were matchedto six controls who did not have severereactions who were seen at that same time and werematched for pregnancy status. as you see here, thecases, there were five cases at vanderbilt, two pregnantand three non-pregnant, and one at duke, non-pregnant,and they were matched for their pregnancy status. what you'll see now area series of cytokines that i will walk you through.

the format of the cytokineassessment are the cytokine is shown here day zero, prior to vaccination is the cytokinelevel, the supplemental visit at the time of the peak cytokineor the peak response, peak local or systemic response which isgenerally two to three days, and then the cytokinelevel at day 28. for all of the individuals,the cases are shown here. the controls are shown here. and for each of thecytokine levels at each

of the determinations, thereare no significant differences between the casesor the controls. and also, remarkably, you'll see that there are really nodifferences in the cases between the beforeand after vaccination, or the time of peak local orsystemic reactions for il-6, il-8, il-10, tnf-alpha and il-5. so in conclusion, tdap waswell tolerated in both pregnant and non-pregnant women.

moderate severe injection sitepain occurred more frequently among the pregnant women,but rates were consistent with the clinically reportedrates for tdap vaccine; 16% for adacel inthe package insert and did not leadto medical visit. fifty-three percent of the pregnant womenreceived prior tdap and rates of moderate severereactions were similar in pregnant womenreceiving their first

or their repeat tdap. both pregnant and non-pregnantwomen had significantly higher antibody responses to all theantigens after vaccination. and the obstetric andfetal outcome data are being collected. this indeed was a veryunited effort consisting of kim fortner, an obcolleague at vanderbilt who worked very hard to enrollour patients, geeta swamy and chip walter and cdc investigators,

karen broder, pedro moro, jennifer liang, and naomi tepper, and alsoagain i want to thank the nvpo and specifically karen blok for their supportand ongoing input. thank you very much. that was a reallywonderful presentation and very reassuring. are there questionsfor dr. edwards? yes, dr. karron.

>> a very nice presentation,kathy. i was wondering ifyou had an opportunity to analyze the antibodyresponses by gestational age. >> we did. and we actually had, you know, read with great interest[inaudible] paper in suggesting that maybe there would be higherantibody responses with younger or with earlier inthe gestation. unfortunately, we were soadherent to our study criteria

that there wasn'tvery much variability in when women receivedthe vaccines. so we would've been -- welooked at that, but there was -- but we were so tightlyclustered in that time period that we did not seethe difference. so i think that we reallycan't adequately address that. >> very nice, kathy,very reassuring. i suspect you didn'thave very many, if any, did you have any women forwhom it was a third pregnancy

and in fact were gettinga third dose of tdap? >> we did not. unfortunately, we havesome highly gravid people, but not quite thatgravid yet at this point. dr. kim. okay. in that case, dr. baker. >> so, kathy, i learned aboutthe duration of immunity to pertussis antigensfrom you and you mentioned that your non-pregnant peoplemight be more highly immunized

than your pregnant peopleas a reason for some of the immune responses. can you comment on thepossibility of differences in circulating pertussis in thecommunity among the two groups of people and was this atime, was the study performed at a time when pertussisactivity, i'm talking about naturalinfection, was high, medium, low, whatever? >> okay, certainly.

well, first of all, thank youfor the question and thank you for your whole career of teaching us how we canimmunize pregnant women safely. so the issues aboutcirculation of pertussis at this particular time,we did not appreciate that that was occurringat either site. we didn't -- we didn't haveongoing serologic studies that might have looked at that. we have not looked atduration of antibody

in this particular studyalthough we are in the process of analyzing data thatwas funded by the nih, where we looked at antibodytiters over two years in women that were vaccinated postpartum. and as you know, the antibodytiters, you know, drop off very, very fast, which is verycurious because, you know, obviously for tetanus anddiphtheria, they do not. so this is very interesting. but even in those patients attwo years, there were still,

you know, some antibody titersfor some of the antigens. so i think and some ofthese women were vaccinated within a year or so inthe non-pregnant group. so i think it's hard tosay, but we don't feel that there was naturaltransmission although, you know, whether there's asymptomaticdisease and, you know, and stacy is acknowledging pertussis is a complicated problem. so i don't know.

>> indeed. ms. stinchfield. >> patsy stinchfieldfrom napnap. thank you, kathy. very well done. so i have a communicating about vaccinating pregnantwomen question for you and it's semantic, so use bothwords "reaction" and "response." and i think one of the thingswhen we vaccinate pregnant women

and they get that local rednessand swelling and the photo that you showed, a pregnantwoman might hear a vaccine reaction equals i can't haveanother one in the future, that it's contraindicated. and i don't thinkthat's the case. and so to turn it to a positivethat's really a local robust immune response and thatthat would be a positive, that that's what youwant to have happen. and so wondering about yourthoughts on thinking about this

in terms of responseversus reaction. >> well, i think that that, youknow, for many years we've tried to look and see whether havinga more vigorous, you know, local immune response translatesto a better serologic response. and i don't, you know, that isn't always consistentlyseen with all antigens. so i think that i would behard to say well, you know, since you had a better response, you'll probably havehigher antibody.

i think that the best thing,the most reassuring thing that i could say and thatwere really the cytokine data which was so nice that people -- first of all, there were onlysix people that had, you know, severe reactions and most,you know, and certainly when they came in we sawthem and measured this. and so i think that thatis really very reassuring. even at the time of thepeak, you know, reaction, these local reactions that werenot systemic cytokine responses

that were elevated. and i think thatis very reassuring. now obviously it's only six but those were the onlypatients that had responses. so i think that -- i don'tknow exactly what will happen in terms of repeated tdap. we did do a study a number ofyears ago that was also funded by cisa, where we looked at children who'd hadlarge local reactions

after their fourth or the fifthdose of, no, their fourth dose of tdap at 18 to 24 monthsand we looked at what happened at their four to six years. and in general, those childrendid have slightly more local responses after their fifthdose than they did at the four, but it wasn't, youknow, remarkable and certainly therewere no severe reactions or no inhibition of activitiesor those sorts of things. so there may be slightly more

but i think we'lljust have to see. there may not as well. >> yes, dr. sun. >> i think in yourmethods, you mentioned that infants were assessed byphone interview and chart review at three and six months. but i was wondering, didyou find anything there? >> those data are still inthe process of being analyzed. we don't have -- all thepatients haven't received that,

you know, that, you know, or haven't reachedtheir magic mark. but it's almost together andwe should have that soon. just empirically speaking orthere were no adverse events of note that i knowof or probably if something bad would'vehappened, i'm quite certain that both chip and iwould've known that. but by and large, we have notheard that yet but certainly that data, those data arebeing assessed and weights

and hospital visits and thosethings are being looked at. so that will be something thatwill be coming out shortly. >> any additional questions? okay, thank you verymuch, dr. edwards. now we're going to move onto dr. reingold who's going to give us a littlebit of an update on the pertussis workgroup. as promised yesterday, i'm back. so another workgroupthat i'm privileged

to chair is the pertussisworkgroup. and this workgroup also haskathy harriman and ruth karron. so we're going to be inneed of other acip members if truly kathy andruth are leaving. but in addition, we alwayshave good representation from a variety of other groups. and like all workgroups,we depend heavily on our cdc lead jennifer liang, who has really done anenormous amount of work

on behalf of the workgroup. so just to remind people,this is another one of those situations where wehave a series of statements that go back nowa number of years. and so the primarymission of the workgroup is to combine these statements anddevelop an updated statement. we do have a draftof that statement. it's gone through severalrevisions already and it's, i don't know if it's goingthrough cdc clearance

at this point, but it's windingits way toward the committee and i believe it's going tobe arriving on your doorstep in time for the october meeting. but basically this alsodoes include new data on tdap reflecting the impactof the acip recommendations, information aroundintervals between boosters use in the elderly, like me, anda variety of other issues. and in addition to theissues around pertussis, we also will be reviewing data

on their relatively modestepidemiology of tetanus and diphtheria inthe united states. that part's easy. so just remind you that,as already been stated, we do have a recommendationto administer dose of tdap during everypregnancy, irrespective of the patient's priorhistory of receiving tdap, and that in the unitedstates we currently recommend that that dose beadministered between 27

and 36 weeks of gestation. and you've alreadyheard about that. but there are a number ofrecently published studies that in fact suggestedvaccination during the second trimester rather thanthe third trimester in fact maximizes antibodyconcentrations in infants or at least two studiesthat show that. and the united kingdomin its wisdom in february of this year actually changedits recommendation such that

that they now recommend thatwomen receive the vaccine as early as 16 weeks' gestationand, however, to do it before, excuse me, after themid-pregnancy ultrasound. presumably if there are anyabnormalities at the time of the ultrasound, they thencan't be blamed on a dose of tdap that hadrecently been given. so the next steps for theworking group are to review data around the time ofvaccination during pregnancy. there are now some additionalstudies, including one

from california, and anational study looking at the effectiveness oftdap given during pregnancy and prevention of pertussisin infants, looking at more around the safety issues which we've already had somediscussion of this morning, issues around programconsiderations. and so the plan is atthe october meeting to both present theconsolidated acip statement and to have additionaldiscussion around the timing

of maternal tdap vaccination,summarizing the existing data and seeing if the aciphas any suggestions around either keepingthe timing the same or changing the timingin the united states. so that's the report of ourworking group and i'd be happy to take any questions. >> thank you, dr. reingold. are there any questions?