Challenges in Estimating the Effectiveness of 2 Doses of COVID-19 Vaccine Beyond 6 Months in England

This paper discusses the challenges in estimating long-term (>6 months) vaccine effectiveness in observational data, primarily due to high uptake of a subsequent third vaccine dose.

Paper information

Elsie M F Horne, William J Hulme, Ruth H Keogh, Tom M Palmer, Elizabeth J Williamson, Edward P K Parker, Venexia M Walker, Rochelle Knight, Yinghui Wei, Kurt Taylor, Louis Fisher, Jessica Morley, Amir Mehrkar, Iain Dillingham, Sebastian Bacon, Ben Goldacre, Jonathan A C Sterne, for the OpenSAFELY Collaborative, CHALLENGES IN ESTIMATING THE EFFECTIVENESS OF 2 DOSES OF COVID-19 VACCINE BEYOND 6 MONTHS IN ENGLAND, American Journal of Epidemiology, Volume 193, Issue 1, January 2024, Pages 227–231,


Understanding how the effectiveness of coronavirus disease 2019 (COVID-19) vaccine changes over time and in response to new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is crucial to scheduling subsequent doses. In a previous study, Horne et al. quantified vaccine effectiveness (VE) over 6 consecutive 4-week periods from 2 weeks to 26 weeks after the second dose. Waning of hazard ratios (HRs) when comparing vaccinated persons with unvaccinated persons was approximately log-linear over time and was consistent across COVID-19–related outcomes and risk-based subgroups. To investigate waning beyond 26 weeks and in the era of the Omicron variant, we extended follow-up to the earliest of 50 weeks after the second dose or March 31, 2022.

We found that it is challenging to estimate the long-term effectiveness of 2 COVID-19 vaccine doses in populations in which uptake of a third dose was high. These challenges also affect investigations of VE against the Omicron variant, whose emergence coincided with rapid uptake of third doses and of incremental effectiveness of a third dose against the second dose.