title: Effectiveness of seasonal influenza vaccination in community-dwelling elderly people: an individual participant data meta-analysis of test-negative design case-control studies.
abstract: Several aggregate data meta-analyses have provided estimates of the effectiveness of influenza vaccination in community-dwelling elderly people. However, these studies ignored the effects of patient-level confounders such as sex, age, and chronic diseases that could bias effectiveness estimates. We aimed to assess the confounder-adjusted effectiveness of influenza vaccines on laboratory-confirmed influenza among elderly people by conducting a global individual participant data meta-analysis.
  
  
  
  In this individual participant data meta-analysis, we considered studies included in a previously conducted aggregate data meta-analysis that included test-negative design case-control studies published up to July 13, 2014. We contacted all authors of the included studies on Dec 1, 2014, to request individual participant data. Patients were excluded if their unique identifier was missing, their vaccination status was unknown, their outcome status was unknown, or they had had suspected influenza infection more than once in the same influenza season. Cases were patients with influenza-like illness symptoms who tested positive for at least one of A H1N1, A H1N1 pdm09, A H3N2, or B viruses; controls were patients with influenza-like illness symptoms who tested negative for these virus types or subtypes. Influenza vaccine effectiveness against overall and subtype-specific laboratory-confirmed influenza were the primary and secondary outcomes. We used a generalised linear mixed model to calculate adjusted vaccine effectiveness according to vaccine match to the circulating strains of influenza virus and intensity of the virus activity (epidemic or non-epidemic). Vaccine effectiveness was defined as the relative reduction in risk of laboratory-confirmed influenza in vaccinated patients compared with unvaccinated patients. We did subgroup analyses to estimate vaccine effectiveness according to hemisphere, age category, and health status.
  
  
  
  We received 23 of the 53 datasets included in the aggregate data meta-analysis. Furthermore, six additional datasets were provided by data collaborators, which resulted in individual participant data for a total of 5210 participants. A total of 4975 patients had the required data for analysis. Of these, 3146 (63%) were controls and 1829 (37%) were cases. Influenza vaccination was significantly effective during epidemic seasons irrespective of vaccine match status (matched adjusted vaccine effectiveness 44·38%, 95% CI 22·63-60·01; mismatched adjusted vaccine effectiveness 20·00%, 95% CI 3·46-33·68; analyses in the imputed dataset). Seasonal influenza vaccination did not show significant effectiveness during non-epidemic seasons. We found substantial variation in vaccine effectiveness across virus types and subtypes, with the highest estimate for A H1N1 pdm09 (53·19%, 10·25-75·58) and the lowest estimate for B virus types (-1·52%, -39·58 to 26·16). Although we observed no significant differences between subgroups in each category (hemisphere, age, and health status), influenza vaccination showed a protective effect among elderly people with cardiovascular disease, lung disease, or aged 75 years and younger.
  
  
  
  Influenza vaccination is moderately effective against laboratory-confirmed influenza in elderly people during epidemic seasons. More research is needed to investigate factors affecting vaccine protection (eg, brand-specific or type-specific vaccine effectiveness and repeated annual vaccination) in elderly people.
  
  
  
  University Medical Center Groningen.
authors.affiliation: Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands; Unit of Pharmacoepidemiology & Pharmacoeconomics (PE2), Department of Pharmacy, University of Groningen, Groningen, Netherlands; British Columbia Centre for Disease Control, Vancouver, BC, Canada; School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada. Electronic address: maryam.darvishian@bccdc.ca.
authors.forename: Maryam
authors.initials: M
authors.lastname: Darvishian
authors.affiliation: Eindhoven University of Technology, Eindhoven, Netherlands.
authors.forename: Edwin R
authors.initials: ER
authors.lastname: van den Heuvel
authors.affiliation: Institute of Environmental Science and Research, Wallaceville, New Zealand.
authors.forename: Ange
authors.initials: A
authors.lastname: Bissielo
authors.affiliation: Instituto de Salud Pública, Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; CIBER Epidemiología y Salud Pública, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Castilla
authors.affiliation: Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa; School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Cohen
authors.affiliation: Unit for Vaccination Programs, Department of Monitoring and Evaluation, Public Health Agency of Sweden, Solna, Sweden.
authors.forename: Helene
authors.initials: H
authors.lastname: Englund
authors.affiliation: Lithuanian University of Health Sciences, Kaunas, Lithuania.
authors.forename: Giedre
authors.initials: G
authors.lastname: Gefenaite
authors.affiliation: Taiwan Centers for Disease Control, Taipei, Taiwan.
authors.forename: Wan-Ting
authors.initials: WT
authors.lastname: Huang
authors.affiliation: Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
authors.forename: Sacha
authors.initials: S
authors.lastname: la Bastide-van Gemert
authors.affiliation: Instituto de Salud Pública, Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; CIBER Epidemiología y Salud Pública, Spain.
authors.forename: Iván
authors.initials: I
authors.lastname: Martinez-Baz
authors.affiliation: National Institute for Communicable Diseases of the National Health Laboratory Services, Johannesburg, South Africa.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: McAnerney
authors.affiliation: Division of Public Health Surveillance and Response, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa.
authors.forename: Genevie M
authors.initials: GM
authors.lastname: Ntshoe
authors.affiliation: Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Japan.
authors.forename: Motoi
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of General Practice and Primary Care, University of Auckland, New Zealand.
authors.forename: Nikki
authors.initials: N
authors.lastname: Turner
authors.affiliation: Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands; Unit of Pharmacoepidemiology & Pharmacoeconomics (PE2), Department of Pharmacy, University of Groningen, Groningen, Netherlands.
authors.forename: Eelko
authors.initials: E
authors.lastname: Hak
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D058872:Epidemics / Q000517:prevention & control; D005260:Female; D006801:Humans; D057187:Independent Living / Q000706:statistics & numerical data*; D007252:Influenza Vaccines / Q000627:therapeutic use*; D007251:Influenza, Human / Q000453:epidemiology* / Q000517:prevention & control*; D008297:Male; D012107:Research Design; D012621:Seasons; D016896:Treatment Outcome; D014611:Vaccination / Q000706:statistics & numerical data*
chemical_list: D007252:Influenza Vaccines