Research Open Access
Like 0



Differential SARS-CoV-2 exposure between vaccinated and unvaccinated individuals may confound vaccine effectiveness (VE) estimates.


We conducted a test-negative case–control study to determine VE against SARS-CoV-2 infection and the presence of confounding by SARS-CoV-2 exposure.


We included adults tested for SARS-CoV-2 at community facilities between 4 July and 8 December 2021 (circulation period of the Delta variant). The VE against SARS-CoV-2 infection after primary vaccination with an mRNA (Comirnaty or Spikevax) or vector-based vaccine (Vaxzevria or Janssen) was calculated using logistic regression adjusting for age, sex and calendar week (Model 1). We additionally adjusted for comorbidity and education level (Model 2) and SARS-CoV-2 exposure (number of close contacts, visiting busy locations, household size, face mask wearing, contact with SARS-CoV-2 case; Model 3). We stratified by age, vaccine type and time since vaccination.


VE against infection (Model 3) was 64% (95% CI: 50–73), only slightly lower than in Models 1 (68%; 95% CI: 58–76) and 2 (67%; 95% CI: 56–75). Estimates stratified by age group, vaccine and time since vaccination remained similar: mRNA VE (Model 3) among people ≥ 50 years decreased significantly (p = 0.01) from 81% (95% CI: 66–91) at < 120 days to 61% (95% CI: 22–80) at ≥ 120 days after vaccination. It decreased from 83% to 59% in Model 1 and from 81% to 56% in Model 2.


SARS-CoV-2 exposure did not majorly confound the estimated COVID-19 VE against infection, suggesting that VE can be estimated accurately using routinely collected data without exposure information.


Article metrics loading...

Loading full text...

Full text loading...



  1. European Medicines Agency (EMA). EMA recommends first COVID-19 vaccine for authorisation in the EU. Amsterdam: EMA: 2020. Available from: https://www.ema.europa.eu/en/news/ema-recommends-first-covid-19-vaccine-authorisation-eu
  2. European Medicines Agency (EMA). EMA recommends COVID-19 vaccine Janssen for authorisation in the EU. Amsterdam: EMA: 2021. Available from: https://www.ema.europa.eu/en/news/ema-recommends-covid-19-vaccine-janssen-authorisation-eu
  3. European Medicines Agency (EMA). EMA recommends COVID-19 vaccine Moderna for authorisation in the EU. Amsterdam: EMA: 2021. Available from: https://www.ema.europa.eu/en/news/ema-recommends-covid-19-vaccine-moderna-authorisation-eu
  4. European Medicines Agency (EMA). EMA recommends COVID-19 vaccine AstraZeneca for authorisation in the EU. Amsterdam: EMA: 2021. Available from: https://www.ema.europa.eu/en/news/ema-recommends-covid-19-vaccine-astrazeneca-authorisation-eu
  5. National Institute for Public Health and the Environment (RIVM). Figures on the COVID-19 vaccination programme. Bilthoven: RIVM; updated 18 Jan 2022. Available from: https://www.rivm.nl/en/covid-19-vaccination/figures-vaccination-programme
  6. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al. , COVE Study Group. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021;384(5):403-16.  https://doi.org/10.1056/NEJMoa2035389  PMID: 33378609 
  7. Falsey AR, Sobieszczyk ME, Hirsch I, Sproule S, Robb ML, Corey L, et al. Phase 3 safety and efficacy of AZD1222 (ChAdOx1 nCoV-19) Covid-19 Vaccine. N Engl J Med. 2021;385(25):2348-60.  https://doi.org/10.1056/NEJMoa2105290  PMID: 34587382 
  8. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383(27):2603-15.  https://doi.org/10.1056/NEJMoa2034577  PMID: 33301246 
  9. Sadoff J, Gray G, Vandebosch A, Cárdenas V, Shukarev G, Grinsztejn B, et al. Safety and efficacy of single-dose Ad26.COV2.S vaccine against Covid-19. N Engl J Med. 2021;384(23):2187-201.  https://doi.org/10.1056/NEJMoa2101544  PMID: 33882225 
  10. Zimmermann P, Curtis N. Factors that influence the immune response to vaccination. Clin Microbiol Rev. 2019;32(2):e00084-18.  https://doi.org/10.1128/CMR.00084-18  PMID: 30867162 
  11. World Health Organization (WHO). Evaluation of COVID-19 vaccine effectiveness: interim guidance, 17 March 2021. Geneva: WHO; 2021. Available from: https://apps.who.int/iris/handle/10665/340301
  12. Hahné S, Bollaerts K, Farrington P. Vaccination programmes epidemiology, monitoring, evaluation. 1 edition. London: Routledge; 2022. 470 p.
  13. Harder T, Külper-Schiek W, Reda S, Treskova-Schwarzbach M, Koch J, Vygen-Bonnet S, et al. Effectiveness of COVID-19 vaccines against SARS-CoV-2 infection with the Delta (B.1.617.2) variant: second interim results of a living systematic review and meta-analysis, 1 January to 25 August 2021. Euro Surveill. 2021;26(41):2100920.  https://doi.org/10.2807/1560-7917.ES.2021.26.41.2100920  PMID: 34651577 
  14. Martínez-Baz I, Trobajo-Sanmartín C, Miqueleiz A, Guevara M, Fernández-Huerta M, Burgui C, et al. Product-specific COVID-19 vaccine effectiveness against secondary infection in close contacts, Navarre, Spain, April to August 2021. Euro Surveill. 2021;26(39):2100894.  https://doi.org/10.2807/1560-7917.ES.2021.26.39.2100894  PMID: 34596016 
  15. Rijksoverheid. Juni 2020: Versoepeling coronamaatregelen en testen voor iedereen. [June 2020: Relaxation of corona measures and testing for everyone]. The Hague: Rijksoverheid; 2020. Dutch. Available from: https://www.rijksoverheid.nl/onderwerpen/coronavirus-tijdlijn/juni-2020-versoepeling-coronamaatregelen-en-testen-voor-iedereen
  16. Statistics Netherlands (CBS). Opleidingsniveau naar gemeenten, wijken en buurten. [Education level by municipality, district and neighbourhood]. The Hague: CBS. [Accessed: Feb 2022]. Dutch. Available from: https://www.cbs.nl/nl-nl/maatwerk/2020/17/opleidingsniveau-naar-gemeenten-wijken-en-buurten
  17. van den Hoogen LL, Verheul MK, Vos ERA, van Hagen CCE, van Boven M, Wong D, et al. SARS-CoV-2 Spike S1-specific IgG kinetic profiles following mRNA or vector-based vaccination in the general Dutch population show distinct kinetics. Sci Rep. 2022;12(1):5935.  https://doi.org/10.1038/s41598-022-10020-6  PMID: 35396570 
  18. National Institute for Public Health and the Environment (RIVM). Variants of the coronavirus SARS-CoV-2. Bilthoven: RIVM; updated 14 Jan 2022. Available from: https://www.rivm.nl/en/coronavirus-covid-19/virus/variants
  19. Hale T, Angrist N, Goldszmidt R, Kira B, Petherick A, Phillips T, et al. A global panel database of pandemic policies (Oxford COVID-19 Government Response Tracker). Nat Hum Behav. 2021;5(4):529-38.  https://doi.org/10.1038/s41562-021-01079-8  PMID: 33686204 
  20. Relationship between number of COVID-19 cases and government response. Oxford: University of Oxford. [Accessed: 14 Jul 2022]. Available from: https://covidtracker.bsg.ox.ac.uk/stringency-scatter
  21. Lopez Bernal J, Andrews N, Gower C, Gallagher E, Simmons R, Thelwall S, et al. Effectiveness of Covid-19 vaccines against the B.1.617.2 (Delta) variant. N Engl J Med. 2021;385(7):585-94.  https://doi.org/10.1056/NEJMoa2108891  PMID: 34289274 
  22. Sheikh A, McMenamin J, Taylor B, Robertson C, Public Health Scotland and the EAVE II Collaborators. SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness. Lancet. 2021;397(10293):2461-2.  https://doi.org/10.1016/S0140-6736(21)01358-1  PMID: 34139198 
  23. Tang P, Hasan MR, Chemaitelly H, Yassine HM, Benslimane FM, Al Khatib HA, et al. BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the SARS-CoV-2 Delta variant in Qatar. Nat Med. 2021;27(12):2136-43.  https://doi.org/10.1038/s41591-021-01583-4  PMID: 34728831 
  24. Kissling E, Hooiveld M, Martínez-Baz I, Mazagatos C, William N, Vilcu A-M, et al. Effectiveness of complete primary vaccination against COVID-19 at primary care and community level during predominant Delta circulation in Europe: multicentre analysis, I-MOVE-COVID-19 and ECDC networks, July to August 2021. Euro Surveill. 2022;27(21):2101104.  https://doi.org/10.2807/1560-7917.ES.2022.27.21.2101104  PMID: 35620997 
  25. Lyngse FP, Mølbak K, Denwood M, Christiansen LE, Møller CH, Rasmussen M, et al. Effect of vaccination on household transmission of SARS-CoV-2 Delta variant of concern. Nat Commun. 2022;13(1):3764.  https://doi.org/10.1038/s41467-022-31494-y  PMID: 35773247 
  26. de Gier B, Andeweg S, Backer JA, Hahné SJ, van den Hof S, de Melker HE, et al. Vaccine effectiveness against SARS-CoV-2 transmission to household contacts during dominance of Delta variant (B.1.617.2), the Netherlands, August to September 2021. Euro Surveill. 2021;26(44):2100977.  https://doi.org/10.2807/1560-7917.ES.2021.26.44.2100977  PMID: 34738514 
  27. Andrews N, Tessier E, Stowe J, Gower C, Kirsebom F, Simmons R, et al. Duration of protection against mild and severe disease by COVID-19 vaccines. N Engl J Med. 2022;386(4):340-50.  https://doi.org/10.1056/NEJMoa2115481  PMID: 35021002 
  28. National Institute for Public Health and the Environment (RIVM). Vaccine-induced protection against an infection with the Delta variant of the coronavirus. Bilthoven: RIVM; 2021. Available from: https://www.rivm.nl/en/news/vaccine-induced-protection-against-infection-with-delta-variant-of-coronavirus
  29. National Institute for Public Health and the Environment (RIVM) COVID-19 epidemiology and surveillance team. Effectiviteit van COVID-19-vaccinatie tegen SARS-CoV-2 infectie in de Delta periode. [Effectiveness of COVID-19 vaccination against SARS-CoV-2 infection in the Delta period]. Bilthoven: RIVM; 2021. Dutch. Available from: https://www.rivm.nl/documenten/effectiviteit-van-covid-19-vaccinatie-tegen-sars-cov-2-infectie-in-delta-periode
  30. Le Bert N, Tan AT, Kunasegaran K, Tham CYL, Hafezi M, Chia A, et al. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature. 2020;584(7821):457-62.  https://doi.org/10.1038/s41586-020-2550-z  PMID: 32668444 
  31. Andeweg SP, de Gier B, Eggink D, van den Ende C, van Maarseveen N, Ali L, et al. Protection of COVID-19 vaccination and previous infection against Omicron BA.1 and Delta SARS-CoV-2 infections, the Netherlands, 22 November 2021- 19 January 2022. medRxiv. 2022:2022.02.06.22270457.  https://doi.org/10.1101/2022.02.06.22270457 
  32. National Institute for Public Health and the Environment (RIVM). COVID-19 dataset. Bilthoven: RIVM. [Accessed: 17 Feb 2022]. Available from: https://data.rivm.nl/covid-19
  33. National Institute for Public Health and the Environment - Ministry of Health WaS. Modelling the spread of the coronavirus SARS-CoV-2 2021. Bilthoven: RIVM; updated 19 Nov 2021. Available from: https://www.rivm.nl/en/coronavirus-covid-19/modelling
  34. Statistics Netherlands (CBS). Herkomst. Hoeveel inwoners van Nederland zijn in het buitenland geboren? [Origin. How many residents of the Netherlands were born abroad?]. The Hague: CBS. [Accessed: 20 Oct 2022]. Dutch. Available from: https://www.cbs.nl/nl-nl/visualisaties/dashboard-bevolking/migratieachtergrond
  35. Statistics Netherlands (CBS) DCSO. Age distribution. The Hague: CBS. [Accessed: 17 Feb 2022]. Available from: https://www.cbs.nl/en-gb/visualisations/dashboard-population/age/age-distribution
  36. Coyer L, Wynberg E, Buster M, Wijffels C, Prins M, Schreijer A, et al. Hospitalisation rates differed by city district and ethnicity during the first wave of COVID-19 in Amsterdam, The Netherlands. BMC Public Health. 2021;21(1):1721.  https://doi.org/10.1186/s12889-021-11782-w  PMID: 34551752 
  37. Coyer L, Boyd A, Schinkel J, Agyemang C, Galenkamp H, Koopman ADM, et al. Differences in SARS-CoV-2 infections during the first and second wave of SARS-CoV-2 between six ethnic groups in Amsterdam, the Netherlands: A population-based longitudinal serological study. Lancet Reg Health Eur. 2022;13:100284.  https://doi.org/10.1016/j.lanepe.2021.100284  PMID: 34927120 

Data & Media loading...

Supplementary data

Submit comment
Comment moderation successfully completed
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error