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CochraneDatabaseofSystematicReviews
Vaccines for preventing influenza in healthy adults (Review)
DemicheliV,JeffersonT,Al-AnsaryLA,FerroniE,RivettiA,DiPietrantonjC
DemicheliV,JeffersonT,Al-AnsaryLA,FerroniE,RivettiA,DiPietrantonjC.
Vaccinesforpreventinginfluenzainhealthyadults.
CochraneDatabaseofSystematicReviews2014,Issue3.Art.No.:CD001269.
DOI:10.1002/14651858.CD001269.pub5.
www.cochranelibrary.com
Vaccinesforpreventinginfluenzainhealthyadults(Review)
Copyright©2014TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Analysis1.1.Comparison1Inactivatedparenteralvaccineversusplaceboor’donothing’,Outcome1Influenza-like
illness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
Analysis1.2.Comparison1Inactivatedparenteralvaccineversusplaceboor’donothing’,Outcome2Influenza. . . 184
Analysis1.3.Comparison1Inactivatedparenteralvaccineversusplaceboor’donothing’,Outcome3Physicianvisits. 186
Analysis1.4.Comparison1Inactivatedparenteralvaccineversusplaceboor’donothing’,Outcome4Daysill. . . 187
Analysis1.5.Comparison1Inactivatedparenteralvaccineversusplaceboor’donothing’,Outcome5Timesanydrugswere
prescribed. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
Analysis1.6.Comparison1Inactivatedparenteralvaccineversusplaceboor’donothing’,Outcome6Timesantibioticwas
prescribed. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
Analysis1.7.Comparison1Inactivatedparenteralvaccineversusplaceboor’donothing’,Outcome7Workingdayslost. 190
Analysis1.8.Comparison1Inactivatedparenteralvaccineversusplaceboor’donothing’,Outcome8Hospitalisations. 191
Analysis1.9.Comparison1Inactivatedparenteralvaccineversusplaceboor’donothing’,Outcome9Clinicalcases
(clinicallydefinedwithoutcleardefinition). . . . . . . . . . . . . . . . . . . . . . . . 192
Analysis1.10.Comparison1Inactivatedparenteralvaccineversusplaceboor’donothing’,Outcome10Localharms. 193
Analysis1.11.Comparison1Inactivatedparenteralvaccineversusplaceboor’donothing’,Outcome11Systemicharms. 195
Analysis2.1.Comparison2Liveaerosolvaccineversusplaceboor’donothing’,Outcome1Influenza-likeillness. . 199
Analysis2.2.Comparison2Liveaerosolvaccineversusplaceboor’donothing’,Outcome2Influenza. . . . . . 200
Analysis2.3.Comparison2Liveaerosolvaccineversusplaceboor’donothing’,Outcome3Influenzacases(clinically
definedwithoutcleardefinition). . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
Analysis2.4.Comparison2Liveaerosolvaccineversusplaceboor’donothing’,Outcome4Localharms. . . . . 202
Analysis2.5.Comparison2Liveaerosolvaccineversusplaceboor’donothing’,Outcome5Systemicharms. . . . 204
Analysis3.1.Comparison3Inactivatedaerosolvaccineversusplaceboor’donothing’,Outcome1Influenza. . . . 206
Analysis3.2.Comparison3Inactivatedaerosolvaccineversusplaceboor’donothing’,Outcome2Localharms. . . 207
Analysis3.3.Comparison3Inactivatedaerosolvaccineversusplaceboor’donothing’,Outcome3Systemicharms. . 208
Analysis4.1.Comparison4Inactivatedparenteralvaccineversusplacebo-cohortstudies,Outcome1Seasonalinactivated
vaccineeffectivenessinmothers-pregnantwomen. . . . . . . . . . . . . . . . . . . . . . 209
Analysis4.2.Comparison4Inactivatedparenteralvaccineversusplacebo-cohortstudies,Outcome2Seasonalinactivated
vaccineeffectivenessinnewborns-pregnantwomen. . . . . . . . . . . . . . . . . . . . . 210
Analysis4.3.Comparison4Inactivatedparenteralvaccineversusplacebo-cohortstudies,Outcome3Seasonalinactivated
vaccineeffectivenessinnewborns-pregnantwomen. . . . . . . . . . . . . . . . . . . . . 211
Analysis4.4.Comparison4Inactivatedparenteralvaccineversusplacebo-cohortstudies,Outcome4H1N1vaccine-
safety-pregnancy-relatedoutcomes-pregnantwomen. . . . . . . . . . . . . . . . . . . . 212
Analysis4.5.Comparison4Inactivatedparenteralvaccineversusplacebo-cohortstudies,Outcome5Seasonalvaccine-
safety-pregnancy-relatedoutcomes-pregnantwomen. . . . . . . . . . . . . . . . . . . . 214
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Analysis5.1.Comparison5Inactivatedparenteralvaccineversusplacebo-case-control,Outcome1Effectivenessin
newborns-pregnantwomen(adjusteddata). . . . . . . . . . . . . . . . . . . . . . . . 215
Analysis5.2.Comparison5Inactivatedparenteralvaccineversusplacebo-case-control,Outcome2Seasonalvaccinesafety
-pregnancy-relatedoutcomes(adjusteddata). . . . . . . . . . . . . . . . . . . . . . . . 215
Analysis6.1.Comparison6Seriousadverseevents-Guillain-Barrésyndrome-cohortstudies,Outcome1Seasonal
influenzavaccinationandGuillain-Barrésyndrome. . . . . . . . . . . . . . . . . . . . . . 216
Analysis7.1.Comparison7Seriousadverseevents-Guillain-Barrésyndrome-case-control,Outcome12009to2010
A/H1N1-generalpopulation(unadjusteddata). . . . . . . . . . . . . . . . . . . . . . . 217
Analysis7.2.Comparison7Seriousadverseevents-Guillain-Barrésyndrome-case-control,Outcome22009to2010
A/H1N1-generalpopulation(adjusteddata). . . . . . . . . . . . . . . . . . . . . . . 218
Analysis7.3.Comparison7Seriousadverseevents-Guillain-Barrésyndrome-case-control,Outcome3Seasonalinfluenza
vaccinationgeneralpopulation(adjusteddata). . . . . . . . . . . . . . . . . . . . . . . 219
Analysis8.1.Comparison8Seriousadverseevents-demyelinatingdiseases(multiplesclerosis,opticneuritis)-cohort
studies,Outcome1Influenzavaccination(seasonal)-demyelinatingdiseases(unadjusteddata). . . . . . 220
Analysis8.2.Comparison8Seriousadverseevents-demyelinatingdiseases(multiplesclerosis,opticneuritis)-cohort
studies,Outcome2Influenzavaccination(H1N1)-demyelinatingdiseases(unadjusted). . . . . . . . . 221
Analysis9.1.Comparison9Seriousadverseevents-demyelinatingdiseases(multiplesclerosis,opticneuritis)-case-
controlstudies,Outcome1Influenzavaccination(seasonal)-generalpopulation-demyelinatingdiseases(unadjusted
data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
Analysis9.2.Comparison9Seriousadverseevents-demyelinatingdiseases(multiplesclerosis,opticneuritis)-case-control
studies,Outcome2Influenzavaccination(seasonal)-generalpopulation-multiplesclerosis(adjusteddata). . 223
Analysis9.3.Comparison9Seriousadverseevents-demyelinatingdiseases(multiplesclerosis,opticneuritis)-case-control
studies,Outcome3Influenzavaccination(seasonal)-generalpopulation-opticneuritis(adjusteddata). . . 223
Analysis10.1.Comparison10Seriousadverseevents-immunethrombocytopaenicpurpura-cohortstudies,Outcome1
Seasonalinfluenzavaccine-HR(adjusteddata). . . . . . . . . . . . . . . . . . . . . . . 224
Analysis10.2.Comparison10Seriousadverseevents-immunethrombocytopaenicpurpura-cohortstudies,Outcome2
Seasonalinfluenzavaccine(unadjusteddata). . . . . . . . . . . . . . . . . . . . . . . . 225
Analysis11.1.Comparison 11Seriousadverseevents-immunethrombocytopaenicpurpura-case-controlstudies,
Outcome1Seasonalinfluenzavaccine-generalpopulation(adjusteddata). . . . . . . . . . . . . 226
Analysis11.2.Comparison 11Seriousadverseevents-immunethrombocytopaenicpurpura-case-controlstudies,
Outcome2Seasonalinfluenzavaccine-generalpopulation(unadjusteddata). . . . . . . . . . . . 227
Analysis12.1.Comparison121968to1969pandemic:inactivatedpolyvalentparenteralvaccineversusplacebo,Outcome
1Influenza-likeillness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
Analysis12.2.Comparison121968to1969pandemic:inactivatedpolyvalentparenteralvaccineversusplacebo,Outcome
2Influenza. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
Analysis12.3.Comparison121968to1969pandemic:inactivatedpolyvalentparenteralvaccineversusplacebo,Outcome
3Hospitalisations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
Analysis12.4.Comparison121968to1969pandemic:inactivatedpolyvalentparenteralvaccineversusplacebo,Outcome
4Pneumonia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
Analysis13.1.Comparison131968to1969pandemic:inactivatedmonovalentparenteralvaccineversusplacebo,Outcome
1Influenza-likeillness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
Analysis13.2.Comparison131968to1969pandemic:inactivatedmonovalentparenteralvaccineversusplacebo,Outcome
2Influenza. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Analysis13.3.Comparison131968to1969pandemic:inactivatedmonovalentparenteralvaccineversusplacebo,Outcome
3Hospitalisations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
Analysis13.4.Comparison131968to1969pandemic:inactivatedmonovalentparenteralvaccineversusplacebo,Outcome
4Pneumonia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Analysis13.5.Comparison131968to1969pandemic:inactivatedmonovalentparenteralvaccineversusplacebo,Outcome
5Workingdayslost. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Analysis13.6.Comparison131968to1969pandemic:inactivatedmonovalentparenteralvaccineversusplacebo,Outcome
6Daysill. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
Analysis14.1.Comparison141968to1969pandemic:inactivatedpolyvalentaerosolvaccineversusplacebo,Outcome1
Influenza-likeillness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
Vaccinesforpreventinginfluenzainhealthyadults(Review) ii
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Analysis15.1.Comparison151968to1969pandemic:inactivatedmonovalentaerosolvaccineversusplacebo,Outcome1
Influenza-likeillness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
Analysis16.1.Comparison161968to1969pandemic:liveaerosolvaccineversusplacebo,Outcome1Influenzacases
(clinicallydefinedwithoutcleardefinition). . . . . . . . . . . . . . . . . . . . . . . . 239
Analysis16.2.Comparison161968to1969pandemic:liveaerosolvaccineversusplacebo,Outcome2Complications
(bronchitis,otitis,pneumonia). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
ADDITIONALTABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
WHAT’SNEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
DIFFERENCESBETWEENPROTOCOLANDREVIEW . . . . . . . . . . . . . . . . . . . . . 263
INDEXTERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
Vaccinesforpreventinginfluenzainhealthyadults(Review) iii
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[InterventionReview]
Vaccines for preventing influenza in healthy adults
VittorioDemicheli1,TomJefferson2,LubnaAAl-Ansary3,ElianaFerroni4,AlessandroRivetti1,CarloDiPietrantonj5
1ServizioRegionalediRiferimentoperl’Epidemiologia,SSEpi-SeREMI-CochraneVaccinesField,AziendaSanitariaLocaleASLAL,
Alessandria,Italy.2TheCochraneCollaboration,Roma,Italy.3DepartmentofFamilyandCommunityMedicine,CollegeofMedicine,
KingSaudUniversity,Riyadh,SaudiArabia.4DepartmentofEpidemiology,LazioRegionalHealthService,Rome,Italy.5Regional
EpidemiologyUnitSeREMI-CochraneVaccinesField,LocalHealthUnitAlessandria-ASLAL,Alessandria,Italy
Contactaddress:VittorioDemicheli,ServizioRegionalediRiferimentoperl’Epidemiologia,SSEpi-SeREMI-CochraneVaccinesField,
AziendaSanitariaLocaleASLAL,ViaVenezia6,Alessandria,Piemonte,15121,[email protected]@libero.it.
Editorialgroup:CochraneAcuteRespiratoryInfectionsGroup.
Publicationstatusanddate:Newsearchforstudiesandcontentupdated(conclusionschanged),publishedinIssue3,2014.
Reviewcontentassessedasup-to-date: 24May2013.
Citation: DemicheliV,JeffersonT,Al-AnsaryLA,FerroniE,RivettiA,DiPietrantonjC.Vaccinesforpreventinginfluenzainhealthy
adults.CochraneDatabaseofSystematicReviews2014,Issue3.Art.No.:CD001269.DOI:10.1002/14651858.CD001269.pub5.
Copyright©2014TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
ABSTRACT
Background
Differenttypesofinfluenzavaccinesarecurrentlyproducedworldwide.Vaccinationofpregnantwomenisrecommendedinternationally,
whilehealthyadultsaretargetedinNorthAmerica.
Objectives
Toidentify,retrieveandassessallstudiesevaluatingtheeffects(efficacy,effectivenessandharm)ofvaccinesagainstinfluenzainhealthy
adults,includingpregnantwomen.
Searchmethods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 2), MEDLINE
(January1966toMay2013)andEMBASE(1990toMay2013).
Selectioncriteria
Randomisedcontrolledtrials(RCTs)orquasi-RCTscomparinginfluenzavaccineswithplaceboornointerventioninnaturallyoccurring
influenzainhealthyindividualsaged16to65years.Wealsoincludedcomparativestudiesassessingseriousandrareharms.
Datacollectionandanalysis
Tworeviewauthorsindependentlyassessedtrialqualityandextracteddata.
Mainresults
We included 90 reportscontaining 116 data sets; among these 69 were clinical trials of over 70,000 people,27 were comparative
cohortstudies(abouteightmillionpeople)and20werecase-controlstudies(nearly25,000people).Weretrieved23reportsofthe
effectivenessandsafetyofvaccineadministrationinpregnantwomen(about1.6millionmother-childcouples).
The overall effectivenessof parenteral inactivated vaccine against influenza-like illness(ILI) is limited, corresponding to a number
neededtovaccinate(NNV)of40(95%confidenceinterval(CI)26to128).Theoverallefficacyofinactivatedvaccinesinpreventing
confirmedinfluenzahasaNNVof71(95%CI64to80).Thedifferencebetweenthesetwovaluesdependsonthedifferentincidenceof
Vaccinesforpreventinginfluenzainhealthyadults(Review) 1
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ILIandconfirmedinfluenzaamongthestudypopulations:15.6%ofunvaccinatedparticipantsversus9.9%ofvaccinatedparticipants
developedILIsymptoms,whilstonly2.4%and1.1%,respectively,developedlaboratory-confirmedinfluenza.
NoRCTsassessingvaccination inpregnantwomenwerefound.Theonlyevidenceavailablecomesfromobservational studieswith
modestmethodological quality. Onthisbasis, vaccination showsvery limitedeffects:NNV92(95% CI63to201) against ILIin
pregnantwomenandNNV27(95%CI18to185)againstlaboratory-confirmedinfluenzainnewbornsfromvaccinatedwomen.
LiveaerosolvaccineshaveanoveralleffectivenesscorrespondingtoaNNV46(95%CI29to115).
Theperformance of one-dose or two-dose whole virion pandemic vaccineswas higher,showing aNNVof16 (95% CI14 to20)
againstILIandaNNVof35(95%CI33to47)againstinfluenza,whilealimitedimpactonhospitalisationwasfound(NNV94,
95%CI70to1022).
Vaccinationhadamodesteffectontimeoffworkandhadnoeffectonhospitaladmissionsorcomplicationrates.Inactivatedvaccines
causedlocalharms.Noevidenceofassociationwithseriousadverseeventswasfound,buttheharmsevidencebasewaslimited.
Theoverallriskofbiasintheincludedtrialsisunclearbecauseitwasnotpossibletoassesstherealimpactofbias.
Authors’conclusions
Influenzavaccineshaveaverymodesteffectinreducinginfluenzasymptomsandworkingdayslostinthegeneralpopulation,including
pregnantwomen.Noevidenceofassociationbetweeninfluenzavaccinationandseriousadverseeventswasfoundinthecomparative
studiesconsideredinthereview.Thisreviewincludes90studies,24ofwhich(26.7%)werefundedtotallyorpartiallybyindustry.Out
ofthe48RCTs,17wereindustry-funded(35.4%).
PLAIN LANGUAGE SUMMARY
Vaccinestopreventinfluenzainhealthyadults
Reviewquestion
Weevaluatedtheeffectofimmunisation withinfluenzavaccinesonpreventinginfluenzaAorBinfections(efficacy),influenza-like
illness(ILI)anditsconsequences(effectiveness),anddeterminedwhetherexposuretoinfluenzavaccinesisassociatedwithseriousor
severeharms.Thetargetpopulationswerehealthyadults,includingpregnantwomenandnewborns.
Background
Over 200 viruses cause influenza and ILI, producing the same symptoms (fever,headache, aches, pains, cough and runny noses).
Withoutlaboratorytests,doctorscannotdistinguishbetweenthemasbothlastfordaysandrarelyleadtodeathorseriousillness.At
best, vaccinesmay only be effectiveagainst influenza Aand B, whichrepresentabout 10% of allcirculatingviruses. Annually,the
WorldHealthOrganizationestimateswhichviralstrainsshouldbeincludedinthenextseason’svaccinations.
Inactivatedvaccineispreparedbytreatinginfluenzaviruseswithaspecificchemicalagentthat“kills”thevirus.Finalpreparationscan
containeitherthecompleteviruses(wholevaccine)ortheactivepartofthem(splitorsubunitvaccines).Thesekindofvaccinesare
normallyintramuscularlyadministered(parenteralroute)
Liveattenuatedvaccinesispreparedbygrowingtheinfluenzavirusesthroughaseriesofcellculturesoranimalembryos.Witheach
passage,theviruseslosetheirabilitytoreplicateinhumancellsbutcanstillstimulatetheimmunesystem.Liveattenuatedvaccineare
administeredasaerosolinthenostrils(intranasalroute).
Thevirusstrainscontainedinthevaccineareusuallythosethatareexpectedtocirculateinthefollowingepidemicseasons(twotype
AandoneBstrains),accordinglytotherecommendationsoftheWorldHealthOrganization(seasonalvaccine).
Pandemicvaccinecontainsonlythevirusstrainthatisresponsibleofthepandemic(i.e.thetypeAH1N1forthe2009/2010pandemic).
Studycharacteristics
TheevidenceiscurrenttoMay2013.Inthisupdate,90reportsof116studiescomparedtheeffectofinfluenzavaccinewithplaceboor
nointervention.Sixty-ninereportswereclinicaltrials(over70,000people),27werecomparativecohortstudies(abouteightmillion
people)and20werecase-controlstudies(nearly25,000people).Ofthe116studies,23(threecase-controland20cohortstudies)were
performedduringpregnancy(about1.6millionmother-childcouples).
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Keyresults
Thepreventiveeffectofparenteralinactivatedinfluenzavaccineonhealthyadultsissmall:atleast40peoplewouldneedvaccination
toavoidoneILIcase(95%confidenceinterval(CI)26to128)and71peoplewouldneedvaccinationtopreventonecaseofinfluenza
(95%CI64to80).Vaccinationshowsnoappreciableeffectonworkingdayslostorhospitalisation.
TheprotectionagainstILIthatisgivenbytheadministrationofinactivatedinfluenzavaccinetopregnantwomenisuncertainorat
leastverylimited;theeffectontheirnewbornsisnotstatisticallysignificant.
Theeffectivenessofliveaerosolvaccinesonhealthyadultsissimilartoinactivatedvaccines:46people(95%CI29to115)wouldneed
immunisationtoavoidoneILIcase.
The administration of seasonal inactivated influenza vaccine is not associated with the onset of multiple sclerosis, optic neuritis
(inflammation of the optic nerve of the eye) or immune thrombocytopaenic purpura (a disease that affects blood platelets). The
administration of pandemic monovalent H1N1 inactivated vaccine is not associated with Guillain-Barré syndrome (a disease that
affectsthenervesofthelimbsandbody).
Evidencesuggeststhattheadministrationofbothseasonaland2009pandemicvaccinesduringpregnancyhasnosignificanteffecton
abortionorneonataldeath.
Qualityoftheevidence
The real impact of biases could not be determined for about 70% of the included studies (e.g. insufficient reporting details, very
differentscoresamongtheitemsevaluated).About20%oftheincludedstudies(mainlycohorts)hadahighriskofbias.Justunder
10%hadgoodmethodologicalquality.
BACKGROUND carry-overprotectionfromyeartoyear,anewvaccination cam-
paignneedstobeorganisedannually,withahugescientificand
logisticefforttoensureproductionanddeliveryofthevaccines.
Descriptionofthecondition
Viralrespiratorydiseaseimposesaheavyburdenonsociety.The
Descriptionoftheintervention
majority of viral respiratory disease (influenza-like illness (ILI))
iscausedbymany differentagentsthatarenotclinicallydistin- Currentlytherearethreetypesofinfluenzavaccines:
guishablefromoneanother.AvariableproportionofILI(7%to 1. wholevirionvaccineswhichconsistofcompletevirusesthat
15%onaverage)iscausedbyinfluenzavirusesandisknownas havebeen’killed’orinactivated,sothattheyarenotinfectious
influenza(Jefferson2009b). butretaintheirstrain-specificantigenicproperties;
Influenzaisanacuterespiratoryinfectioncausedbyavirusofthe 2. subunitvirionvaccines,whicharemadeofsurfaceantigens
Orthomyxoviridaefamily.Threeserotypesareknown(A,BandC). (HandN)only;
Influenza causes an acute febrile illness with myalgia, headache 3. splitvirionvaccinesinwhichtheviralstructureisbroken
and cough. Although the median duration of the acute illness upbyadisruptingagent.
isthreedays,cough andmalaise canpersistforweeks.Compli- Thesevaccinescontainbothsurfaceandinternalantigens.Inad-
cationsofinfluenzaincludeotitismedia,pneumonia, secondary dition,avarietyofnon-Europeanmanufacturersproduceliveat-
bacterialpneumonia,exacerbationsofchronicrespiratorydisease tenuatedvaccines.Traditionally,wholevirionvaccinesarethought
andbronchiolitisinchildren.Additionally,influenzacancausea tobethelesswelltoleratedbecauseofthepresenceofalipidstra-
rangeofnon-respiratorycomplicationsincludingfebrileconvul- tumonthesurfaceoftheviralparticles(aremnantofthehostcell
sions,Reye’ssyndromeandmyocarditis(Wiselka1994).Effortsto membranecoatingthevirion,whenbuddingfromthehostcell).
preventorminimisetheimpactofseasonalinfluenzainthesecond Influenza vaccines are produced worldwide. Periodic antigenic
partofthe20thcenturycentredontheuseofvaccines.Due to driftsandshiftsposeproblemsforvaccineproductionandprocure-
theyearlychangesinviralantigenicconfigurationandthelackof ment,asanewvaccinecloselymatchingthecirculatingantigenic
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configurationmustbeproducedandprocuredforthebeginning Pregnantwomenareincludedamongpriorityrecipientsforsea-
ofeachnewinfluenza’season’.Toachievethis,theWorldHealth sonal influenza immunisation in many countries (AIH 2013;
Organization (WHO) has established a worldwide surveillance GreenBook2013;NACI2012;STIKO2010),becauseoftherisk
system,allowingtheidentificationandisolationofviralstrainscir- ofinfluenza-associatedmorbidityduringpregnancy,thepossible
culatingthedifferentpartsoftheglobe.Sentinelpracticesrecover adverseneonataloutcomesassociatedwithmaternalinfluenzain-
viral particles fromthe nasopharynx of patients with influenza- fections,andbasedontheevidencethatvaccinationofpregnant
likesymptomsandthesamplesareswiftlysenttothelaboratories womenprotectstheirnewbornsfrominfluenzaandinfluenza-re-
of the national influenza centres (110 laboratories in 79 coun- latedhospitalisations(NACI2012).
tries).Whennewstrainsaredetectedthesamplesaresenttoone Inactivatedinfluenzavaccinecouldbeadministeredatanystage
ofthefourWHOreferencecentres(London,Atlanta,Tokyoand ofpregnancy,whereaslivevaccineisnotlicensedforuseduring
Melbourne)forantigenicanalysis.Informationonthecirculating pregnancyastheavailabledataaboutsafetyandefficacyinmothers
strainisthensenttotheWHO,whichinFebruaryofeachyear andbabiesareverylimited(ACIP2010;GreenBook2013).
recommends,throughacommittee,thestrainstobeincludedin
thevaccinefortheforthcoming’season’.Individualgovernments
may or maynot followtheWHOrecommendations. Australia, Whyitisimportanttodothisreview
NewZealandand,morerecently,SouthAfricafollowtheirown
Giventheveryhighcostofyearlyvaccinationforlargepartsofthe
recommendationsforvaccinecontent.Surveillanceandearlyiden-
population,theextremevariabilityofinfluenzaincidenceduring
tificationthusplayacentralpartinthecompositionofthevaccine.
each’season’andtheheterogeneityofpublichealthrecommenda-
tions,wecarriedoutasystematicreviewoftheevidence.Toen-
hanceitsrelevancefordecision-makers,inthe2007updateofthe
Howtheinterventionmightwork
reviewweincludedcomparativenon-randomisedstudiesreport-
Everyvaccinationcampaignhasstatedaimsagainstwhichtheef- ingevidenceofseriousorrareharms(orboth)(Jefferson2007).In
fects of the campaign must be measured. Perhaps the most de- thepresentupdate(2013),wehavealsoincludedevidenceabout
taileddocumentpresentingtherationaleforacomprehensivepre- influenzavaccinationinpregnantwomenandnewborns.
ventiveprogrammewasthatbytheUSAdvisoryCommitteeon
ImmunizationPractice(ACIP),publishedin2006(ACIP2006).
Thedocumentidentified11categoriesofpeopleathighriskof
complicationsfrominfluenza,amongwhicharehealthyadults50
OBJECTIVES
to65yearsofageandhealthcareworkers.Therationaleforpolicy
choicesrestsontheheavyburdenthatinfluenzaimposesonthe To identify, retrieve and assess all studies evaluating the effects
populationsandonthebenefitsaccruingfromvaccinatingthem. (efficacy,effectivenessandharm)ofvaccinesagainstinfluenzain
Reductionsincasesandcomplications(suchasexcesshospitalisa- healthyadults,includingpregnantwomen.
tions,absencefromwork,mortalityandhealthcarecontacts)and
Wedefined’effects’asfollows:
theinterruptionoftransmission aretheprincipalargumentsfor
extendingvaccinationtohealthyadultsaged50to65years(ACIP
1. efficacyasthecapacityofthevaccinestopreventinfluenza
2006).
AorBanditscomplications;
TheACIP2010documentupdaterecommendsroutinevaccina-
tionforallparticipantsagedsixmonthsandolder.Itunderlines 2. effectivenessasthecapacityofthevaccinestoprevent
theimportanceoffocusingvaccinationefforts,whenvaccination influenza-likeillnessanditsconsequences;and
suppliesarelimited,onhealthyadultswhoareatincreasedriskof
3. harmasanyharmfuleventpotentiallyassociatedwith
developingseverecomplicationsfrominfluenza,suchas:
• peopleaged50yearsorover; exposuretoinfluenzavaccines.
• womenwhoareorwillbepregnantduringtheinfluenza
season;
• healthcarepersonnel; METHODS
• householdcontactsandcaregiversofchildrenagedbelow
fiveyearsandadultsaged50yearsorover,withparticular
emphasisonvaccinatingcontactsofchildrenyoungerthansix Criteriaforconsideringstudiesforthisreview
monthsofage;and
• householdcontactsandcaregiversofpersonswithmedical
conditionsthatputthemathigherriskofseverecomplications
Typesofstudies
frominfluenza(ACIP2010).
Vaccinesforpreventinginfluenzainhealthyadults(Review) 4
Copyright©2014TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Anyrandomisedcontrolledtrial(RCT)orquasi-RCTcomparing death,stillbirth),pretermbirth(lessthan37weeks),maternal
influenzavaccinesinhumanswithplaceboornointervention,or death.
comparing types, doses or schedules of influenza vaccine. Only 3. Neonataloutcomes:congenitalmalformations(minorand
studiesassessingprotectionfromexposuretonaturallyoccurring major),neonataldeath.
influenzawereconsidered.
Comparative non-randomised studies were included if they re-
Secondaryoutcomes
portedevidenceontheassociationbetweeninfluenzavaccinesand
seriousadverseeffects,suchasGuillain-Barrésyndromeoroculo- 1. Localadverseeffectsincludeinduration,sorenessand
respiratorysyndromes,oriftheyreportedeffectivenessorefficacy rednessatthesiteofinoculation.
dataforvaccineadministrationduringpregnancy.
WedefinedasRCTsstudiesinwhichitappearedthattheindivid-
uals(orotherexperimentalunits)includedinthestudyweredef- Searchmethodsforidentificationofstudies
initelyorpossiblyassignedprospectivelytooneoftwo(ormore)
alternativeformsofhealthcareusingrandomallocation.Astudy
wasquasi-randomised whenitappearedthattheindividuals (or Electronicsearches
otherexperimentalunits)followedinthestudyweredefinitelyor
We searched the Cochrane Central Register of Controlled Tri-
possiblyassignedprospectivelytooneoftwo(ormore)alternative
als (CENTRAL) (The Cochrane Library 2013, Issue 2), which
formsofhealthcareusingsomequasi-random methodofalloca-
containstheCochraneAcuteRespiratoryInfectionsGroup’sSpe-
tion(suchasbyalternation,dateofbirthorcaserecordnumber).
cialised Register, MEDLINE (PubMed) (January 1966 to May
2013)andEMBASE.com(1990toMay2013).Searchstrategies
usedforthepresentversionofthereviewarereportedintheap-
Typesofparticipants
pendices(seeAppendix1fortrialsandAppendix2forobserva-
Healthyindividualsaged16to65years,irrespectiveofinfluenza tionalstudiessearches).
immunestatus.Studiesconsideringmorethan25%ofindividuals See Appendix 3 for strategies used in the 2010 update and
outside this age range were excluded fromthe review. Pregnant Appendix4fortheMEDLINEsearchstrategyusedin2004.There
womentogetherwiththeirnewbornswerealsoincluded. werenolanguageorpublicationrestrictions.
Typesofinterventions Searchingotherresources
Live,attenuatedorkilledvaccines,orfractionsthereof,adminis- Toidentifyfurthertrials,wereadthebibliographiesofretrieved
teredbyanyroute,irrespectiveofantigenicconfiguration. articlesandhandsearchedthejournal Vaccinefromitsfirstissue
totheendof2009.Theresultsofthehandsearchesareincluded
inCENTRAL.Inordertolocateunpublishedtrialsforthefirst
Typesofoutcomemeasures editionofthisreview, wewrotetothefollowing:manufacturers
andfirstorcorrespondingtrialauthorsofstudiesinthereview.
Primaryoutcomes
Datacollectionandanalysis
Clinical
1. Numbersandseriousness(complicationsandworkingdays Selectionofstudies
lost)ofsymptomaticinfluenzaandinfluenza-likeillness(ILI) Two review authors(AR,CDP) independently excludedallini-
casesoccurringinvaccineandplacebogroups. tiallyidentifiedand retrievedarticlesnotfulfillingtheinclusion
criteria.Inthecaseofdisagreement,onereviewauthor(VD)acted
asarbitrator.
Harms
1. Numberandseriousnessofadverseeffects(systemicand
severe).Systemicadverseeffectsincludecasesofmalaise,nausea, Dataextractionandmanagement
fever,arthralgia,rash,headacheandmoregeneralisedandserious Tworeviewauthors(AR,CDP)performeddataextractionusing
signs,suchasneurologicalharms. adataextractionform(Appendix5).Wecheckedandenteredthe
2. Maternaloutcomesandoutcomesrelatedtothecourseof dataintoReviewManager(RevMan2012)software.Weextracted
pregnancy.Theseincludeabortion(spontaneous,internal,fetal dataonthefollowing:
Vaccinesforpreventinginfluenzainhealthyadults(Review) 5
Copyright©2014TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
• methodologicalqualityofstudies; • Highriskofbias:iftherewasnoblinding.
• studydesign(Appendix6); • Unclearriskofbias:ifinsufficientinformationwas
• descriptionofsetting; provided.
• characteristicsofparticipants;
• descriptionofvaccines(contentandantigenicmatch);
• descriptionofoutcomes; Incompleteoutcomedata
• publicationstatus; Numberoflossestofollow-up:
• dateofstudy; • Lowriskofbias:nomissingdataortheproportionof
• locationofstudy. missingdatacomparedwiththeobservedeventriskwasnot
enoughtohaveaclinicallyrelevantimpactontheintervention
Onereviewauthor(CDP)carriedoutstatisticalanalyses.
effectestimate.
• Highriskofbias:whentheproportionofmissingdata
Assessmentofriskofbiasinincludedstudies comparedwithobservedeventriskwaslargeenoughtoinduce
clinicallyrelevantbiasintheinterventioneffectestimate.
• Unclearriskofbias:ifinsufficientinformationwas
Experimentalstudies(trials) provided.
The review authors independently assessed the methodological
quality of theincluded studies using criteriafromthe Cochrane
Non-experimentalstudies
HandbookforSystematicReviewsofInterventions(Higgins2011).
One review author (VD) acted as arbitrator in the case of dis- Wecarriedoutqualityassessmentofnon-randomisedstudiesinre-
agreementbetweenthetworeviewauthors(CDP,AR)inassigning lationtothepresenceofpotentialconfounders,whichcouldmake
qualityjudgements. interpretationoftheresultsdifficult.Weevaluatedthequalityof
Weclassifiedstudiesaccordingtothefollowingkeydomainsfor case-control(prospectiveandretrospective)andcohortstudiesus-
assessingriskofbias(Higgins2011). ing the appropriate Newcastle-OttawaScales(NOS)(Appendix
7).
Usingqualityattheanalysisstageasameansofinterpretingthe
Randomsequencegeneration results,weassigned’Riskofbias’categories(Higgins2011):
• Lowriskofbias:if,forexample,atableofrandomnumbers • Lowriskofbias:plausiblebiasunlikelytoseriouslyalterthe
orcomputer-generatedrandomnumberswereused. results.
• Highriskofbias:if,forexample,alternation,dateofbirth, • Unclearriskofbias:plausiblebiasthatraisessomedoubt
dayoftheweekorcaserecordnumberwereused. abouttheresults.
• Unclearriskofbias:ifinsufficientinformationwas • Highriskofbias:plausiblebiasthatseriouslyweakens
provided. confidenceintheresults.
Allocationconcealment Measuresoftreatmenteffect
• Lowriskofbias:if,forexample,numberedorcoded Weusedtheriskratio(RR)andits95%confidenceinterval(CI)as
identicalcontainerswereadministeredsequentially,anon-site thesummarymeasure.Wecalculatedvaccineefficacy(oreffective-
computersystemthatcouldonlybeaccessedafterenteringthe ness)asVE=1-RR,expressedasapercentage,forcohortandRCT/
characteristicsofanenrolledparticipant,orseriallynumbered, controlledclinicaltrial(CCT)studies.Forcase-controlstudieswe
opaque,sealedenvelopes,wereused,orsealedenvelopesthat adoptedanoddsratio(OR)with95%CIs.
werenotsequentiallynumberedoropaquewereused. Toenhancerelevancetoeverydaypractice,wealsoexpressedthe
• Highriskofbias:if,forexample,anopentableofrandom summarymeasureofthemostreliableandsignificantcomparisons
numberswasused. (thosefromRCTswithinfluenzacasesasanoutcomebyagegroup)
• Unclearriskofbias:ifinsufficientinformationwas as arisk difference (RD). Thisis a measure of absolute efficacy
provided. ofthevaccines,whichincorporatessignificantinformation such
astheincidenceinthecontrolarmandallowsthecalculationof
itsreciprocal,thenumberneededtotreat(NNT)orinthiscase
Blinding thenumberneededtovaccinate(NNV).TheNNVexpressesthe
• Lowriskofbias:ifadequatedouble-blinding,forexample, number of adults needed to be vaccinated to prevent one case
placebovaccine,orsingle-blinding(i.e.blindedoutcome ofinfluenza.TheNNVcanbecomputedas1/RD.Sincemeta-
assessment)wereused. analysisestimatesfromRDareaffectedbyspuriousheterogeneity
Vaccinesforpreventinginfluenzainhealthyadults(Review) 6
Copyright©2014TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.