AFEWREASONSTOSAYNO,THANKS,TOINFLUENZA/FLUVACCINES(EVIDENCE BASE COCHRANE REVIEWS versus INDUSTRIAL BASE CDC AND ECDC

1 RECOMMENDATIONS)

SelectionbyJuanGrvas,MD,PhD,HonoraryProfessorPublicHealth(AutonomousUniversity, Madrid,Spain),VisitingProfessorInternationalHealth(NationalSchoolofPublicHealth,Madrid, Spain)jgervasc@meditex.eswww.equipocesca.org Madrid,Spain.September2012 Mainsourceofinformation: http://www.thecochranelibrary.com/details/collection/978807/InfluenzaevidencefromCochrane Reviews.html

What says the CDC (Centers for Disease Control and Prevention, USA) about influenza/flu vaccines? http://www.cdc.gov/flu/pdf/protect/visflu.pdf All people 6 months of age and older should get flu vaccine. Vaccination is especially important for people at higher risk of severe influenza and their close contacts, including healthcare personnel and close contacts of children younger than 6 months.

What say the European Union and the ECDC (European Centre for Disease Prevention and Control) about influenza/flu vaccines? http://ec.europa.eu/healtheu/europe_for_patients/flu_vaccination/index_en.htm Following a proposal by the Commission, the Health Ministers of the European Union (EU) countries adopted on 22 December 2009 a recommendation on seasonal flu vaccination recommending that EU countries try and get 75% of the 'at risk' groups, including elderly and healthcare workers, vaccinated against seasonal flu by 2015.
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What says the scientific evidence?

1- ABOUT HEALTHY CHILDREN http://www.ncbi.nlm.nih.gov/pubmed/22895945 Wecouldfindnousabledataforthoseagedtwoyearsoryounger.Inactivatedvaccinesinchildren aged two years or younger are not significantly more efficacious than placebo. Influenzavaccinesareefficaciousinpreventingcasesofinfluenzainchildrenolderthantwoyears ofage,butlittleevidenceisavailableforchildrenyoungerthantwoyearsofage.Therewasa differencebetweenvaccineefficacyandeffectiveness,partlyduetodifferingdatasets,settingsand viralcirculationpatterns. Nosafetycomparisonscouldbecarriedout,emphasisingtheneedfor standardisationofmethodsandpresentationofvaccinesafetydatainfuturestudies.Inspecific cases, influenza vaccines were associated with serious harms such as narcolepsy and febrile convulsions.Itwassurprisingtofindonlyonestudyofinactivatedvaccineinchildrenundertwo years,givencurrentrecommendationstovaccinatehealthychildrenfromsixmonthsofageinthe USA,Canada,partsofEuropeandAustralia.Ifimmunisationinchildrenistoberecommendedasa public health policy, largescale studies assessing important outcomes, and directly comparing vaccinetypesareurgentlyrequired.Thedegreeofscrutinyneededtoidentifyallglobalcasesof potential harms is beyond the resources of this review. This review includes trials funded by industry.Anearliersystematicreviewof274influenzavaccinestudiespublishedupto2007found industryfunded studies were published in more prestigious journals and cited more than other studiesindependentlyfrommethodologicalqualityandsize.Studiesfundedfrompublicsources weresignificantlylesslikelytoreportconclusionsfavourabletothevaccines.Thereviewshowed thatreliableevidenceoninfluenzavaccinesisthinbutthereisevidenceofwidespreadmanipulation ofconclusionsandspuriousnotorietyofthestudies.Thecontentandconclusionsofthisreview shouldbeinterpretedinthelightofthisfinding.

2- ABOUT HEALTHY CHILDREN, ADOLESCENT, ADULTS AND ELDERLY http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2907815/?tool=pmcentrez Vaccinesareeffectiveinreducinginfectionandschoolabsenceinchildrenover2yearsold,but there is no evidence that they reduce transmission, hospitalisation, pneumonia, or death. 2

Liveorinactivatedvaccinesareeffectiveinreducinginfectionandinslightlyreducingabsencefrom workinadults,butthereisnoevidencethattheyreducetransmission,hospitalisation,pneumonia, ordeath. There is poor-quality evidence from cohort studies that vaccines are effective in elderly people living in institutions, but there is little good-quality evidence for the elderly population in general. http://www.ncbi.nlm.nih.gov/pubmed/17443504 Influenzavaccinesareeffectiveinreducingcasesofinfluenza,especiallywhenthecontentpredicts accuratelycirculatingtypesandcirculationishigh.However,theyarelesseffectiveinreducing casesofinfluenzalikeillnessandhaveamodestimpactonworkingdayslost.Thereisinsufficient evidencetoassesstheirimpactoncomplications.Wholevirionmonovalentvaccinesmayperform bestinapandemic. http://www.thelancet.com/journals/laninf/article/PIIS14733099(11)70295X/abstract Influenzavaccinescanprovidemoderateprotectionagainstvirologicallyconfirmedinfluenza,but suchprotectionisgreatlyreducedorabsentinsomeseasons.Evidenceforprotectioninadultsaged 65yearsorolderislacking.Lifeattenuatedinfluenzavaccinesconsistentlyshowhighestefficacyin youngchildren(aged6monthsto7years). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2749164/ Thehighestqualityclusterrandomisedtrialssuggestedthatspreadofrespiratoryvirusescanbe preventedbyhygienicmeasuresinyoungerchildrenandwithinhouseholds.Evidencethatthemore uncomfortableandexpensiveN95masksweresuperiortosimplesurgicalmaskswaslimited,but theycausedskinirritation.Theincrementaleffectofaddingvirucidalsorantisepticstonormal handwashingtoreducerespiratorydiseaseremainsuncertain.Globalmeasures,suchasscreeningat entryports,werenotproperlyevaluated.Evidencewaslimitedforsocialdistancingbeingeffective, especiallyifrelatedtoriskofexposurethatis,thehighertheriskthelongerthedistancingperiod. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2643439/?tool=pubmed Weidentified259primarystudies(274datasets).Higherqualitystudiesweresignificantlymore likely to show concordance between data presented and conclusions (odds ratio 16.35, 95% confidenceinterval4.24to63.04)andlesslikelytofavoureffectivenessofvaccines(0.04,0.02to 0.09).Governmentfundedstudieswerelesslikelytohaveconclusionsfavouringthevaccines(0.45, 0.26to0.90).Ahighermeanjournalimpactfactorwasassociatedwithcompleteorpartialindustry fundingcomparedwithgovernmentorprivatefundingandnofunding(differencesbetweenmeans 3

5.04).Studysizewasnotassociatedwithconcordance,contentoftakehomemessage,funding,and studyquality.Highercitationindexfactorwasassociatedwithpartialorcompleteindustryfunding. Thiswassensitivetotheexclusionfromtheanalysisofstudieswithundeclaredfunding.

3- ABOUT CHILDREN, ADULTS AND ELDERLY PATIENTS Children receiving chemotherapy for cancer http://www.escriber.com/userfiles/ccoch/file/CD006484.pdf Paediatriconcologypatientsreceivingchemotherapyareabletogenerateanimmuneresponsetothe inuenza vaccine, but it remains unclear whether this immune response protects them from inuenzainfectionoritscomplications. Weareawaitingresultsfromwelldesignedrandomised clinicaltrialsaddressingtheclinicalbenetofinuenzavaccinationinthesepatients. Children and adults with bronchiestasis http://www.ncbi.nlm.nih.gov/pubmed/17636836 There is neither evidence for, nor against, routine annual influenza vaccination for children and adults with bronchiectasis. Children, adolescents and adults with asthma http://ajrccm.atsjournals.org/content/169/4/488.long Influenza-related asthma exacerbations were of similar severity in both groups; they lasted 3.1 days shorter in the vaccine group (95% confidence interval, 6.2 to 0.002 days, p = 0.06). We conclude that influenza vaccination did not result in a significant reduction of the number, severity, or duration of asthma exacerbations caused by influenza. Additional studies are warranted to justify routine influenza vaccination of children with asthma. http://www.ncbi.nlm.nih.gov/pubmed/11034684 There is not enough evidence to assess the benefits and risks of influenza vaccination for people with asthma. Patients with chronic obstructive pulmonary disease (COPD) http://www.ncbi.nlm.nih.gov/pubmed/16437444 It appears, from the limited number of studies performed, that inactivated vaccine reduces exacerbations in COPD patients. The size of effect was similar to that seen in large observational 4

studies, and was due to a reduction in exacerbations occurring three or more weeks after vaccination, and due to influenza. There is a mild increase in transient local adverse effects with vaccination, but no evidence of an increase in early exacerbations. Patients with cystic fibrosis http://www.ncbi.nlm.nih.gov/pubmed/19821281 There is currently no evidence from randomised studies that influenza vaccine given to people with CF is of benefit to them. There remains a need for a well-constructed clinical study, that assesses the effectiveness of influenza vaccination on important clinical outcome measures.

4ABOUTELDERLYPATIENTSINGENERAL,ASHOTINTHEDARK http://jid.oxfordjournals.org/content/201/2/186.full.pdf+htm Becauseoftheavailabilityofeffectiveinfluenzavaccines,randomizedplacebocontrolledtrials would be unethical, but observational studies of influenza vaccine efficacy, which have predominatedsincethe1970s,havegenerallyshownexcellentvaccineeffectivenessinpreventing deathfromallcauses,withreductionsinmortalityduringinfluenzaseasonof30%50%.Recently, thisbenefithasbeencalledintoquestion.Simonsenetalfoundthattotalexcessmortalityfrom influenzawasintherange5%10%,makingclaimsof30%50%reductioninmortalityfromthe vaccineunrealistic.Jacksonetal.reportedthatvaccinationappearedtobeevenbetteratpreventing deathbeforetheinfluenzaseasonthanduringthetimewhentheviruswascirculating.Thisrevealed aflawinobservationalstudies,andwhathadpreviouslybeentakenforvaccineeffectivenesswas thenthoughttoactuallybeselectionbias. http://aje.oxfordjournals.org/content/170/5/650.abstract Vaccinecoverageaveraged63%;excessmortalitywhenthefluviruswascirculatingaveraged7.8%. In analyses that omitted weeks when flu circulated, the odds ratio measuring the vaccination mortalityassociationincreasedmonotonicallyfrom0.34earlyinNovemberto0.56inJanuary,0.67 inApril,and0.76inAugust.Thisreflectsthetrajectoryofselectioneffectsintheabsenceofflu.In analysesthatincludedweekswithfluandadjustmentforselectioneffects,fluseasonmultipliedthe oddsratioby0.954.Thecorrespondingvaccineeffectivenessestimatewas4.6%(95%confidence interval:0.7,8.3). http://archinte.jamanetwork.com/article.aspx?articleid=1108791

http://www.ncbi.nlm.nih.gov/m/pubmed/22371873/ ItisworthnotingthatresultsofseveralstudiesintheUnitedStatessuggestthat thebenefitof influenzavaccineonmortalityriskamongtheelderlyissmall.Itispossiblethatthereductionin mortalityriskisabout6%,themaximumattainablebenefitofinfluenzavaccinationamongelderly people. http://www.bmj.com/content/339/bmj.b4651 Please,maywehavearandomizedclinicaltrialnow?

5- ABOUT HEALTH CARE PROFESSIONALS WHO WORK WITH ELDERLY http://summaries.cochrane.org/CD005187/influenzavaccinationforhealthcareworkerswhowork withtheelderly We conclude that there is no evidence that only vaccinating healthcare workers prevents laboratoryproven influenza, pneumonia, and death from pneumonia in elderly residents in long-term care facilities. Other interventions such as hand washing, masks, early detection of influenza with nasal swabs, anti-virals, quarantine, restricting visitors and asking healthcare workers with an influenzalike illness not to attend work might protect individuals over 60 in long-term care facilities and high quality randomised controlled trials testing combinations of these interventions are needed.

6- ABOUT THE DECLINE OF INDUCED PROTECTION http://www.ncbi.nlm.nih.gov/pubmed/6357060 http://www.nature.com/nature/journal/v471/n7337/full/471157a.html Natural protection last more than 50 years. Flu virus produces what we name as "immunity of original sin", which can last up to 50 years, as demonstrated the swine flu (H1N1) in 2009, with protection of those born before 1957. In a similar way, people aged 50 years and more are protected against H1N2 flu (Asian flu), because having circulated the virus 1957 to 1968. http://jid.oxfordjournals.org/content/197/4/490.full http://www.equipocesca.org/wpcontent/uploads/2011/09/fluvaccineterminator2011.pdf Vaccine protection last less than one year, around 5 months.

7- VACCINE ADVERSE EFFECTS http://www.ncbi.nlm.nih.gov/pubmed/22582209 The rate of Guillain Barr syndrome immediately following pH1N1 vaccination was 57% higher than in person-time unexposed to vaccine (adjusted rate ratio = 1.57, 95% confidence interval: 1.02, 2.21), corresponding to 0.74 excess Guillain Barr syndrome cases per million pH1N1 vaccine doses (95% confidence interval: 0.04, 1.56). http://www.ncbi.nlm.nih.gov/pubmed/22470453 The 2009 vaccine-attributable risk of developing narcolepsy was 1:16,000 vaccinated 4 to 19 yearold (95% confidence interval 1:13,000-1:21,000). http://www.dohc.ie/publications/pdf/Final_Report_of_National_Narcolepsy_Study_Steering_Comm ittee.pdf?direct=1 Twenty eight of these 32 cases occurred in children/adolescents aged 5-19 years old. Based on the first contact with health care because of narcolepsy symptoms, the incidence of narcolepsy during the primary follow-up time (01/04/2009 to 31/12/2010) was 5.8 [95% CI: 3.5-9.0] per 100,000 person years in the vaccinated and 0.5 [95% CI: 0.2-1.0] per 100,000 person years in the unvaccinated individuals. Thus was a highly statistically significant 13-fold higher risk of narcolepsy in vaccinated compared to unvaccinated individuals. http://www.ncbi.nlm.nih.gov/pubmed/21929484 The 2010 trivalent influenza vaccine manufactured by CSL Biotherapies was associated with increased febrile reactions, including febrile convulsions, among Australian children.

8- INFLUENZA VACCINATION: POLICY VERSUS EVIDENCE http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1626345/?tool=pmcentrez Each year enormous effort goes into producing influenza vaccines for that specific year and deliveringthemtoappropriatesectionsofthepopulation.Isthiseffortjustified?No.Evidencefrom systematicreviewsshowsthatinactivatedvaccineshavelittleornoeffectontheeffectsmeasured. Reasonsforthecurrentgapbetweenpolicyandevidenceareunclear,butgiventhehugeresources involved,areevaluationshouldbeurgentlyundertaken . http://download.thelancet.com/flatcontentassets/H1N1flu/vaccination/vaccination48.pdf

Whatever policy is chosen, there is an urgent need to replace current practices with accountable policy-making. In this scenario, systematic synthesis of evidence should play a central role in making ethical decisions, in which the inuence of lobbies, activism, ideology, and lucre are at least recognized. http://www.equipocesca.org/wpcontent/uploads/2011/09/fluvaccineterminator2011.pdf

For how long they will ask professionals and patients for vaccination against scienceandethics?