Effectiveness of inactivated quadrivalent influenza vaccine in the 2015/2016 season as assessed in both a test-negative case-control study design and a traditional case-control study design


Both traditional case-control studies (TCCSs) and test-negative case-control studies (TNCCSs) are commonly used to assess influenza vaccine effectiveness (VE). To compensate for the fact that observational studies are susceptible to bias, we combined both methods to assess VE in one geographical area during the 2015/2016 season, when influenza A (H1N1)pdm was dominant. Our TNCCS covered 331 children aged 6 months to 15 years who visited our hospital with fever, including 182 with influenza, and our TCCS covered 812 pediatric outpatients aged 6 months to 15 years, including 214 with influenza. Influenza infection and vaccination history were reviewed, and VE was calculated as (1 − odds ratio) × 100. In the TNCCS, VE against influenza A was 68% (95% CI 47–81) overall, and 70% (48–83) for those given two doses; against influenza B, VE was 37% (− 12–64) overall and 49% (2–74) for two doses. In the TCCS, VE against influenza A was 44% (15–63) overall and 44% (13–64) for two doses, and VE against influenza B was 24% (− 19–52) overall and 41% (3–64) for two doses.

Conclusion: Both studies confirmed significant VE against influenza A, significant two-dose VE against influenza B, and better two-dose VE than one-dose VE.

What is Known:
• Influenza vaccine effectiveness (VE) varies from year to year.
• Observational studies are conventionally used for VE assessment. However, they are inherently susceptible to bias and confounding.
What is New:
• This is the first report of influenza VE assessment using more than one observational study and performed in a specific area during the same season.
• VE estimates obtained in our traditional case-control study were lower than those in our test-negative case-control study, but both studies found significant VE against influenza.

This is a preview of subscription content, access via your institution.

Fig. 1



Traditional case-control study


Test-negative case-control study


Vaccine effectiveness


  1. 1.

    Belongia EA, Kieke BA, Donahue JG, Greenlee RT, Balish A, Foust A, Lindstrom S, Shay DK (2009) Marshfield influenza study group. Effectiveness of inactivated influenza vaccines varied substantially with antigenic match from the 2004-2005 season to the 2006-2007 season. J Infect Dis 199:159–167

    Article  PubMed  Google Scholar 

  2. 2.

    Brendan Flannery, Sue B. Reynolds, Lenee Blanton, et al (2017) Influenza vaccine effectiveness against pediatric deaths: 2010-2014. Pediatrics 139: e20164244

  3. 3.

    Chung JR, Flannery B, Thompson MG, Gaglani M, Jackson ML, Monto AS, Nowalk MP, Talbot HK, Treanor JJ, Belongia EA, Murthy K, Jackson LA, Petrie JG, Zimmerman RK, Griffin MR, McLean HQ, Fry AM (2016) Seasonal effectiveness of live attenuated and inactivated influenza vaccine. Pediatrics 137:e20153279

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Dixon GA, Moore HC, Kelly H, Jacoby P, Carcione D, Williams S, Smith D, Keil AD, van Buynder P, Richmond PC, the WAIVE study team (2010) Lessons from the first year of the WAIVE study investigating the protective effect of influenza vaccine against laboratory-confirmed influenza in hospitalized children aged 6-59 months. Influenza Other Respir Viruses 4:231–234

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Jackson ML, Nelson JC (2013) The test-negative design for estimating influenza vaccine effectiveness. Vaccine 31:2165–2168

    Article  PubMed  Google Scholar 

  6. 6.

    Kissling E, Nunes B, Robertson C, et al (2009) I-Move towards monitoring seasonal and pandemic influenza vaccine effectiveness: lessons learnt from a pilot multi-centric case-control study in Europe, 2008–9. Euro Surveill 14(44)

  7. 7.

    Kelly H, Carville K, Grant K, Jacoby P, Tran T, Barr I (2009) Estimation of influenza vaccine effectiveness from routine surveillance data. PLoS One 4:e5079

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. 8.

    National Institute of Infectious Diseases (2015) Age group composition of reported cases of influenza virus-associated encephalitis from 2009/10 to 2014/15 seasons. http://www.nih.go.jp/niid/images/iasr/36/429/graph/df42951.gif

  9. 9.

    National Institute of Infectious Diseases (2016) Number of reported influenza virus isolation/detection for 2015/16 season. http://www.nih.go.jp/niid/images/iasr/2016/11/441tt02.gif

  10. 10.

    National Institute of Infectious Diseases (2016) Overview of the 2015/16 influenza season. Infectious Agents Surveillance Report 37:211–213. http://www.nih.go.jp/niid/ja/flu-m/flutoppage/592-idsc/iasr-topic/6871-441t.html

  11. 11.

    National Institute of Infectious Diseases (2015) Influenza 2014/15 season, Japan. IASR 36:199–201. http://www.niid.go.jp/niid/en/iasr-vol36-e/865-iasr/6096-tpc429.html

  12. 12.

    Nohynek H, Baum U, Syrjänen R, Ikonen N, Sundman J, Jokinen J (2016) Effectiveness of the live attenuated and the inactivated influenza vaccine in two-year-olds—a nationwide cohort study Finland, influenza season 2015/16. Euro Surveill 21(38)

  13. 13.

    Orenstein EW, De Serres G, Haber MJ, Shay DK, Bridges CB, Gargiullo P, Orenstein WA (2007) Methodologic issues regarding the use of three observational study designs to assess influenza vaccine effectiveness. Int J Epidemiol 36:623–631

    Article  PubMed  Google Scholar 

  14. 14.

    Ozasa K, Washio M (2009) Issues associated with evaluating the effectiveness of influenza vaccination. Jpn J Public Health 56:18–24

    Google Scholar 

  15. 15.

    Regan AK, Klerk ND, Moore HC, Omer SB, Shellam G, Effler PV (2016) Effectiveness of seasonal trivalent influenza vaccination against hospital-attended acute respiratory infections in pregnant women: a retrospective cohort study. Vaccine 34:3649–3656

    Article  PubMed  Google Scholar 

  16. 16.

    Shinjoh M, Sugaya N, Yamaguchi Y, Tomidokoro Y, Sekiguchi S, Mitamura K, Fujino M, Shiro H, Komiyama O, Taguchi N, Nakata Y, Yoshida N, Narabayashi A, Myokai M, Sato M, Furuichi M, Baba H, Fujita H, Sato A, Ookawara I, Tsunematsu K, Yoshida M, Kono M, Tanaka F, Kawakami C, Kimiya T, Takahashi T, Iwata S, Keio Pediatric Influenza Research Group (2015) Effectiveness of trivalent inactivated influenza vaccine in children estimated by a test-negative case-control design study based on influenza rapid diagnostic test results. PLoS One 10:e0136539

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. 17.

    Shuler CM, Iwamoto M, Bridges CB, Marin M, Neeman R, Gargiullo P, Yoder TA, Keyserling HL, Terebuh PD (2007) Vaccine effectiveness against medically attended, laboratory-confirmed influenza among children aged 6 to 59 months, 2003-2004. Pediatrics 119:e587–e595

    Article  PubMed  Google Scholar 

  18. 18.

    Skowronski DM, Gilbert M, Tweed SA et al (2005) Effectiveness of vaccine against medical consultation due to laboratory-confirmed influenza: results from a sentinel physician pilot project in British Columbia, 2004-2005. Can Commun Dis Rep 31:181–191

    Google Scholar 

  19. 19.

    Skowronski DM, De Serres G, Crowcroft NS et al (2010) Association between the 2008-09 seasonal influenza vaccine and pandemic H1N1 illness during spring-summer 2009: four observational studies from Canada. PLoS Med 7:e1000258

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Sugaya N, Takeuchi Y (2005) Mass vaccination of schoolchildren against influenza and its impact on the influenza-associated mortality rate among children in Japan. Clin Infect Dis 41:939–947

    Article  PubMed  Google Scholar 

  21. 21.

    Sugaya N, Shinjoh M, Kawakami C, Yamaguchi Y, Yoshida M, Baba H, Ishikawa M, Kono M, Sekiguchi S, Kimiya T, Mitamura K, Fujino M, Komiyama O, Yoshida N, Tsunematsu K, Narabayashi A, Nakata Y, Sato A, Taguchi N, Fujita H, Toki M, Myokai M, Ookawara I, Takahashi T (2016) Trivalent inactivated influenza vaccine effective against influenza A(H3N2) variant viruses in children during the 2014/15 season, Japan. Euro Surveill 21(42)

  22. 22.

    The Ministry of Health, Labour and Welfare (2016) Influenza Q&A Q31: are there cases of mortality from influenza vaccination? http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou01/qa.html

Download references


This work was supported by a grant for medical research from Tokyo Metropolitan Government.

Author information




T.K., M.S., S.S., and N.S. designed the study. T.K., M.A., and H.T. collected and analyzed data. T.K., M.S., M.A., and S.S wrote the manuscript. N.S. and T.T. critically reviewed the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Takahisa Kimiya.

Ethics declarations

Conflict of interest

This work was supported by a grant for medical research from Tokyo Metropolitan Government. Author Norio Sugaya has received lecture fees from Astellas, Daiichi Sankyo, Denka Seiken, and Takeda, but none of these talks were connected with the work presented here. Author Masayoshi Shinjoh has also received lecture fees from Japan Vaccine and MSD, but again, the talks were unconnected with the studies describe in this paper. No other authors declare any potential conflicts of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Communicated by Nicole Ritz

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kimiya, T., Shinjoh, M., Anzo, M. et al. Effectiveness of inactivated quadrivalent influenza vaccine in the 2015/2016 season as assessed in both a test-negative case-control study design and a traditional case-control study design. Eur J Pediatr 177, 1009–1017 (2018). https://doi.org/10.1007/s00431-018-3145-7

Download citation


  • Influenza vaccine effectiveness
  • Inactivated quadrivalent influenza vaccine
  • 2015/2016 season
  • Test-negative case-control study
  • Traditional case-control study