influenza vaccine and antiviral agents_cdc_mmwr 2008 57

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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2 Early Release July 17, 2008

>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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4

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

12


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

influenza vaccine and antiviral agents_cdc_mmwr 2008 57

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