The Effectiveness of COVID-19 Vaccines to Prevent Long COVID Symptoms: Staggered Cohort Analyses of Data from the UK, Spain, and Estonia

Abstract

Background: While vaccines have proved effective to prevent severe COVID-19, their impact to prevent long-term symptoms is not yet fully understood.

Methods: We conducted staggered cohort studies using primary care records from both the UK and Catalonia (Spain) and national health claims from Estonia. All adults registered for at least 180 days as of 01/2021 (UK), 02/2021 (Spain) and 01/2021 (Estonia) comprised the source population. Vaccination status was used as a time-varying exposure, staggered by vaccine rollout period. Vaccinated people were further classified by vaccine brand according to their first dose received. Long COVID was defined as having at least one WHO-listed symptoms ≥90days following SARS-CoV-2 infection with no history of that symptom in the previous 180days. Propensity score overlap weighting was applied separately for each cohort to minimise confounding. Sub-distribution Hazard Ratios (sHR) were calculated to estimate vaccine effectiveness against long COVID, and empirically calibrated using Negative Control Outcomes to minimise residual confounding. Random effects meta-analyses across staggered cohorts were conducted to pool overall effect estimates.

Findings: More than 1,618,395; 5,729,915; 2,744,821 and 77,603 vaccinated people and 1,640,371; 5,860,564; 2,588,518 and 302,267 unvaccinated people were included from CPRD GOLD (UK), CPRD AURUM (UK), SIDIAP (Spain) and CORIVA (Estonia). Of these, 3,147 long COVID cases were identified in CPRD GOLD, 36,490 in CPRD AURUM, 121,535 in SIDIAP, and 20,332 in CORIVA. Overall sHR were 0·55 [95%CI 0·46-0·65], 0·64 [0·55-0·74], 0·84 [0·75-0·93] and 0·62 [0·49-0·78] respectively. Comparative effectiveness analyses showed better protection for BNT162b2 compared to ChAdOx1: sHR 0·77 [0·60-0·99] in CPRD GOLD, 0·73 [0·67-0·79] in CPRD AURUM.

Interpretation: Vaccination against COVID-19 consistently reduced the risk of long COVID symptoms. Our results highlight the importance of vaccination to prevent persistent COVID symptoms, particularly in young people.

Funding: This manuscript reports on independent research funded by the National Institute for Health and Care Research (NIHR) (COV-LT2-0006). The research was supported by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre (BRC). DPA is funded through a NIHR Senior Research Fellowship (Grant number SRF-2018–11-ST2-004). Funding to perform the study in the SIDIAP database was provided by the Real-World Epidemiology (RWEpi) research group at IDIAPJGol. AU reports funding from the European Regional Development Fund (RITA 1/02-120).

Declaration of Interest: DPA’s department has received grant/s from Amgen, Chiesi-Taylor, Lilly, Janssen, Novartis, and UCB Biopharma, the European Medicines Agency and the Innovative Medicines Initiative. His research group has received consultancy fees from Astra Zeneca and UCB Biopharma. Amgen, Astellas, Janssen, Synapse Management Partners and UCB Biopharma have funded or supported training programmes organised by DPA's department. RK’s research group has received consultancy fees from AstraZeneca, and the Estonian Ministry of Social Affairs through the RITA CORIVA and RITA MAITT projects. AU reports funding from the European Regional Development Fund (RITA 1/02-120) for her institution. HN reports support from the European Health Data & Evidence Network (EHDEN) project grant, Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806968 for harmonization of the Norwegian registry data into OMOP CDM. TDS reports funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 806968 for the institute to map the SIDIAP data to the OMOP CDM. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. All other authors declare no conflict of interest.

Ethical Approval: The study was approved by the CPRD’s Research Data Governance Process, Protocol No 21_000557 and the Clinical Research Ethics committee of Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol) (approval number 4R22/133) and the Research Ethics Committee of the University of Tartu (approval No. 330/T-10).

Keywords: Post-COVID-19 condition, Post-COVID-19 sequalae, pharmacoepidemiology, public health, cohort study