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8/8/2019 Influenza Vaccine and Antiviral Agents_CDC_MMWR 2008 57
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Morbidity and Mortality Weekly Reportwww.cdc.gov/mmwr
Early Release July 17, 2008 / Vol. 57
Prevention and Control of Influenza
Recommendations of the Advisory Committeeon Immunization Practices (ACIP), 2008
depardepardepardepardepartment of health and human sertment of health and human sertment of health and human sertment of health and human sertment of health and human servicesvicesvicesvicesvices
Centers for Disease Control and PreventionCenters for Disease Control and PreventionCenters for Disease Control and PreventionCenters for Disease Control and PreventionCenters for Disease Control and Prevention
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Early Release
TheMMWRseries of publications is published by the CoordinatingCenter for Health Information and Service, Centers for DiseaseControl and Prevention (CDC), U.S. Department of Health andHuman Services, Atlanta, GA 30333.
Suggested Citation: Centers for Disease Control and Prevention.[Title]. MMWR Early Release 2008;57[Date]:[inclusive page numbers].
Centers for Disease Control and Prevention
Julie L. Gerberding, MD, MPHDirector
Tanja Popovic, MD, PhDChief Science Officer
James W. Stephens, PhDAssociate Director for Science
Steven L. Solomon, MDDirector, Coordinating Center for Health Information and Service
Jay M. Bernhardt, PhD, MPHDirector, National Center for Health Marketing
Katherine L. Daniel, PhDDeputy Director, National Center for Health Marketing
Editorial and Production Staff
Frederic E. Shaw, MD, JDEditor, MMWRSeries
Susan F. Davis, MD(Acting)Assistant Editor, MMWR Series
Teresa F. Rutledge(Acting)Managing Editor, MMWR Series
David C. Johnson(Acting)Lead Technical Writer-Editor
David C. JohnsonProject Editor
Peter M. Jenkins(Acting)Lead Visual Information Specialist
Lynda G. CupellMalbea A. LaPete
Visual Information Specialists
Quang M. Doan, MBAErica R. Shaver
Information Technology Specialists
Editorial Board
William L. Roper, MD, MPH, Chapel Hill, NC, ChairmanVirginia A. Caine, MD, Indianapolis, IN
David W. Fleming, MD, Seattle, WAWilliam E. Halperin, MD, DrPH, MPH, Newark, NJ
Margaret A. Hamburg, MD, Washington, DCKing K. Holmes, MD, PhD, Seattle, WADeborah Holtzman, PhD, Atlanta, GA
John K. Iglehart, Bethesda, MDDennis G. Maki, MD, Madison, WISue Mallonee, MPH, Oklahoma City, OKStanley A. Plotkin, MD, Doylestown, PA
Patricia Quinlisk, MD, MPH, Des Moines, IAPatrick L. Remington, MD, MPH, Madison, WI
Barbara K. Rimer, DrPH, Chapel Hill, NCJohn V. Rullan, MD, MPH, San Juan, PR
Anne Schuchat, MD, Atlanta, GADixie E. Snider, MD, MPH, Atlanta, GA
John W. Ward, MD, Atlanta, GA
CONTENTS
Introduction......................................................................... 1
Methods .............................................................................. 3
Primary Changes and Updates in the Recommendations ..... 3
Background and Epidemiology ............................................ 4
Influenza Vaccine Efficacy, Effectiveness, and Safety ............ 8
Recommendations for Using TIV and LAIV During the
200809 Influenza Season .............................................. 25
Additional Information About Vaccination of Specific
Populations ...................................................................... 26
Recommendations for Vaccination Administration
and Vaccination Programs ............................................... 30
Future Directions for Research and Recommendations
Related to Influenza Vaccine ............................................ 33
Seasonal Influenza Vaccine and Avian or Swine Influenza ... 34
Recommendations for Using Antiviral Agents for
Seasonal Influenza .......................................................... 35
Sources of Information Regarding Influenza
and Its Surveillance ......................................................... 44
Responding to Adverse Events After Vaccination ................ 44
National Vaccine Injury Compensation Program ................ 44
Reporting of Serious Adverse Events After Antiviral
Medications ..................................................................... 44
Additional Information Regarding Influenza Virus
Infection Control Among Specific Populations .................. 44
References......................................................................... 45
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1Vol. 57 Early Release
Prevention and Control of Influenza
Recommendations of the Advisory Committeeon Immunization Practices (ACIP), 2008
Preparedby
AnthonyE.Fiore,MD1
DavidK.Shay,MD1
KarenBroder,MD2
JohnK.Iskander,MD2
TimothyM.Uyeki,MD1
GinaMootrey,DO3
JosephS.Bresee,MD1
NancyJ.Cox,PhD1 1Influenza Division, National Center for Immunization and Respiratory Diseases
2Immunization Safety Office, Office of the Chief Science Officer, Office of the Director3Immunization Services Division, National Center for Immunization and Respiratory Diseases
Summary
This report updates the 2007 recommendations by CDCs Advisory Committee on Immunization Practices (ACIP) regardingthe use of influenza vaccine and antiviral agents (CDC. Prevention and control of influenza: recommendations of the AdvisoryCommittee on Immunization Practices [ACIP]. MMWR 2007;56[No. RR6]). The 2008 recommendations include new andupdated information. Principal updates and changes include 1) a new recommendation that annual vaccination be adminis-tered to all children aged 518 years, beginning in the 200809 influenza season, if feasible, but no later than the 200910influenza season; 2) a recommendation that annual vaccination of all children aged 6 months through 4 years (59 months)continue to be a primary focus of vaccination efforts because these children are at higher risk for influenza complications com-pared with older children; 3) a new recommendation that either trivalent inactivated influenza vaccine or live, attenuatedinfluenza vaccine (LAIV) be used when vaccinating healthy persons aged 2 through 49 years (the previous recommendation wasto administer LAIV to person aged 549 years); 4) a recommendation that vaccines containing the 200809 trivalent vaccinevirus strains A/Brisbane/59/2007 (H1N1)like, A/Brisbane/10/2007 (H3N2)like, and B/Florida/4/2006like antigens be used;and, 5) new information on antiviral resistance among influenza viruses in the United States. Persons for whom vaccination is
recommended are listed in boxes 1 and 2. These recommendations also include a summary of safety data for U.S. licensedinfluenza vaccines. This report and other information are available at CDCs influenza website (http://www.cdc.gov/flu),including any updates or supplements to these recommendations that might be required during the 200809 influenza season.Vaccination and healthcare providers should be alert to announcements of recommendation updates and should check the CDCinfluenza website periodically for additional information.
group,but rates of infectionare highestamongchildrenIntroduction(13).Ratesofseriousillnessanddeatharehighestamong
IntheUnitedStates,annualepidemicsofinfluenzaoccur personsaged>65years,childrenaged6months(whodoesnothavecontraindicationstovaccina-NationalCenterforImmunizationandRespiratoryDiseases,CDC, tion)toreducethelikelihoodofbecomingillwithinfluenza1600CliftonRoad,NE,MSA-20,Atlanta,GA30333.Telephone: oroftransmittinginfluenzatoothers.Trivalentinactivate404-639-3747;Fax:404-639-3866;E-mail:[email protected].
influenza vaccine (TIV)canbeusedfor any person aged
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>6months,includingthosewithhigh-riskconditions(Boxes1and2).Live,attenuatedinfluenzavaccine(LAIV)maybeused forhealthy,nonpregnantpersonsaged249years. Ifvaccinesupplyislimited,priorityforvaccinationistypicallyassignedtopersonsinspecificgroupsandofspecificageswhoare,orarecontactsof,personsathigherriskfor influenza
complications.BecausethesafetyoreffectivenessofLAIVhasnotbeenestablishedinpersonswithunderlyingmedicalconditionsthatconferahigherriskforinfluenzacomplications,thesepersonsshouldonlybevaccinatedwithTIV.Influenzavirusesundergofrequentantigenicchange(i.e.,antigenicdrift),andpersonsrecommendedforvaccinationmustreceiveanannualvaccinationagainsttheinfluenzavirusesforecastedtobeincirculation.Althoughvaccinationcoveragehasincreased
BOX 1. Summary of influenza vaccination recommendations,2008: children and adolescents aged 6 months18 years
Vaccinationofallchildrenaged6months18yearsshouldbeginbeforeorduringthe200809influenzaseasoniffeasible,butnolaterthanduringthe200910influenzaseason.Vaccinationofallchildrenaged518yearsisanewACIPrecommendation.
Childrenand adolescents athighrisk forinfluenzacomplicationsshouldcontinuetobeafocusofvaccinationeffortsasprovidersandprogramstransitiontoroutinelyvaccinatingallchildrenandadolescents.Recommendationsforthesechildrenhavenotchanged.Childrenandadolescentsathigher risk forinfluenzacomplicationarethose:
aged6months4years;whohavechronicpulmonary(includingasthma),
cardiovascular (excepthypertension), renal,hepatic,hematologicalormetabolicdisorders(includingdiabetesmellitus);
whoareimmunosuppressed(includingimmunosuppressioncausedbymedicationsorbyhumanimmunodeficiencyvirus);
whohaveanycondition(e.g., cognitivedysfunction,spinalcordinjuries,seizuredisorders,orotherneuromusculardisorders)thatcancompromiserespiratoryfunctionorthehandlingofrespiratorysecretionsorthat
canincreasetheriskforaspiration; whoarereceivinglong-termaspirintherapywhothere
foremightbeatriskforexperiencingReyesyndromeafterinfluenzavirusinfection;
whoareresidentsofchronic-carefacilities;and, whowillbepregnantduringtheinfluenzaseason.
Note: Childrenaged
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Methods
CDCsAdvisoryCommitteeonImmunizationPractices(ACIP)providesannualrecommendationsforthepreventionandcontrolofinfluenza.TheACIPInfluenzaVaccineWorkingGroup*meetsmonthlythroughouttheyeartodiscuss
newlypublishedstudies,reviewcurrentguidelines,andconsiderpotentialrevisionstotherecommendations.AstheyreviewtheannualrecommendationsforACIPconsiderationofthefullcommittee,membersoftheworkinggroupconsideravarietyofissues,includingburdenofinfluenzaillness,vaccineeffectiveness,safetyandcoverageingroupsrecommended for vaccination,feasibility, cost-effectiveness,andanticipatedvaccinesupply.Workinggroupmembersalsorequestperiodicupdatesonvaccineandantiviralproduction,supply,safetyandefficacyfromvaccinologists,epidemiologists,andmanufacturers.Stateandlocalvaccinationprogramrepresentativesareconsulted.Influenzasurveillanceandanti
viralresistancedatawereobtainedfromCDCsInfluenzaDivision.TheVaccines andRelated Biological ProductsAdvisoryCommitteeprovidesadviceonvaccinestrainselectiontotheFoodandDrugAdministration(FDA),whichselectstheviralstrainstobeusedintheannualtrivalentinfluenzavaccines.
Published,peer-reviewedstudiesaretheprimarysourceofdatausedbyACIPinmakingrecommendationsforthepreventionandcontrolofinfluenza,butunpublisheddatathatarerelevanttoissuesunderdiscussionalsomightbeconsidered.Amongstudiesdiscussedorcited,thoseofgreatestscientificqualityandthosethatmeasuredinfluenza-specific
outcomesarethemostinfluential.Forexample,population-basedestimatesthatuseoutcomesassociatedwithlaboratory-confirmedinfluenzavirusinfectionoutcomescontributethemostspecificdataforestimatesofinfluenzaburden.Thebestevidenceforvaccineorantiviralefficacyandeffectivenesscomesfromrandomizedcontrolledtrialsthatassesslaboratory-confirmedinfluenzainfectionsasanoutcomemeasureandconsiderfactorssuchastimingandintensityofinfluenzacirculationanddegreeofmatchbetweenvaccinestrainsandwildcirculatingstrains(8,9).Randomized,placebo-controlledtrialscannotbeperformedethicallyinpopulationsforwhichvaccinationalreadyisrecommended,butobservationalstudiesthatassessoutcomesassociatedwithlaboratory-confirmedinfluenzainfectioncanprovideimportantvaccineorantiviraleffectivenessdata.Randomized,placebo-controlledclinicaltrialsarethebestsourceofvaccineandantiviralsafetydataforcommonadverseevents;however,suchstudiesdonothavethepowertoidentifyrarebutpotentiallyseriousadverseevents.
*Alistofmembersappearsonpage59ofthisreport.
Thefrequencyofrareadverseeventsthatmightbeassociatewithvaccinationorantiviraltreatmentisbestassessedbyretrospectivereviewsofcomputerizedmedicalrecordsfromlargelinkedclinicaldatabases,andbyreviewingmedicalchartsofpersonswhoareidentifiedashavingapotentialadverseevenaftervaccination(10,11).Vaccinecoveragedatafroma
nationallyrepresentative,randomlyselectedpopulationthatincludesverificationofvaccinationthroughhealth-carerecordreviewissuperiortocoveragedataderivedfromlimitedpopulationsorwithoutverificationofvaccinationbutisrarelyavailableforolderchildrenoradults(12).Finally,studiesthatassesvaccinationprogrampracticesthatimprovevaccinationcoveragearemostinfluentialinformulatingrecommendationsithestudydesignincludesanoninterventioncomparisongroupIncitedstudiesthatincludedstatisticalcomparisons,adifferencewasconsideredtobestatisticallysignificantifthep-valuewas
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vaccinatedpreviously atanytimewitheitherLAIVorTIV(dosesseparatedby>4weeks);2dosesarerequiredforprotectioninthesechildren.Childrenaged6months8yearswhoreceivedonly1doseintheirfirstyearofvaccinationshouldreceive2dosesthefollowingyear.LAIVshouldnotbeadministeredtochildrenaged49yearsshouldreceiveTIV.
The200809trivalentvaccinevirusstrainsareA/Brisbane/59/2007(H1N1)-like,A/Brisbane/10/2007(H3N2)-like,andB/Florida/4/2006-likeantigens.
Oseltamivir-resistant influenzaA (H1N1)strains havebeenidentifiedintheUnitedStatesandsomeothercountries.However,oseltamivirorzanamivircontinuetobetherecommendedantiviralsfortreatmentofinfluenzabecauseotherinfluenzavirusstrainsremainsensitivetooseltamivir,andresistancelevelstootherantiviralmedicationsremainhigh.
Background and Epidemiology
Biology of Influenza
InfluenzaAandB are the two typesof influenzavirusesthatcauseepidemichumandisease.InfluenzaAvirusesare
categorizedintosubtypesonthebasisoftwosurfaceantigens:hemagglutininandneuraminidase.Since1977,influenzaA(H1N1)viruses,influenzaA(H3N2)viruses,andinfluenzaBviruseshavecirculatedglobally.InfluenzaA(H1N2)virusesthatprobably emergedaftergenetic reassortmentbetweenhumanA(H3N2)andA(H1N1)virusesalsohavebeenidentifiedinsomeinfluenzaseasons.BothinfluenzaAsubtypesandBvirusesarefurtherseparatedintogroupsonthebasisofantigenicsimilarities.Newinfluenzavirusvariantsresultfromfrequentantigenicchange(i.e.,antigenicdrift)resultingfrompointmutationsthatoccurduringviralreplication(13).
CurrentlycirculatinginfluenzaBvirusesareseparatedintotwodistinctgeneticlineages(YamagataandVictoria)butarenotcategorizedintosubtypes.InfluenzaBvirusesundergoantigenicdriftlessrapidlythaninfluenzaAviruses.InfluenzaBvirusesfrombothlineageshavecirculatedinmostrecentinfluenzaseasons(13).
Immunitytothesurfaceantigens,particularlythehemagglutinin,reducesthelikelihoodofinfection(14).Antibodyagainstoneinfluenzavirustypeorsubtypeconferslimitedor
noprotectionagainstanothertypeorsubtypeofinfluenzavirus.Furthermore,antibodytooneantigenictypeorsubtypeofinfluenzavirusmightnotprotectagainstinfectionwithanewantigenicvariantofthesametypeorsubtype(15)Frequentemergenceofantigenicvariantsthroughantigenicdriftisthevirologicbasisforseasonalepidemicsandisthe
reasonforannuallyreassessingtheneedtochangeoneormoreoftherecommendedstrainsforinfluenzavaccines.
Moredramaticchanges,orantigenicshifts,occurlessfrequently.AntigenicshiftoccurswhenanewsubtypeofinfluenzaAvirusappearsandcanresultintheemergenceofanovelinfluenzaAviruswiththepotentialtocauseapandemicNewinfluenzaAsubtypeshavethepotentialtocauseapandemicwhentheyareabletocausehumanillnessanddemonstrateefficienthuman-to-humantransmissionandthereislittleornopreviouslyexistingimmunityamonghumans(13).
Clinical Signs and Symptomsof Influenza
Influenzavirusesarespreadfrompersontopersonprimarilythroughlarge-particlerespiratorydroplettransmission(e.g.,whenaninfectedpersoncoughsorsneezesnearasusceptibleperson)(16).Transmissionvialarge-particledropletrequiresclosecontactbetweensourceandrecipientpersons,becausedropletsdonotremainsuspendedintheairandgenerallytravelonlyashortdistance(
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althoughcoughandmalaisecanpersistfor>2weeks.However,influenzavirusinfectionscancauseprimaryinfluenzaviralpneumonia;exacerbateunderlyingmedicalconditions(e.g.,pulmonaryorcardiacdisease);leadtosecondarybacterialpneumonia,sinusitis, orotitismedia; orcontribute tocoinfectionswithotherviralorbacterialpathogens(3436).
Youngchildrenwithinfluenzavirusinfectionmighthaveinitialsymptomsmimickingbacterialsepsiswithhighfevers(3538),andfebrileseizureshavebeenreportedin6%20%ofchildrenhospitalizedwithinfluenzavirusinfection(32,35,39).Population-basedstudiesamonghospitalizedchildrenwithlaboratory-confirmedinfluenzahavedemonstratedthat although themajority of hospitalizations are brief(
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During seasonalinfluenzaepidemics from19791980through20002001,theestimatedannualoverallnumberofinfluenza-associatedhospitalizationsintheUnitedStatesrangedfromapproximately55,000to431,000perannualepidemic(mean:226,000)(7).Theestimatedannualnumberofdeathsattributedtoinfluenzafromthe199091influ
enzaseasonthrough199899rangedfrom17,000to51,000perepidemic(mean:36,000)(6).IntheUnitedStates,theestimatednumberofinfluenza-associateddeathsincreasedduring19901999.Thisincreasewasattributedinparttothesubstantialincreaseinthenumberofpersonsaged>65yearswhowereatincreasedriskfordeathfrominfluenzacomplications(6).Inonestudy,anaverageofapproximately19,000influenza-associatedpulmonaryandcirculatorydeathsperinfluenzaseasonoccurredduring19761990,comparedwithanaverageofapproximately36,000deathsperseasonduring19901999(6).Inaddition,influenzaA(H3N2)viruses,whichhavebeenassociatedwithhighermortality(54),predominatedin90%ofinfluenzaseasonsduring19901999,comparedwith57%ofseasonsduring19761990(6).
Influenzavirusescausediseaseamongpersonsinallagegroups(15).Ratesofinfectionarehighestamongchildren,buttherisksforcomplications,hospitalizations,anddeathsfrominfluenzaarehigheramongpersonsaged>65years,youngchildren,andpersonsofanyagewhohavemedicalconditionsthatplacethematincreasedriskforcomplicationsfrominfluenza(1,4,5,5558).Estimatedratesofinfluenza-associatedhospitalizationsanddeathsvariedsubstantiallybyagegroupinstudiesconductedduringdifferentinfluenzaepi
demics.During19901999,estimatedaverageratesofinfluenza-associatedpulmonaryandcirculatorydeathsper100,000personswere0.40.6amongpersonsaged049years,7.5amongpersonsaged5064years,and98.3amongpersonsaged>65years(6).
Children
Amongchildrenaged
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6
8
10
Epidemic threshold
Seasonal baseline
50 10 20 30 40 50 10 20 30 40 50 10 20 30 40 50 10 20 30 40 50 10 20
2004 2005 2006 2007 2008
Week and year
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withhigh-riskmedicalconditionsareapproximately250500per100,000children(56,58,67).
Influenza-associateddeathsareuncommonamongchildren.Anestimatedannualaverageof92influenza-relateddeaths(0.4deathsper100,000persons)occurredamongchildrenaged65years(6).Of153laboratory-confirmedinfluenza-relatedpediatricdeathsreportedduringthe200304influenzaseason,96(63%)deathsoccurredamongchildrenaged65years( 6).Riskforinfluenza-associateddeathwashighestamongtheoldeselderly,withpersonsaged>85years16timesmorelikelytodiefromaninfluenza-associatedillnessthanpersonsaged6569years(6).
Thedurationofinfluenzasymptomsisprolongedandtheseverityofinfluenzaillnessincreasedamongpersonswithhumanimmunodeficiencyvirus(HIV)infection(7377).Aretrospectivestudyofyoungandmiddle-agedwomenenrolledinTennesseesMedicaidprogramdeterminedthattheattributableriskforcardiopulmonaryhospitalizationsamongwomenwithHIVinfectionwashigherduringinfluenzaseasonsthanitwaseitherbeforeorafterinfluenzawascirculating.TheriskforhospitalizationwashigherforHIV-infectedwomenthanitwasforwomenwithotherunderlyingmedicaconditions(78).Anotherstudyestimatedthattheriskfoinfluenza-relateddeathwas94146deathsper100,000personswithacquiredimmunodeficiencysyndrome(AIDS),comparedwith0.91.0deathsper100,000personsaged2554
yearsand6470deathsper100,000personsaged>65yearsinthegeneralpopulation(79).Influenza-associatedexcessdeathsamongpregnantwomen
werereportedduringthepandemicsof19181919and19571958(8083).Casereportsandseveralepidemiologicstudie
FIGURE 3. Percentage of all deaths attributed to pneumoniaand influenza in the 122 cities mortality reporting system United States, 20042008
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alsoindicatethatpregnancyincreasestheriskforinfluenzacomplications(8489)forthemother.Themajorityofstudiesthathaveattemptedtoassesstheeffectof influenzaonpregnantwomenhavemeasuredchangesinexcesshospitalizationsforrespiratoryillnessduringinfluenzaseasonbutnotlaboratory-confirmedinfluenzahospitalizations.Pregnant
womenhaveanincreasednumberofmedicalvisitsforrespiratoryillnessesduringinfluenzaseasoncomparedwithnonpregnantwomen(90).Hospitalizedpregnantwomenwithrespiratoryillnessduringinfluenzaseasonhaveincreasedlengthsofstaycomparedwithhospitalizedpregnantwomenwithoutrespiratoryillness.Ratesofhospitalizationforrespiratoryillnessweretwiceascommonduringinfluenzaseason(91).Aretrospectivecohortstudyofapproximately134,000pregnantwomenconductedinNovaScotiaduring19902002comparedmedicalrecorddataforpregnantwomentodatafromthesamewomenduringtheyearbeforepregnancy.Amongpregnantwomen,0.4%werehospitalizedand25%visitedaclinicianduringpregnancyforarespiratoryillness.The rate of third-trimester hospital admissionsduringtheinfluenzaseasonwasfivetimeshigherthantherateduringtheinfluenzaseasonintheyearbeforepregnancyandmorethantwiceashighastherateduringthenoninfluenzaseason.Anexcessof1,210hospitaladmissionsinthethirdtrimesterper100,000pregnantwomenwithcomorbiditiesand68admissionsper100,000womenwithoutcomorbiditieswasreported(92).Inonestudy,pregnantwomenwithrespiratoryhospitalizationsdidnothaveanincreaseinadverseperinataloutcomesordeliverycomplications(93);however,
anotherstudyindicatedanincreaseindeliverycomplications(91).However,infantsborntowomenwithlaboratory-confirmedinfluenzaduringpregnancydonothavehigherratesoflowbirthweight,congenitalabnormalities,orlowApgarscorescomparedwithinfantsborntouninfectedwomen(88,94).
Options for Controlling Influenza
Themosteffectivestrategyforpreventinginfluenzaisannualvaccination.Strategiesthatfocusonprovidingroutinevaccinationtopersonsathigherriskforinfluenzacomplicationshavelongbeenrecommended,althoughcoverageamongthemajorityofthesegroupsremainslow.Routinevaccinationofcertainpersons(e.g.,children,contactsofpersonsatriskforinfluenzacomplications,andHCP)whoserveasasourceofinfluenzavirustransmissionmightprovideadditionalprotectiontopersonsatriskforinfluenzacomplicationsandreducetheoverallinfluenzaburden,butcoveragelevelsamongthesepersonsneedstobeincreasedbeforeeffectsontransmissioncanbereliablymeasured.Antiviral
drugsusedforchemoprophylaxisortreatmentofinfluenzaareadjunctstovaccinebutarenotsubstitutesforannualvaccination.However,antiviraldrugsmightbeunderusedamongthosehospitalizedwithinfluenza(95).Nonpharmacologicinterventions(e.g.,advisingfrequenthandwashingandimprovedrespiratoryhygiene)arereasonableandinexpensive;
thesestrategieshavebeendemonstratedtoreducerespiratorydiseases(96,97)buthavenotbeenstudiedadequatelytodetermineiftheyreducetransmissionofinfluenzavirus.Similarly,fewdataareavailabletoassesstheeffectsofcommunity-levelrespiratorydiseasemitigationstrategies(e.g.,closinschools,avoidingmassgatherings,orusingrespiratoryprotection)onreducinginfluenzavirustransmissionduringtypicalseasonalinfluenzaepidemics(98,99).
Influenza Vaccine Efficacy,Effectiveness, and Safety
Evaluating Influenza Vaccine Efficacyand Effectiveness Studies
Theefficacy(i.e.,preventionofillnessamongvaccinatedpersonsincontrolledtrials)andeffectiveness(i.e.,preventionofillnessinvaccinatedpopulations)ofinfluenzavaccinedependinpartontheageandimmunocompetenceofthvaccinerecipient,thedegreeofsimilaritybetweentheviruseinthevaccineandthoseincirculation(seeEffectivenessofInfluenzaVaccinationwhenCirculatingInfluenzaVirusStrainsDifferfromVaccineStrains),andtheoutcomebeingmea
sured.Influenzavaccineefficacyandeffectivenessstudieshaveusedmultiplepossibleoutcomemeasures,includingthepreventionofmedicallyattendedacuterespiratoryillness(MAARI),preventionof laboratory-confirmedinfluenzavirusillness,preventionofinfluenzaorpneumonia-associatedhospitalizationsordeaths,orpreventionofseroconversiontocirculatinginfluenzavirusstrains.Efficacyoreffectivenessfomorespecificoutcomessuchaslaboratory-confirmedinfluenzatypicallywillbehigherthanforlessspecificoutcomesuchasMAARIbecausethecausesofMAARIincludeinfectionswithotherpathogensthatinfluenzavaccinationwouldnotbeexpectedtoprevent(100).Observationalstudiesthat
compareless-specificoutcomesamongvaccinatedpopulationstothoseamongunvaccinatedpopulationsaresubjecttobiasesthataredifficultto control forduring analyses.Foexample,anobservationalstudythatdeterminesthatinfluenzavaccinationreducesoverallmortalitymightbebiasedifhealthierpersonsinthestudyaremorelikelytobevaccinated(101,102).Randomizedcontrolledtrialsthatmeasurelaboratory-confirmedinfluenzavirusinfectionsastheoutcome
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arethemostpersuasiveevidenceofvaccineefficacy,butsuchtrialscannotbeconductedethicallyamonggroupsrecommendedtoreceivevaccineannually.
Influenza Vaccine Composition
BothLAIV andTIVcontainstrains of influenzavirusesthatareantigenicallyequivalenttotheannuallyrecommendedstrains:oneinfluenzaA(H3N2)virus,oneinfluenzaA(H1N1)virus,andoneinfluenzaBvirus.Eachyear,oneormorevirusstrainsinthevaccinemightbechangedonthebasisofglobalsurveillanceforinfluenzavirusesandtheemergenceandspreadofnewstrains.Allthreevaccinevirusstrainswerechangedfortherecommendedvaccineforthe200809influenzaseason,comparedwiththe200708season(seeRecommendationsforUsingTIVandLAIVDuringthe200809InfluenzaSeason).Virusesforbothtypesofcurrentlylicensedvaccinesaregrownineggs.Bothvaccinesareadmin
isteredannuallytoprovideoptimalprotectionagainstinfluenzavirusinfection(Table1).BothTIVandLAIVarewidelyavailableintheUnitedStates.Althoughbothtypesofvaccinesareexpectedtobeeffective,thevaccinesdifferinseveralrespects(Table1).
Major Differences Between TIVand LAIV
DuringthepreparationofTIV,thevaccinevirusesaremadenoninfectious(i.e.,inactivatedorkilled)(103).OnlysubvirionandpurifiedsurfaceantigenpreparationsofTIV(often
referredtoassplitandsubunitvaccines,respectively)areavailableintheUnitedStates.TIVcontainskilledvirusesandthuscannotcauseinfluenza.LAIVcontainslive,attenuatedvirusesthathavethepotentialtocausemildsignsorsymptomssuchasrunnynose,nasalcongestion,feverorsorethroat.LAIVisadministeredintranasallybysprayer,whereasTIVisadministeredintramuscularlybyinjection.LAIVislicensedforuseamongnonpregnantpersonsaged249years;safetyhasnotbeenestablishedinpersonswithunderlyingmedicalconditionsthatconferahigherriskofinfluenzacomplications.TIVislicensedforuseamongpersonsaged>6months,includingthosewhoarehealthyandthosewithchronicmedi
calconditions(Table1).
Correlates of Protection afterVaccination
Immunecorrelatesofprotectionagainstinfluenzainfectionaftervaccinationincludeserumhemagglutinationinhibitionantibodyandneutralizingantibody( 14,104).Increasedlevelsofantibodyinducedbyvaccinationdecreasetheriskfor
illnesscausedbystrainsthatareantigenicallysimilartothosstrainsofthesametypeorsubtypeincludedinthevaccine(105108).Themajorityofhealthychildrenandadultshavhightitersofantibodyaftervaccination(106,109).Althoughimmunecorrelatessuchasachievementofcertainantibodytitersaftervaccinationcorrelatewellwithimmunityonapopu
lationlevel,thesignificanceofreachingorfailingtoreachacertainantibodythresholdisnotwellunderstoodontheindividuallevel.OtherimmunologiccorrelatesofprotectionthamightbestindicateclinicalprotectionafterreceiptofanintranasalvaccinesuchasLAIV(e.g.,mucosalantibody)aremoredifficulttomeasure(103,110).
Immunogenicity, Efficacy,and Effectiveness of TIV
Children
Childrenaged>6monthstypicallyhaveprotectivelevelsoanti-influenzaantibodyagainstspecificinfluenzavirusstrainafterreceivingtherecommendednumberofdosesofinfluenzavaccine(104,109,111116).Inmostseasons,oneormorevaccineantigensarechangedcomparedtothepreviousseason.Inconsecutiveyearswhenvaccineantigenschange,childrenaged4weeksduringthestudyseason(121).
Theantibodyresponseamongchildrenathigherriskfor
influenza-relatedcomplications(e.g.,childrenwithchronicmedicalconditions)mightbelowerthanthosetypicallyreportedamonghealthychildren(122,123).However,antibodyresponsesamongchildrenwithasthmaaresimilartothoseohealthychildrenandarenotsubstantiallyalteredduringasthmaexacerbationsrequiringshort-termprednisonetreatment( 124)
Vaccineeffectivenessstudiesalsohaveindicatedthat2dosesareneededtoprovideadequateprotectionduringthefirstseasonthatyoungchildrenarevaccinated.Amongchildrenaged
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TABLE 1. Live, attenuated influenza vaccine (LAIV) compared with inactivated influenza vaccine (TIV) for seasonal influenza,United States formulations.
Factor LAIV TIV
Routeofadministration Intranasalspray Intramuscularinjection
Typeofvaccine Live-attenuatedvirus Killedvirus
No.ofincludedvirusstrains Three(twoinfluenzaA, Three(twoinfluenzaA,
one
influenzaB) one
influenzaB)
Vaccinevirusstrainsupdated Annually Annually
Frequencyofadministration Annually* Annually*
Approvedage Personsaged249yrs Personsaged>6months
Intervalbetween2dosesrecommendedforchildrenaged>6months8yearswhoare 4weeks 4weeksreceivinginfluenzavaccineforthefirsttime
Canbeadministeredtopersonswithmedicalriskfactorsforinfluenza-relatedcomplications No Yes
Canbeadministeredtochildrenwithasthmaorchildrenaged24yearswithwheezingduringtheprecedingyear
No Yes
Canbeadministeredtofamilymembersorclosecontactsofimmunosuppressedpersonsnot Yes Yes
requiring
a
protected
environment
Canbeadministeredtofamilymembersorclosecontactsofimmunosuppressedpersons No Yesrequiringaprotectedenvironment (e.g.,hematopoieticstemcelltransplantrecipient)
Canbeadministeredtofamilymembersorclosecontactsofpersonsathighriskbutnot Yes Yesseverelyimmunosuppressed
Canbesimultaneouslyadministeredwithothervaccines Yes Yes**
Ifnotsimultaneouslyadministered,canbeadministeredwithin4weeksofanotherlivevaccine Prudenttospace Yes4weeksapart
Ifnotsimultaneouslyadministered,canbeadministeredwithin4weeksofaninactivatedvaccine Yes Yes
* Childrenaged6months8yearswhohaveneverreceivedinfluenzavaccinebeforeshouldreceive2doses.Thosewhoonlyreceive1doseintheirfirsyearofvaccinationshouldreceive2dosesinthefollowingyear,spaced4weeksapart.
Persons
at
high
riskfor
complications
ofinfluenza
infection
because
ofunderlyingmedical
conditions
should
not
receiveLAIV.Persons
at
higher
riskfocomplications
of influenza
infection
because
ofunderlyingmedical
conditions
include
adults
and
childrenwith
chronic
disorders
ofthe
pulmonary
ocardiovascularsystems;adultsandchildrenwithchronicmetabolicdiseases(includingdiabetesmellitus),renaldysfunction,hemoglobinopathies,oimmunnosuppression;childrenandadolescents receiving long-termaspirin therapy (at risk fordevelopingReyesyndromeafter wild-type influenzainfection);personswhohaveanycondition(e.g.,cognitivedysfunction,spinalcordinjuries,seizuredisorders,orotherneuromusculardisorders)thatcancompromiserespiratoryfunctionorthehandlingofrespiratorysecretionsorthatcanincreasetheriskforaspiration;pregnantwomen;andresidentsonursinghomesandotherchronic-carefacilitiesthathousepersonswithchronicmedicalconditions.
CliniciansandvaccinationprogramsshouldscreenforpossiblereactiveairwaysdiseaseswhenconsideringuseofLAIVforchildrenaged24years,andshouldavoiduseofthisvaccineinchildrenwithasthmaorarecentwheezingepisode.Health-careprovidersshouldconsultthemedicalrecord,whenavailable,toidentifychildrenaged24yearswithasthmaorrecurrentwheezingthatmightindicateasthma.Inaddition,toidentifychildrenwhomightbeatgreaterriskforasthmaandpossiblyatincreasedriskforwheezingafterreceivingLAIV,parentsorcaregiversofchildrenaged24yearsshouldbeasked:Inthepast12months,hasahealth-careproviderevertoldyouthatyourchildhadwheezingorasthma?Childrenwhoseparentsorcaregiversansweryestothisquestionandchildrenwhohaveasthmaorwhohadawheezingepisodenotedinthemedicalrecordduringthepreceding12monthsshouldnotreceiveFluMist.
Liveattenuatedinfluenzavaccinecoadministrationhasbeenevaluatedsystematicallyonlyamongchildrenaged1215monthswhoreceivedmeaslesmumpsandrubellavaccineorvaricellavaccine.
**Inactivated influenzavaccinecoadministrationhasbeenevaluatedsystematicallyonlyamongadultswhoreceivedpneumococcalpolysaccharideo
zoster
vaccine.
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drenaregiven2doses,arethebasisfortherecommendationthatallchildrenaged6months,althoughestimates
havevaried.Inarandomizedtrialconductedduringfiveinfluenzaseasons(19851990)intheUnitedStatesamongchildrenaged115years,annualvaccinationreducedlaboratory-confirmedinfluenzaAsubstantially(77%91%)(106).Alimited1-yearplacebo-controlledstudyreportedvaccineefficacyagainstlaboratory-confirmedinfluenzaillnessof56%amonghealthychildrenaged39yearsand100%amonghealthy childrenand adolescents aged1018years(127).Arandomized,double-blind,placebo-controlledtrialconductedduringtwoinfluenzaseasonsamongchildrenaged624monthsindicatedthatefficacywas66%againstculture-confirmedinfluenzaillnessduring19992000,butdidnotsignificantlyreduceculture-confirmedinfluenzaillnessduring20002001(128).Inanonrandomizedcontrolledtrialamongchildrenaged26yearsand714yearswhohadasthma,vaccineefficacywas54%and78%againstlaboratory-confirmedinfluenzatypeAinfectionand22%and60%againstlaboratory-confirmedinfluenza typeB infection,respectively.Vaccinatedchildrenaged26yearswithasthmadidnothavesubstantiallyfewertypeBinfluenzavirusinfectionscomparedwiththecontrolgroupinthisstudy(129).Vaccinationalsomightprovideprotectionagainst asthmaexacerbations(130);however,otherstudiesofchildrenwith
asthmahavenotdemonstrateddecreasedexacerbations( 131).Becauseoftherecognizedinfluenza-relateddiseaseburdenamongchildrenwithotherchronicdiseasesorimmunosuppressionandthelong-standingrecommendationforvaccinationofthesechildren,randomizedplacebo-controlledstudiestostudyefficacyinthesechildrenhavenotbeenconductedbecauseofethicalconsiderations.
A retrospective study conducted among approximately30,000childrenaged6months8yearsduringaninfluenzaseason(200304)withasuboptimalvaccinematchindicatedvaccineeffectivenessof51%againstmedicallyattended,clinicallydiagnosedpneumoniaorinfluenza(i.e.,nolaboratory
confirmationofinfluenza)amongfullyvaccinatedchildren,and 49% among approximately 5,000childrenaged623months(125).AnotherretrospectivestudyofsimilarsizeconductedduringthesameinfluenzaseasoninDenverbutlimitedtohealthychildrenaged621monthsestimatedclinicaleffectivenessof2TIVdosestobe87%againstpneumoniaorinfluenza-relatedofficevisits( 121).Amongchildren,TIVeffectivenessmightincreasewithage(106,132).
TIVhasbeendemonstratedtoreduceacuteotitismediainsomestudies.TwostudieshavereportedthatTIVdecreasetheriskforinfluenza-associatedotitismediabyapproximately30%amongchildrenwithmeanagesof20and27monthsrespectively(133,134).However,alargestudyconductedamongchildrenwithameanageof14monthsindicatedtha
TIVwasnoteffectiveagainstacuteotitismedia(128).Influenzavaccineeffectivenessagainstacuteotitismedia,whichicausedbya varietyofpathogensandisnottypicallydiagnosedusinginfluenzavirusculture,wouldbeexpectedtoberelativelylowwhenassessinganonspecificclinicaloutcome.
Adults Aged
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aseasonwhenviruseswerewell-matchedtovaccineviruses.Effectivenessdidnotdecreasewithincreasingseverityofunderlyinglungdisease(151).
Studiesusingless specificoutcomes,withoutlaboratoryconfirmationofinfluenzavirusinfection,typicallyhavedemonstratedsubstantialreductionsinhospitalizationsordeaths
amongadultswithriskfactorsforinfluenzacomplications.Inacase-controlstudyconductedinDenmarkamongadultswithunderlyingmedicalconditionsaged60yearsreportedavaccineefficacyo58%againstinfluenzarespiratoryillnessduringaseasonwhenthevaccinestrainswereconsideredtobewell-matchedtocirculatingstrains,butindicatedthatefficacywasloweramongthoseaged>70years(178).InfluenzavaccineeffectivenessinpreventingMAARIamongtheelderlyinnursinghomeshasbeenestimatedat20%40%(179,180),andreportedoutbreaksamongwell-vaccinatednursinghomepopulationshavesuggestedthatvaccinationmightnothaveanysignifican
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effectivenesswhencirculatingstrainsaredriftedfromvaccinestrains(181,182).Incontrast,somestudieshaveindicatedthatvaccinationcanbeup to80% effectivein preventinginfluenza-relateddeath(179,183185).Amongelderlypersons notliving innursinghomesor similar chronic-carefacilities,influenzavaccineis27%70%effectiveinprevent
inghospitalizationforpneumoniaandinfluenza(186188).Influenzavaccinationreducesthefrequencyofsecondarycomplicationsandreducestheriskforinfluenza-relatedhospitalizationanddeathamongcommunity-dwellingadultsaged>65yearswithandwithouthigh-riskmedicalconditions(e.g.,heartdiseaseanddiabetes)(187192).However,studiesdemonstratinglargereductionsinhospitalizationsanddeathsamongthevaccinated elderlyhavebeenconductedusingmedicalrecorddatabasesandhavenotmeasuredreductionsinlaboratory-confirmedinfluenzaillness.Thesestudieshavebeenchallengedbecauseofconcernsthattheyhavenotadequatelycontrolledfordifferencesinthepropensityforhealthierper
sonstobemorelikelythanlesshealthypersonstoreceivevaccination(101,102,183,193195).
TIV Dosage, Administration,and Storage
ThecompositionofTIVvariesaccordingtomanufacturerandpackageinsertsshouldbeconsulted.TIVformulationsinmultidosevialscontainthevaccinepreservativethimerosal
preservative-freesingledosepreparationsalsoareavailableTIVshouldbestoredat35F46F(2C8C)andshouldnotbefrozen.TIVthathasbeenfrozenshouldbediscardedDosagerecommendationsandschedulesvaryaccordingtoagegroup(Table2).Vaccinepreparedforapreviousinfluenzaseasonshouldnotbeadministeredtoprovideprotectionforanysubsequentseason.
TheintramuscularrouteisrecommendedforTIV.Adultsandolderchildrenshouldbevaccinatedinthedeltoidmuscle.Aneedle lengthof>1 inch(>25mm)shouldbeconsideredforpersonsintheseagegroupsbecauseneedlesof36mos>36mos
>6mos
No. of
doses
1or2
1or2
1or2
1or2
Route
Intramuscular
Intramuscular
Intramuscular
Intramuscular
TIV* Fluvirin NovartisVaccine 5.0mLmulti-dosevial0.5mLpre-filled
syringe
24.54yrs>4
yrs
1or2
1
or
2Intramuscular
Intramuscular
TIV* Fluarix GlaxoSmithKline 0.5mLpre-filledsyringe 18yrs 1 Intramuscular
TIV* FluLuval GlaxoSmithKline 5.0mLmulti-dosevial 25 >18years 1 Intramuscular
TIV* Afluria CSLBiotherapies 0.5mLpre-filledsyringe5.0mLmulti-dosevial
025
>18years>18years
11 Intramuscular
LAIV FluMist** MedImmune 0.2mLsprayer 0 249yrs 1or2 Intranasal
* Trivalent inactivatedvaccine(TIV).A0.5-mLdose contains15 mcgeachofA/Brisbane/59/2007 (H1N1)-like,A/Brisbane/10/2007 (H3N2)-like,andB/Florida/4/2006-likeantigens.
Twodosesadministeredatleast1monthapartarerecommendedforchildrenaged6months8yearswhoarereceivingTIVforthefirsttimeandthosewhoonlyreceived1doseintheirfirstyearofvaccinationshouldreceive2dosesinthefollowingyear.
For adultsand older children, the recommended siteofvaccination is thedeltoid muscle.Thepreferred site for infantsand young children is theanterolateralaspectofthethigh.
Live
attenuated
influenza
vaccine(LAIV).A
0.2-mLdose
contains
106.57.5
fluorescentfocal
units
oflive
attenuated
influenza
virus
reassortants
ofeachofthethreestrainsforthe200809influenzaseason:A/Brisbane/59/2007(H1N1),A/Brisbane/10/2007(H3N2),andB/Florida/4/2006.**FluMistisshippedrefrigeratedandstoredintherefrigeratorat2Cto8Cafterarrivalinthevaccinationclinic.Thedoseis0.2mLdividedequallybetweeneachnostril.Health-careprovidersshouldconsult the medical record,whenavailable, to identifychildrenaged24yearswithasthmaor recurrenwheezingthatmightindicateasthma.Inaddition,toidentifychildrenwhomightbeatgreaterriskforasthmaandpossiblyatincreasedriskforwheezingafterreceivingLAIV,parentsorcaregiversofchildrenaged24yearsshouldbeasked:Inthepast12months,hasahealth-careproviderevertoldyouthatyourchildhadwheezingorasthma?Childrenwhoseparentsorcaregiversansweryestothisquestionandchildrenwhohaveasthmaorwhohadawheezingepisodenotedinthemedicalrecordduringthepreceding12months,shouldnotreceiveFluMist.
Twodosesadministeredatleast4weeksapartarerecommendedforchildrenaged28yearswhoarereceivingLAIVforthefirsttime,andthosewhoonlyreceived1doseintheirfirstyearofvaccinationshouldreceive2dosesinthefollowingyear.
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Infantsandyoungchildrenshouldbevaccinatedintheanterolateralaspectof thethigh.Aneedlelengthof7/81inchshouldbeusedforchildrenaged
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Among children with high-risk medical conditions, onestudyof52childrenaged6months3yearsreportedfeveramong27%andirritabilityandinsomniaamong25%( 113);andastudyamong33childrenaged618monthsreportedthatonechildhadirritabilityandonehadafeverandseizureaftervaccination(211).Noplacebocomparisongroupwas
usedinthesestudies.
Immunocompromised Persons
DatademonstratingsafetyofTIVforHIV-infectedpersonsarelimited,butnoevidenceexiststhatvaccinationhasaclinicallyimportantimpactonHIVinfectionorimmunocompetence.Onestudydemonstratedatransient(i.e.,24week)increaseinHIVRNA(ribonucleicacid)levels inoneHIV-infectedpersonafterinfluenzavirusinfection(212).StudieshavedemonstratedatransientincreaseinreplicationofHIV-1intheplasmaorperipheralbloodmononuclearcells
ofHIV-infectedpersonsaftervaccineadministration(159,213).However,morerecentandbetter-designedstudieshavenotdocumentedasubstantialincreaseinthereplicationofHIV(214217).CD4+T-lymphocytecellcountsorprogressionofHIVdiseasehavenotbeendemonstratedtochangesubstantiallyafterinfluenzavaccinationamongHIV-infectedpersonscomparedwithunvaccinatedHIV-infectedpersons(159,218).LimitedinformationisavailableabouttheeffectofantiretroviraltherapyonincreasesinHIVRNAlevelsaftereithernaturalinfluenzavirusinfectionorinfluenzavaccination(73,219).
Dataaresimilarlylimitedforpersonswithotherimmuno
compromisingconditions.Insmallstudies,vaccinationdidnotaffectallograftfunctionorcauserejectionepisodesinrecipientsofkidneytransplants( 162,164),hearttransplants(163),orlivertransplants(165).
Hypersensitivity
Immediateandpresumablyallergicreactions(e.g.,hives,angioedema,allergicasthma,andsystemicanaphylaxis)occurrarelyafterinfluenzavaccination(220,221).Thesereactionsprobablyresultfromhypersensitivitytocertainvaccinecomponents;themajorityofreactionsprobablyarecaused
byresidualeggprotein.Althoughinfluenzavaccinescontainonlyalimitedquantityofeggprotein,thisproteincaninduceimmediatehypersensitivityreactionsamongpersonswhohavesevereeggallergy.Manufacturersuseavarietyofdifferentcompoundstoinactivateinfluenzavirusesandaddantibioticstopreventbacterialcontamination.Packageinsertsshouldbeconsultedforadditionalinformation.
Personswhohavehadhivesorswellingofthelipsortongueorwhohaveexperiencedacuterespiratorydistressorwhocollapseaftereatingeggs,shouldconsultaphysicianfoappropriateevaluationtohelpdetermineifvaccineshouldbeadministered.PersonswhohavedocumentedimmunoglobulinE(IgE)-mediatedhypersensitivitytoeggs,includingthose
whohavehadoccupationalasthmarelatedtoeggexposureootherallergicresponsestoeggprotein,alsomightbeatincreasedriskforallergicreactionstoinfluenzavaccine,andconsultationwithaphysicianbeforevaccinationshouldbeconsidered(222224).
Hypersensitivityreactionstoothervaccinecomponentscanoccurbutarerare.Althoughexposuretovaccinescontainingthimerosal can lead tohypersensitivity, themajorityofpatientsdonothavereactionstothimerosalwhenitisadministeredasacomponentofvaccines,evenwhenpatchorintradermaltestsforthimerosalindicatehypersensitivity(225,226)Whenreported,hypersensitivity tothimerosal typicallyhasconsistedoflocaldelayedhypersensitivityreactions(225).
Guillain-Barr Syndrome and TIV
TheannualincidenceofGuillain-BarrSyndrome(GBS)is1020casesper1millionadults(227).Substantialevidenceexiststhatmultipleinfectiousillnesses,mostnotablyCampylobacter jejuni gastrointestinalinfectionsandupperrespiratorytractinfections,areassociatedwithGBS(228230)The1976swineinfluenzavaccinewasassociatedwithanincreasedfrequencyofGBS(231,232),estimatedatoneadditionalcaseofGBSper100,000personsvaccinated.The
riskforinfluenzavaccine-associatedGBSwashigheramongpersonsaged>25yearsthanamongpersonsaged
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during19922004demonstratedasmallbutstatisticallysignificanttemporalassociationbetweenreceivinginfluenzavaccinationandsubsequenthospitaladmissionforGBS.However,noincreaseincasesofGBSatthepopulationlevelwasreportedafterintroductionofamasspublicinfluenzavaccinationprograminOntariobeginningin2000(237).Data
fromVAERShavedocumenteddecreasedreportingofGBSoccurringaftervaccinationacrossagegroupsovertime,despiteoverallincreasedreportingofother,non-GBSconditionsoccurringafteradministrationofinfluenzavaccine(203).CasesofGBSafterinfluenzavirusinfectionhavebeenreported,butnootherepidemiologicstudieshavedocumentedsuchanassociation(238,239).RecentlypublisheddatafromtheUnitedKingdoms General Practice ResearchDatabase(GPRD)foundinfluenzavaccinetobeprotectiveagainstGBS,althoughitisunclearifthiswasassociatedwithprotectionagainstinfluenzaorconfoundingbecauseofahealthyvaccinee(e.g.,healthierpersonsmightbemorelikelytobevaccinatedandarelowerriskforGBS)(240).AseparateGPRDanalysisfoundnoassociationbetweenvaccinationandGBSovera9yearperiod;onlythreecasesofGBSoccurredwithin6weeksafterinfluenzavaccine(241).
IfGBSisasideeffectofinfluenzavaccinesotherthan1976swineinfluenzavaccine,theestimatedriskforGBS(onthebasisofthefewstudiesthathavedemonstratedanassociationbetweenvaccinationandGBS)islow(i.e.,approximatelyoneadditionalcaseper1millionpersonsvaccinated).Thepotentialbenefitsofinfluenzavaccinationinpreventingseriousillness,hospitalization,anddeathsubstantiallyoutweighthese
estimatesofriskforvaccine-associatedGBS.NoevidenceindicatesthatthecasefatalityratioforGBSdiffersamongvaccinatedpersonsandthosenotvaccinated.
Use of TIV among Patients witha History of GBS
TheincidenceofGBSamongthegeneralpopulationislow,butpersonswithahistoryofGBShaveasubstantiallygreaterlikelihoodofsubsequentlyexperiencingGBSthanpersonswithoutsuchahistory(227).Thus,thelikelihoodofcoincidentally experiencingGBS after influenza vaccinationis
expectedtobegreateramongpersonswithahistoryofGBSthanamongpersonswithnohistoryofthissyndrome.WhetherinfluenzavaccinationspecificallymightincreasetheriskforrecurrenceofGBSisunknown.However,avoidingvaccinatingpersonswhoarenotathighriskforsevereinfluenzacomplicationsandwhoareknowntohaveexperiencedGBSwithin6weeksafterapreviousinfluenzavaccinationmightbeprudentasaprecaution.Asanalternative,physiciansmightconsider using influenza antiviral chemoprophylaxis for these
persons.Althoughdataarelimited,theestablishedbenefitsoinfluenzavaccinationmightoutweightherisksformanypersonswhohaveahistoryofGBSandwhoarealsoathighriskforseverecomplicationsfrominfluenza.
Vaccine Preservative (Thimerosal)in Multidose Vials of TIV
Thimerosal,amercury-containinganti-bacterialcompoundhasbeenusedasapreservativeinvaccinessincethe1930s(242)andisused inmultidosevialpreparationsofTIVtoreducethelikelihoodofbacterialcontamination.Noscientificevidenceindicatesthatthimerosalinvaccines,includinginfluenzavaccines,isacauseofadverseeventsotherthanoccasionlocalhypersensitivityreactionsinvaccinerecipientsInaddition,noscientificevidenceexiststhatthimerosal-containingvaccinesareacauseofadverseeventsamongchildrenborntowomenwhoreceivedvaccineduringpregnancy
Evidenceisaccumulatingthatsupportstheabsenceofsubstantialriskforneurodevelopmentdisordersorotherharmresulting fromexposure to thimerosal-containingvaccine(243250).However,continuingpublicconcernaboutexposuretomercuryinvaccineswasviewedasapotentialbarriertoachievinghighervaccinecoveragelevelsandreducingtheburdenofvaccine-preventablediseases.Therefore,theU.SPublicHealthServiceandotherorganizationsrecommendedthat effortsbemade toeliminateor reduce thethimerosacontentinvaccinesaspartofastrategytoreducemercuryexposuresfromallsources(243,245,247).Sincemid-2001vaccinesroutinelyrecommendedforinfantsaged
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nodifferenceinthesafetyprofileofpreservative-containingcomparedwithpreservative-freeTIVvaccinesininfantsaged623months(202).
Nonetheless,certainstateshaveenactedlegislationbanningtheadministrationofvaccinescontainingmercury;theprovisionsdefiningmercurycontentvary(251).LAIVandmany
ofthesingledosevialorsyringepreparationsofTIVarethimerosal-free,andthenumberofinfluenzavaccinedosesthatdonotcontainthimerosalasapreservativeisexpectedtoincrease(Table2).However,theselawsmightpresentabarriertovaccinationunlessinfluenzavaccinesthatdonotcontainthimerosalasapreservativeareeasilyavailableinthosestates.
TheU.S.vaccinesupplyforinfantsandpregnantwomenisinaperiodoftransitionduringwhichtheavailabilityofthimerosal-reducedorthimerosal-freevaccineintendedforthesegroupsisbeingexpandedbymanufacturersasafeasiblemeansoffurtherreducinganinfantscumulativeexposuretomercury.Otherenvironmentalsourcesofmercuryexposurearemoredifficultorimpossibletoavoidoreliminate(243).
LAIV Dosage, Administration,and Storage
EachdoseofLAIVcontainsthesamethreevaccineantigensusedinTIV.However,theantigensareconstitutedaslive,attenuated,cold-adapted,temperature-sensitivevaccineviruses.AdditionalcomponentsofLAIVincludeeggallantoicfluid,monosodiumglutamate,sucrose,phosphate,andglutamatebuffer;andhydrolyzedporcinegelatin.LAIVdoesnot contain thimerosal. LAIV ismade from attenuatedvirusesthatareonlyabletoreplicateefficientlyattemperaturespresentinthenasalmucosa.LAIVdoesnotcausesystemicsymptomsofinfluenzainvaccinerecipients,althoughaminorityofrecipientsexperiencenasalcongestion,whichisprobablyaresultofeithereffectsofintranasalvaccineadministrationorlocalviralreplicationorfever(252).
LAIVisintendedforintranasaladministrationonlyandshouldnotbeadministeredbytheintramuscular,intradermal,orintravenousroute.LAIVisnotlicensedforvaccinationofchildrenaged49years.LAIVis supplied ina prefilled, single-use sprayer containing
0.2mLofvaccine.Approximately0.1mL(i.e.,halfofthetotalsprayercontents)issprayedintothefirstnostrilwhiletherecipientisintheuprightposition.Anattacheddose-dividerclipis removedfromthesprayerto administerthesecondhalfofthedoseintotheothernostril.LAIVisshippedtoendusersat35F46F(2C8C).LAIVshouldbestoredat35F46F(2C8C)onreceiptandcanremainatthattemperatureuntiltheexpirationdateisreached(252).Vac
cinepreparedforapreviousinfluenzaseasonshouldnotbadministeredtoprovideprotectionforanysubsequentseason.
Shedding, Transmission, and Stabilityof Vaccine Viruses
AvailabledataindicatethatbothchildrenandadultsvaccinatedwithLAIVcanshedvaccinevirusesaftervaccinationalthoughinloweramountsthanoccurtypicallywithsheddingofwild-typeinfluenzaviruses.Inrareinstances,shedvaccinevirusescanbetransmittedfromvaccinerecipientstounvaccinatedpersons.However,seriousillnesseshavenotbeenreportedamongunvaccinatedpersonswhohavebeeninfectedinadvertentlywithvaccineviruses.
Onestudyofchildrenaged836monthsinachildcarecenterassessedtransmissibilityofvaccinevirusesfrom98vaccinatedto99unvaccinatedsubjects;80%ofvaccinerecipientsshedoneormorevirusstrains(meanduration:7.6days).
OneinfluenzatypeBvaccinestrainisolatewasrecoveredfromaplaceborecipientandwasconfirmedtobevaccine-typevirusThetypeBisolateretainedthecold-adapted,temperature-sensitive,attenuatedphenotype,and itpossessedthe samegeneticsequenceasavirusshedfromavaccinerecipientwhwasinthesameplaygroup.TheplaceborecipientfromwhomtheinfluenzatypeBvaccinestrainwasisolatedhadsymptomsofamildupperrespiratoryillnessbutdidnotexperienceanyseriousclinicalevents.TheestimatedprobabilityoacquiringvaccinevirusafterclosecontactwithasingleLAIVrecipientinthischildcarepopulationwas0.6%2.4%(253)
StudiesassessingwhethervaccinevirusesareshedhavebeenbasedonviralculturesorPCRdetectionofvaccinevirusesinnasalaspiratesfrompersonswhohavereceivedLAIV.Onestudyof20healthyvaccinatedadultsaged1849yearsdemonstratedthatthemajorityofsheddingoccurredwithinthefirst3daysaftervaccination,althoughthevaccineviruswasdetectedinonesubjectonday7aftervaccinereceipt.DurationortypeofsymptomsassociatedwithreceiptofLAIVdidnotcorrelatewithdetectionofvaccinevirusesinnasalaspirates(254).Anotherstudyin14healthyadultsaged1849yearsindicatedthat50%oftheseadultshadviralantigendetectedbydirectimmunofluorescenceorrapidantigentest
within7daysofvaccination.Themajorityofsampleswithdetectableviruswerecollectedonday2or3(255).Vaccinestrainviruswasdetectedfromnasalsecretionsinone(2%)o57HIV-infectedadultswhoreceivedLAIV,noneof54HIV-negativeparticipants(256),andthree(13%)of23HIVinfectedchildrencomparedwithseven(28%)of25childrenwhowerenotHIV-infected(257).Noparticipantsinthesestudieshaddetectablevirusbeyond10daysafterreceipto
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LAIV.Thepossibilityofperson-to-persontransmissionofvaccineviruseswasnotassessedinthesestudies(254257).
Inclinicaltrials,virusesisolatedfromvaccinerecipientshavebeenphenotypicallystable.Inonestudy,nasalandthroatswabspecimenswerecollected from17studyparticipantsfor 2weeksaftervaccinereceipt(258).Virusisolateswereanalyzed
bymultiplegenetictechniques.AllisolatesretainedtheLAIVgenotypeafterreplicationinthehumanhost,andallretainedthe cold-adaptedand temperature-sensitivephenotypes. Astudyconductedinachild-caresettingdemonstratedthatlimitedgeneticchangeoccurredintheLAIVstrainsfollowingreplicationinthevaccinerecipients(259).
Immunogenicity, Efficacy,and Effectiveness of LAIV
LAIVvirusstrainsreplicateprimarilyinnasopharyngealepithelialcells.Theprotectivemechanismsinducedbyvacci
nationwithLAIVarenotunderstoodcompletelybutappeartoinvolveboth serumand nasalsecretoryantibodies.TheimmunogenicityoftheapprovedLAIVhasbeenassessedinmultiplestudiesconductedamongchildrenandadults(106,260266).No singlelaboratorymeasurement closelycorrelateswithprotectiveimmunityinducedbyLAIV(261).
Healthy Children
Arandomized,double-blind,placebo-controlledtrialamong1,602healthychildrenaged1571monthsassessedtheefficacyofLAIVagainstculture-confirmedinfluenzaduringtwoseasons(267,268).Thistrialincludedasubsetofchildren
aged6071monthswhoreceived2dosesinthefirstseason.Inseasonone(199697),whenvaccineandcirculatingvirusstrainswerewell-matched,efficacyagainstculture-confirmedinfluenzawas94%forparticipantswhoreceived2dosesofLAIVseparatedby>6weeks,and89%forthosewhoreceived1dose.Inseasontwo,whentheA(H3N2)componentinthevaccinewasnotwell-matchedwithcirculatingvirusstrains,efficacy(1dose)was86%,for anoverallefficacyovertwoinfluenzaseasonsof92%.ReceiptofLAIValsoresultedin21%fewerfebrileillnessesandasignificantdecreaseinacuteotitismediarequiringantibiotics(267,269).Otherrandomized,placebo-controlledtrialsdemonstratingtheefficacyofLAIVinyoungchildrenagainstculture-confirmedinfluenzaincludeastudyconductedamongchildrenaged635monthsattendingchildcarecentersduringconsecutiveinfluenzaseasons(270),inwhich85%89%efficacywasobserved,andastudyconductedamongchildrenaged1236monthslivinginAsiaduringconsecutiveinfluenzaseasons,inwhich64%70%efficacywasdocumented(271).Inonecommunity-based,nonrandomizedopen-labelstudy,reductionsinMAARI
wereobservedamongchildrenwhoreceived1doseofLAIVduringthe199000and200001influenzaseasonseventhoughantigenicallydriftedinfluenzaA/H1N1andBvirusewerecirculatingduringthatseason(272).LAIVefficacyinpreventinglaboratoryconfirmedinfluenzahasalsobeendemonstratedinstudiescomparingtheefficacyofLAIVwithTIV
ratherthanwithaplacebo(seeComparisonsof LAIVandTIVEfficacyorEffectiveness).
Healthy Adults
A randomized, double-blind, placebo-controlled trial oLAIVeffectivenessamong4,561healthyworkingadultsaged1864yearsassessedmultipleendpoints,includingreductionsinself-reportedrespiratorytractillnesswithoutlaboratoryconfirmation,workloss,health-carevisits,andmedicationuseduringinfluenzaoutbreakperiods(273).Thestudywaconductedduringthe199798influenzaseason,whenthevaccine and circulatingA (H3N2) strainswerenotwell
matched.ThefrequencyoffebrileillnesseswasnotsignificantlydecreasedamongLAIVrecipientscomparedwiththosewhoreceivedplacebo.However,vaccinerecipientshadsignificantlyfewerseverefebrileillnesses(19%reduction)andfebrileupperrespiratorytractillnesses(24%reduction),andsignificantreductionsindaysofillness,daysofworklost,dayswithhealth-careprovidervisits,anduseofprescriptionantibioticsandover-the-countermedications(273).Efficacyagainstculture-confirmedinfluenzainarandomized,placebo-controlledstudywas57%,althoughefficacyinthisstudywasnotdemonstratedtobesignificantlygreaterthanplacebo(155).
Adverse Events after Receipt of LAIV
Healthy Children Aged 218 Years
Inasubsetofhealthychildrenaged6071monthsfromoneclinicaltrial(233),certainsignsandsymptomswerereportedmoreoftenafterthefirstdoseamongLAIVrecipients(n=214)thanamongplaceborecipients(n=95),includingrunnynose(48%and44%,respectively);headache(18%and12%,respectively);vomiting(5%and3%,respectively);andmyalgias(6%and4%,respectively).Howeverthesedifferenceswerenotstatisticallysignificant.Inothertri
als,signsandsymptomsreportedafterLAIVadministrationhaveincludedrunnynoseornasalcongestion(20%75%)headache(2%46%),fever(026%),vomiting(3%13%),abdominalpain(2%),andmyalgias(021%)(106,260,263265,270,273276).These symptoms wereassociatedmoreoftenwiththefirstdoseandwereself-limited.
Inarandomizedtrialpublishedin2007,LAIVandTIVwere compared among children aged 659 months (277)Childrenwithmedicallydiagnosedortreatedwheezingwithin
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42daysbeforeenrollment,orahistoryofsevereasthma,wereexcludedfromthisstudy.Amongchildrenaged2459monthswhoreceivedLAIV,the rateofmedically significantwheezing,usingapre-specifieddefinition,wasnotgreatercomparedwiththosewhoreceivedTIV(277);wheezingwasobservedmorefrequentlyamongyoungerLAIVrecipientsinthisstudy
(seePersonsatHigherRiskfromInfluenza-RelatedComplications).Inapreviousrandomizedplacebo-controlledsafetytrialamongchildrenaged12months17yearswithoutahistoryofasthmabyparentalreport,anelevatedriskforasthmaevents(RR=4.06,CI=1.2917.86)wasdocumentedamong728childrenaged1835monthswhoreceivedLAIV.Ofthe16childrenwithasthma-relatedeventsinthisstudy,sevenhadahistoryofasthmaonthebasisofsubsequentmedicalrecordreview.Nonerequiredhospitalization,andelevatedrisksforasthmawerenotobservedinotheragegroups(276).
Anotherstudywasconductedamong>11,000childrenaged18months18yearsinwhich18,780dosesofvaccinewereadministeredfor4years.Forchildrenaged18months4years,noincreasewasreportedinasthmavisits015daysaftervaccinationcomparedwiththeprevaccinationperiod.Asignificantincreaseinasthmaeventswasreported1542daysaftervaccination,butonlyinvaccineyear1(278).
InitialdatafromVAERSduring20072008,followingACIPrecommendation forLAIVuse inchildrenaged24years,donotsuggestaconcernforwheezingafterLAIVinyoungchildren.HoweverdataalsosuggestuptakeofLAIVislimitedandcontinuedsafetymonitoringforwheezingeventsafterLAIVisindicated(CDC,unpublisheddata,2008).
Adults Aged 1949 Years
Amongadults,runnynoseornasalcongestion(28%78%),headache(16%44%),andsorethroat(15%27%)havebeenreportedmoreoftenamongvaccinerecipientsthanplaceborecipients(252,279).Inoneclinicaltrialamongasubsetofhealthyadultsaged1849years,signsandsymptomsreportedmorefrequentlyamongLAIVrecipients(n=2,548)thanplaceborecipients(n=1,290)within7daysaftereachdoseincludedcough (14%and11%,respectively);runnynose(45%and27%, respectively); sore throat (28%and17%,respectively);chills(9%and6%,respectively);andtiredness/
weakness(26%and22%,respectively)(279).Persons at Higher Risk for Influenza-RelatedComplications
LimiteddataassessingthesafetyofLAIVuseforcertaingroupsathigherriskforinfluenza-relatedcomplicationsareavailable.Inonestudyof54HIV-infectedpersonsaged1858yearsandwithCD4counts>200cells/mm3whoreceivedLAIV,noseriousadverseeventswerereportedduringa
1-monthfollow-upperiod(256).Similarly,onestudydemonstratednosignificantdifferenceinthefrequencyofadverseeventsorviralsheddingamongHIV-infectedchildrenaged18yearsoneffectiveantiretroviraltherapywhowereadministeredLAIV,comparedwithHIV-uninfectedchildrenreceivingLAIV(257).LAIVwaswell-toleratedamongadultsaged
>65yearswithchronicmedicalconditions(280).ThesefindingssuggestthatpersonsatriskforinfluenzacomplicationwhohaveinadvertentexposuretoLAIVwouldnothavesignificantadverseeventsorprolongedviralsheddingandthapersonswhohavecontactwithpersonsathigherriskforinfluenza-relatedcomplicationsmayreceiveLAIV.
Serious Adverse Events
SeriousadverseeventsafteradministrationofLAIVrequiringmedicalattentionamonghealthychildrenaged517yearsorhealthyadultsaged1849yearsoccurredatarateof
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tionalstudyconductedinRussiademonstratedreductionsinILIamongthecommunity-dwellingelderlyafterimplementationofavaccinationprogramusingTIVforchildrenaged36years(57%coverageachieved)andchildrenandadolescentsaged717years(72%coverageachieved)(300).Inanonrandomizedcommunity-basedstudyconductedoverthree
influenzaseasons,8%18%reductionsintheincidenceofMAARIduringtheinfluenzaseasonamongadultsaged>35 yearswereobservedin communitiesin whichLAIVwasofferedtoallchildrenaged>18months(estimatedcoveragerate:20%25%)comparedwithcommunitieswithsuchvaccinationprograms(297).Inasubsequentinfluenzaseason,thesameinvestigatorsdocumenteda9%reductioninMAARIratesduringtheinfluenzaseasonamongpersonsaged3544yearsininterventioncommunities,wherecoveragewasestimatedat31%amongschoolchildren,comparedwithcontrolcommunities.However,MAARIratesamongpersonsaged>45yearswerelowerintheinterventioncommunitiesregardlessofthepresenceofinfluenzainthecommunity,suggestingthatlowerratescouldnotbeattributedtovaccinationofschoolchildrenagainstinfluenza(301).
Effectiveness of Influenza Vaccinationwhen Circulating Influenza VirusStrains Differ from Vaccine Strains
Manufacturingtrivalentinfluenzavirusvaccinesisachallengingprocessthattakes68monthstocomplete.Thismanufacturingtimeframerequiresthatinfluenzavaccinestrainsfor
influenzavaccinesusedintheUnitedStatesmustbeselectedinFebruaryofeachyearbytheFDAtoallowtimeformanufacturerstopreparevaccinesforthenextinfluenzaseason.Vaccinestrainselectionsarebasedonglobalviralsurveillancedatathatisusedtoidentifytrendsinantigenicchangesamongcirculatinginfluenzavirusesandtheavailabilityofsuitablevaccineviruscandidates.
Vaccinationcanprovidereducedbutsubstantialcross-protectionagainstdriftedstrainsinsomeseasons,includingreductionsinsevereoutcomessuchashospitalization.Usuallyoneormorecirculatingviruseswithantigenicchangescomparedwiththevaccinestrainsareidentifiedineachinflu
enzaseason.However,assessmentoftheclinicaleffectivenessofinfluenzavaccinescannotbedeterminedsolelybylaboratoryevaluationofthedegreeofantigenicmatchbetweenvaccineandcirculatingstrains.Insomeinfluenzaseasons,circulatinginfluenzaviruseswithsignificantantigenicdifferencespredominateand,comparedwithseasonswhenvaccineandcirculatingstrainsarewell-matched,reductionsinvaccineeffectivenessaresometimesobserved(126,139,145,147,191).However,evenduringyearswhenvaccinestrains
werenotantigenicallywellmatchedtocirculatingstrains,substantialprotectionhasbeenobservedagainstsevereoutcomes,presumablybecauseofvaccine-inducedcross-reactingantibodies(139,145,147,273).Forexample,inonestudyconductedduringaninfluenzaseason(200304)whenthepredominantcirculatingstrainwasaninfluenzaA(H3N2
virusthatwasantigenicallydifferentfromthatseasonsvaccinestrain,effectivenessamongpersonsaged5064yearagainstlaboratory-confirmedinfluenzaillnesswas60%amonghealthypersonsand48%amongpersonswithmedicalconditionsthatincreaseriskforinfluenzacomplications(147).Aninterim,within-seasonanalysisduringthe200708influenzaseasonindicatedthatvaccineeffectivenesswas44%overall54%amonghealthypersonsaged549years,and58%againstinfluenzaA,despitethefindingthatvirusescirculatinginthstudyareawerepredominatelyadriftedinfluenzaAH3N2andainfluenzaBstrainfromadifferentlineagecomparedwithvaccinestrains (302).Amongchildren,bothTIVandLAIVprovideprotectionagainst infectioneven inseasonwhenvaccinesand circulatingstrains arenotwell matchedVaccineeffectivenessagainstILIwas49%69%intwoobservationalstudies,and49%againstmedicallyattended,laboratory-confirmedinfluenzainacase-controlstudyconductedamongyoungchildrenduringthe200304influenzaseasonwhenadriftedinfluenzaAH3N2strainpredominated,basedonviralsurveillancedata( 121,125).However,continuedimprovementsincollectingrepresentativecirculatingvirusesandusesurveillancedatatoforecastantigenicdriftareneededShorteningmanufacturingtimetoincreasethetimetoiden
tifygoodvaccinecandidatestrainsfromamongthemostrecentcirculatingstrainsalsoisimportant.Datafrommultipleseasonsandcollectedinaconsistentmannerareneededtobetterunderstandvaccineeffectivenessduringseasonswhencirculatingandvaccinevirusstrainsarenotwell-matched.
Cost-Effectiveness of InfluenzaVaccination
Economicstudiesofinfluenzavaccinationaredifficulttcomparebecausetheyhaveuseddifferentmeasuresofbothcostsand benefits (e.g., cost-only, cost-effectiveness,cost
benefit,orcost-utility).However,moststudiesfindthatvaccinationreducesorminimizeshealthcare,societal,andindividualcosts,ortheproductivitylossesandabsenteeismassociatedwithinfluenzaillness.OnenationalstudyestimatedtheannualeconomicburdenofseasonalinfluenzaintheUnitedStates(using2003populationanddollars)tobe$87.1billion,including$10.4billionindirectmedicalcosts(303)
StudiesofinfluenzavaccinationintheUnitedStatesamongpersonsaged>65yearshavedocumentedsubstantialreduc
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tionsinhospitalizationsanddeathsandoverallsocietalcostsavings(186,187).Studiescomparingadultsindifferentagegroupsalsofindthatvaccinationiseconomicallybeneficial.Onestudythatcomparedtheeconomicimpactofvaccinationamongpersonsaged>65yearswiththoseaged1564yearsindicatedthatvaccinationresultedinanetsavingsper
quality-adjustedlifeyear(QALY)andthattheMedicareprogramsavedcostsoftreatingillnessbypayingforvaccination(304).Astudyofalargerpopulationcomparingpersonsaged5064yearswiththoseaged>65years estimatedthecost-effectivenessofinfluenzavaccinationtobe$28,000perQALYsaved(in2000dollars)inpersonsaged5064yearscomparedwith$980perQALYsavedamongpersons aged>65years(305).
Economicanalysesamongadultsaged50yearsandforhigh-riskadultsofallages.Forhealthyadultsaged1849years,preventinganepisodeofinfluenzawouldcost$90ifvaccinationweredeliveredinapharmacysetting,$210inamassvaccinationsetting,and$870duringascheduleddoctorsofficevisit(315).Medicarepaymentratesinrecentyearshavebeenlessthanthecostsassociatedwithpro
vidingvaccinationinamedicalpractice(316).
Vaccination Coverage Levels
Continuedannualmonitoringisneededtodeterminetheeffectsonvaccinationcoverageofvaccinesupplydelaysandshortages,changesininfluenzavaccinationrecommendationandtargetgroupsforvaccination,reimbursementratesforvaccineandvaccineadministration,andotherfactorsrelatedtovaccinationcoverageamongadultsandchildren.Oneothenationalhealthobjectivesfor2010includesachievinganinfluenzavaccinationcoveragelevelof90%forpersonsaged
>65yearsandamongnursinghomeresidents(317,318);newstrategiestoimprovecoverageareneededtoachievethesobjectives(319,320).Increasingvaccinationcoverageamongpersonswhohavehigh-riskconditionsandareaged65yearsand5064yearsincreasedslightlyfrom32%and65%,respectivelyto36%and66%(Table3)and
appeartobeapproachingcoveragelevelsobservedbeforethe200405vaccineshortageyear.In200506and200607estimatedvaccinationcoveragelevelsamongadultswithhigh-riskconditionsaged1849yearswere23%and26%,respectively,substantiallylowerthanthe Healthy People 2000 andHealthy People 2010 objectivesof60%(Table3)(317,318).
Opportunitiestovaccinatepersonsatriskforinfluenzacomplications (e.g., duringhospitalizations forother causesoftenaremissed.InastudyofhospitalizedMedicarepatients,only31.6%werevaccinatedbeforeadmission,1.9%duringadmission,and10.6%afteradmission(321).AstudyinNewYork City during 20012005 among 7,063 children aged623monthsindicatedthat2-dosevaccinecoverageincreasedfrom1.6%to23.7%.Althoughtheaveragenumberofmedicalvisitsduringwhichanopportunitytobevaccinateddecreasedduringthecourseofthestudyfrom2.9to2.0perchild,55%ofallvisitsduringthefinalyearofthestudystillrepresentedamissedvaccinationopportunity(322).Usingstandingordersinhospitalsincreasesvaccinationratesamonghospitalizedpersons(323).Inonesurvey,thestrongestpre
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TABLE 3. Influenza vaccination* coverage levels for the 200506 and 200607 influenza seasons, among population groups National Health Interview Survey (NHIS), United States, 2006 and 2007, and National Immunization Survey (NIS), 2006
200506 season 200607 season
Crude Influenza Crude Influenza
sample vaccination level sample vaccination level
Population Group size % (95% CI) size % (95% CI)
Persons with an age indication
Aged
623mos(NIS) 13,546
32.2
(30.933.5) NA
Aged24yrs 611 26.4 (22.231.0) 853 37.9 (34.241.7)Aged5064yrs 2,843 31.6 (29.533.8) 3,746 36.0 (34.038.0)
Aged>65yrs 2,328 64.5 (62.666.8) 3,086 65.6 (63.367.9)
Persons with high-risk conditions**Aged517yrs 376 22.1 (17.128.2) 387 33.0 (26.240.7)
Aged1849yrs 937 23.4 (20.226.9) 1,186 25.5 (22.428.9)
Aged5064yrs 878 44.3 (40.248.5) 1,117 46.1 (42.849.4)Aged1864yrs 1,815 33.4 (30.536.5) 2,303 35.3 (33.037.7)
Persons without high-risk conditions
Aged517yrs 2,679 12.4 (10.914.1) 3,307 17.5 (15.919.2)Aged1849yrs 6,275 13.4 (12.414.6) 7,905 15.3 (14.216.4)
Aged5064yrs 1,956 26.0 (23.728.4) 2,619 31.8 (29.534.1)
Pregnant women 126 12.3 (7.220.4) 177 13.4 (8.520.5)
Health-care workers 833 41.8 (37.446.3) NA
Household contacts of persons at high risk,including children aged
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Reported vaccinationlevelsare low among children atincreasedriskforinfluenzacomplications.Coverageamongchildrenaged217yearswithasthmaforthe200405influenzaseasonwasestimatedtobe29%(329).Onestudyreported79%vaccinationcoverageamongchildrenattendingacysticfibrosistreatmentcenter(330).Duringthefirst
seasonforwhichACIPrecommendedthatallchildrenaged6months23monthsreceivevaccination,33%receivedoneormoredoseofinfluenzavaccination,and18%received2dosesiftheywereunvaccinatedpreviously(331).AmongchildrenenrolledinHMOswhohadreceivedafirstdoseduring20012004,seconddosecoveragevariedfrom29%to44%amongchildrenaged623monthsandfrom12%to24%amongchildrenaged28years(332).ArapidanalysisofinfluenzavaccinationcoveragelevelsamongmembersofanHMOinNorthernCaliforniademonstratedthatduring20042005,thefirstyearoftherecommendationforvaccinationofchildrenaged623months,1-dosecoveragewas57%(333).Duringthe200506influenzaseason,thesecondseasonforwhichACIPrecommendedthatallchildrenaged6months23monthsreceivevaccination,coverageremainedlowanddidnotincreasesubstantiallyfromthe200405season.Datacollectedin2006bytheNationalImmunizationSurveyindicatedthatforthe200506season,32%ofchildrenaged623monthsreceivedatleast1doseofinfluenzavaccineand21%werefullyvaccinated(i.e.,received1or2dosesdependingonpreviousvaccinationhistory);however,resultsvariedsubstantiallyamongstates(334).Ashasbeenreportedforolderadults,aphysicianrecommendationforvaccinationandthepercep
tionthathavingachildbevaccinatedisasmartideawereassociatedpositivelywithlikelihoodofvaccinationofchildrenaged623months(335).Similarly,childrenwithasthmaweremorelikelytobevaccinatediftheirparentsrecalledaphysicianrecommendationtobevaccinatedorbelievedthatthevaccineworkedwell(336).Implementationofareminder/recallsysteminapediatricclinicincreasedthepercentageofchildrenwithasthmaorreactiveairwaysdiseasereceivingvaccinationfrom5%to32%(337).
AlthoughannualvaccinationisrecommendedforHCPandisa highpriority forreducing morbidityassociated withinfluenzainhealth-caresettingsandforexpandinginfluenza
vaccineuse(338340),nationalsurveydatademonstratedavaccinationcoveragelevelofonly42%amongHCPduringthe200506season(Table3).VaccinationofHCPhasbeenassociatedwithreducedworkabsenteeism(286)andwithfewerdeathsamongnursinghomepatients(292,293)andelderlyhospitalizedpatients(294).Factorsassociatedwithahigher
rateofinfluenzavaccinationamongHCPincludeolderage,beingahospitalemployee,havingemployerprovidedhealthcareinsurance,havinghadpneumococcalorhepatitisBvaccinationinthepast,orhavingvisitedahealth-careprofessionaduringtheprecedingyear.Non-HispanicblackHCPwerelesslikelythannon-HispanicwhiteHCPtobevaccinated
(341).BeliefsthatarefrequentlycitedbyHCPwhodeclinevaccinationincludedoubtsabouttheriskforinfluenzaandtheneedforvaccination,concernsaboutvaccineeffectivenessandsideeffects,anddislikeofinjections(342).
Vaccinecoverageamongpregnantwomenhasnotincreasedsignificantlyduringtheprecedingdecade.(343).Only12%and13%ofpregnantwomenparticipatinginthe2006and2007NHISreportedvaccinationduringthe200506and200607seasons,respectively,excludingpregnantwomenwhoreporteddiabetes,heartdisease,lungdisease,andotherselectedhigh-riskconditions(Table3).Inastudyofinfluenzavaccineacceptancebypregnantwomen,71%ofthoswhowereofferedthevaccinechosetobevaccinated(344)However,a1999surveyofobstetriciansandgynecologistsdeterminedthatonly39%administeredinfluenzavaccinetoobstetricpatientsintheirpractices,although86%agreedthatpregnantwomensriskforinfluenza-relatedmorbidityandmortalityincreasesduringthelasttwotrimesters(345).
Influenzavaccinationcoverageinallgroupsrecommendedforvaccinationremainssuboptimal.Despitethetimingofthepeakofinfluenzadisease,administrationofvaccinedecreasesubstantiallyafterNovember.AccordingtoresultsfromtheNHISregardingthetwomostrecentinfluenzaseasonsfor
which these data are available, approximately 84% of alinfluenzavaccinationwereadministeredduringSeptemberNovember.Amongpersonsaged>65years,thepercentageoSeptemberNovembervaccinationswas92%(346).BecausemanypersonsrecommendedforvaccinationremainunvaccinatedattheendofNovember,CDCencouragespublichealthpartnersandhealth-careproviderstoconductvaccinationclinicsandotheractivitiesthatpromoteinfluenzavaccinationannuallyduringNationalInfluenzaVaccinationWeekandthroughouttheremainderoftheinfluenzaseason.
Self-reportofinfluenzavaccinationamongadults,comparedwithdeterminingvaccinationstatusfromthemedicalrecord
isasensitiveandspecificsourceofinformation(347).Patientself-reportsshouldbeacceptedasevidenceofinfluenzavaccinationinclinicalpractice(347).However,informationonthevalidityofparentsreportsofpediatricinfluenzavaccinationisnotyetavailable.
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Recommendations for UsingTIV and LAIV During the
200809 Influenza Season
BothTIVandLAIVpreparedforthe200809seasonwillincludeA/Brisbane/59/2007(H1N1)-like,A/Brisbane/10/
2007(H3N2)-like,andB/Florida/4/2006-likeantigens.TheseviruseswillbeusedbecausetheyarerepresentativeofinfluenzavirusesthatareforecastedtobecirculatingintheUnitedStatesduringthe200809influenzaseasonandhavefavorablegrowthpropertiesineggs.
TIVandLAIVcanbeusedtoreducetheriskforinfluenzavirusinfectionanditscomplications.Vaccinationprovidersshouldadministerinfluenzavaccinetoanypersonwhowishestoreducethelikelihoodofbecomingillwithinfluenzaortransmittinginfluenzatoothersshouldtheybecomeinfected.
Healthy,nonpregnantpersonsaged249yearscanchoosetoreceiveeithervaccine.SomeTIVformulationsareFDA-licensedforuseinpersonsasyoungasage6months(seeRecommendedVaccinesforDifferentAgeGroups).TIVislicensedforuseinpersonswithhigh-riskconditions.LAIVisFDA-licensedforuseonlyforpersonsaged249years.Inaddition,FDAhasindicatedthatthesafetyofLAIVhasnotbeenestablishedinpersonswithunderlyingmedicalconditionsthatconferahigherriskforinfluenzacomplications.Allchildrenaged6months8yearswhohavenotbeenvaccinatedpreviouslyatanytimewithatleast1doseofeitherLAIVorTIVshouldreceive2dosesofage-appropriatevaccineinthesameseason,withasingledoseduringsubsequent
seasons.
Target Groups for Vaccination
Influenzavaccineshouldbeprovidedtoallpersonswhowanttoreducetheriskofbecoming illwith influenzaoroftransmittingittoothers.However,emphasisonprovidingroutinevaccinationannuallytocertaingroupsathigherriskforinfluenzainfectionorcomplicationsisadvised,includingall childrenaged6 months18years,allpersonsaged>50years,andotheradultsatriskformedicalcomplicationsfrominfluenzaormorelikelytorequiremedicalcareshouldreceiveinfluenzavaccineannually.Inaddition,allpersonswholivewithorcareforpersonsathighriskforinfluenza-relatedcomplications,includingcontactsofchildrenaged
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anytimeshouldreceive1doseofthe200809influenzavaccine.Childrenaged6months8yearswhoonlyreceivedasinglevaccinationduringa seasonbefore200708shouldreceive1doseofthe200809influenzavaccine.Ifpossible,bothdosesshouldbeadministeredbeforeonsetofinfluenzaseason.However,vaccination,includingtheseconddose, is
recommendedevenafterinfluenzavirusbeginstocirculateinacommunity.
HCP and Other Persons Who CanTransmit Influenza to Thoseat High Risk
Healthypersonswhoareinfectedwithinfluenzavirus,includingthosewithsubclinicalinfection,cantransmitinfluenzavirustopersonsathigherriskforcomplicationsfrominfluenza.InadditiontoHCP,groupsthatcantransmitinfluenzatohigh-riskpersonsandthatshouldbevaccinated
include employeesofassistedlivingandotherresidencesforper
sonsingroupsathighrisk; personswhoprovidehomecaretopersonsingroupsat
highrisk;and householdcontacts (including children)ofpersons in
groupsathighrisk.Inaddition,becausechildrenaged
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LAIVtransmissionfromarecentlyvaccinatedpersoncausingclinicallyimportantillnessinanimmunocompromisedcontacthasnotbeenreported.TherationaleforavoidinguseofLAIVamongHCPorotherclosecontactsofseverelyimmunocompromisedpatientsisthetheoreticalriskthatalive,attenuatedvaccineviruscouldbetransmittedtothe
severelyimmunosuppressedperson.Asaprecautionarymeasure,HCPwhoreceiveLAIVshouldavoidprovidingcareforseverelyimmunosuppressedpatientsfor7daysaftervaccination.HospitalvisitorswhohavereceivedLAIVshouldavoidcontactwithseverelyimmunosuppressedpersonsinprotectedenvironmentsfor7daysaftervaccinationbutshouldnotberestrictedfromvisitinglessseverelyimmunosuppressedpatients.
NopreferenceisindicatedforTIVusebypersonswhohaveclosecontactwithpersonswithlesserdegreesofimmunosuppression(e.g.,personswithdiabetes,personswithasthmawhotakecorticosteroids,personswhohaverecentlyreceivedchemotherapyorradiationbutwhoarenotbeingcaredforinaprotectiveenvironmentasdefinedabove,orpersonsinfectedwithHIV)orforTIVusebyHCPorotherhealthynonpregnantpersonsaged249yearsinclosecontactwithpersonsinallothergroupsathighrisk.
Pregnant Women
Pregnantwomenareatriskforinfluenzacomplications,andallwomenwhoarepregnantorwillbepregnantduringinfluenzaseasonshouldbevaccinated.TheAmericanCollegeofObstetriciansandGynecologistsandtheAmericanAcademyofFamilyPhysiciansalsohaverecommendedroutinevacci
nationofallpregnantwomen(357).NopreferenceisindicatedforuseofTIV thatdoesnotcontainthimerosalas apreservative(seeVaccinePreservative[Thimerosal]inMultidoseVialsofTIV)foranygrouprecommendedforvaccination,includingpregnantwomen.LAIVisnotlicensedforuseinpregnantwomen.However,pregnantwomendonotneedtoavoidcontactwithpersonsrecentlyvaccinatedwithLAIV.
Breastfeeding Mothers
Vaccinationisrecommendedforallpersons,including
breastfeedingwomen,whoarecontactsofinfantsorchildrenaged
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Recommended Vaccines for DifferentAge Groups
Whenvaccinatingchildrenaged635monthswithTIV,health-careprovidersshoulduseTIVthathasbeenlicensedbytheFDAforthisagegroup(i.e.,TIVmanufacturedby
SanofiPasteur([FluZone]).TIVfromNovartis(Fluvirin)isFDA-approvedintheUnitedStatesforuseamongpersonsaged>4years.TIVfromGlaxoSmithKline(FluarixandFluLaval)orCSLBiotherapies(Afluria)islabeledforuseinpersonsaged>18yearsbecausedatatodemonstrateefficacyamongyoungerpersonshavenotbeenprovidedtoFDA.LAIVfromMedImmune(FluMist)islicensedforusebyhealthynonpregnantpersonsaged249years(Table1).Avaccinedosedoesnotneedtoberepeatedifinadvertentlyadministeredtoapersonwhodoesnothaveanageindicationforthevaccine formulation given. Expanded ageand risk groupindicationsforlicensedvaccinesarelikelyoverthenextsev
eralyears,andvaccinationprovidersshouldbealerttothesechanges.Inaddition,severalnewvaccineformulationsarebeingevaluatedinimmunogenicityandefficacytrials;whenlicensed,thesenewproductswillincreasetheinfluenzavaccinesupplyandprovideadditionalvaccinechoicesforpractitionersandtheirpatients.
Influenza Vaccines and Useof Influenza Antiviral Medications
AdministrationofTIVandinfluenzaantiviralsduringthesamemedicalvisitisacceptable.Theeffectonsafetyand
effectivenessofLAIVcoadministrationwithinfluenzaantiviralmedicationshasnotbeenstudied.However,becauseinfluenzaantiviralsreducereplicationofinfluenzaviruses,LAIVshouldnotbeadministereduntil48hoursaftercessationofinfluenzaantiviraltherapy,andinfluenzaantiviralmedicationsshouldnotbeadministeredfor2weeksafterreceiptofLAIV.Personsreceivingantiviralswithintheperiod2daysbefore to14 days aftervaccinationwithLAIVshould berevaccinatedatalaterdate(197,252).
Persons Who Should Not Be Vaccinated
with TIVTIVshouldnotbeadministeredtopersonsknowntohaveanaphylactichypersensitivitytoeggsortoothercomponentsoftheinfluenzavaccine.Prophylacticuseofantiviralagentsisanoptionforpreventinginfluenzaamongsuchpersons.Informationaboutvaccinecomponentsislocatedinpackageinsertsfromeachmanufacturer.Personswithmoderatetosevereacutefebrileillnessusuallyshouldnotbevaccinateduntiltheirsymptomshaveabated.However,minorillnesses
withorwithoutfeverdonotcontraindicateuseofinfluenzavaccine.GBSwithin6weeksfollowing apreviousdoseoTIVisconsideredtobeaprecautionforuseofTIV.
Considerations When Using LAIV
LAIVisanoptionforvaccinationofhealthy,nonpregnanpersonsaged249years,includingHCPandotherclosecontacts of high-risk persons (exceptingseverely immunocompromisedpersonswhorequirecareinaprotectedenvironment).NopreferenceisindicatedforLAIVorTIVwhenconsideringvaccinationofhealthy,nonpregnantpersonsaged249years.Useofthetermhealthyinthisrecommendationreferstopersonswhodonothaveanyoftheunderlyingmedicalconditionsthatconferhighriskforseverecomplications(seePersonsWhoShouldNotBeVaccinatedwithLAIV).However,duringperiodswheninactivatedvaccineisinshortsupply,useofLAIVisencouragedwhenfea
sibleforeligiblepersons(includingHCP)becauseuseofLAIVbythesepersonsmightincreaseavailabilityofTIVforpersonsingroupstargetedforvaccination,butwhocannoreceiveLAIV.PossibleadvantagesofLAIVincludeitspotentialtoinduceabroadmucosalandsystemicimmuneresponseinchildren,itseaseofadministration,andthepossiblyincreasedacceptabilityofanintranasalratherthanintramuscularrouteofadministration.
Ifthevaccinerecipientsneezesafteradministration,thedoseshouldnotberepeated.However,ifnasalcongestionispresenthatmightimpededeliveryofthevaccinetothenasopharyngealmucosa,deferralofadministrationshouldbeconsidered
untilresolutionoftheillness,orTIVshouldbeadministeredinstead.Nodataexistaboutconcomitantuseofnasalcorticosteroidsorotherintranasalmedications(252).
AlthoughFDAlicensureofLAIVexcludeschildrenaged24yearswithahistoryofasthmaorrecurrentwheezing,thepreciserisk,ifany,ofwheezingcausedbyLAIVamongtheschildrenisunknownbecauseexperiencewithLAIVamongtheseyoungchildrenislimited.Youngchildrenmightnothaveahistoryofrecurrentwheezingiftheirexposuretorespiratoryviruseshasbeenlimitedbecauseoftheirage.Certainchildrenmighthaveahistoryofwheezingwithrespiratoryillnessesbuthavenothadasthmadiagnosed.Thefollowingscreeningrecommendationsshouldbeusedtoassistpersonswhoadministerinfluenzavaccinesinprovidingtheappropriatevaccineforchildrenaged24years.
CliniciansandvaccinationprogramsshouldscreenforpossiblereactiveairwaysdiseaseswhenconsideringuseofLAIVforchildrenaged24years,andshouldavoiduseofthisvaccineinchildrenwithasthmaorarecentwheezingepisode.Health-careprovidersshouldconsultthemedicalrecord,when
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available,toidentifychildrenaged24yearswithasthmaorrecurrentwheezingthatmightindicateasthma.Inaddition,toidentifychildrenwhomightbeatgreaterriskforasthmaandpossiblyatincreasedriskforwheezingafterreceivingLAIV,parentsorcaregiversofchildrenaged24 yearsshouldbeasked:Inthepast12months,hasahealth-careproviderever
toldyouthatyourchildhadwheezingorasthma?Childrenwhoseparentsorcaregiversansweryestothisquestionandchildrenwhohaveasthmaorwhohadawheezingepisodenotedinthemedicalrecordduringthepreceding12monthsshouldnotreceiveLAIV.TIVisavailableforuseinchildrenwithasthmaorpossiblereactiveairwaysdiseases(363).
LAIVcanbeadministeredtopersonswithminoracuteillnesses(e.g.,diarrheaormildupperrespiratorytractinfectionwithorwithoutfever).However,ifnasalcongestionispresentthatmightimpededeliveryofthevaccinetothenasopharyngealmucosa,deferralofadministrationshouldbeconsidereduntilresolutionoftheillness.
Persons Who Should Not Be Vaccinatedwith LAIV
TheeffectivenessorsafetyofLAIVisnotknownforthefollowinggroups,andthesepersonsshouldnotbevaccinatedwithLAIV:
personswithahistoryofhypersensitivity,includinganaphylaxis,toanyofthecomponentsofLAIVortoeggs.
personsaged50years; personswithanyoftheunderlyingmedicalconditions
thatserveasanindicationforroutineinfluenzavaccination,includingasthma,reactiveairwaysdisease,orotherchro