Persistence in risk and effect of COVID-19 vaccination on long-term health consequences after SARS-CoV-2 infection


Data source

In this retrospective cohort study, routine electronic medical records were retrieved from the Hong Kong Hospital Authority (HKHA). The Hospital Authority is a statutory body that manages all public hospitals and their ambulatory clinics in Hong Kong. The service is available to all HK residents (> 7.2 million) covering ~80% of all routine hospital admissions38. Electronic medical records from the HKHA database consisted of disease diagnoses recorded in planned or unplanned doctor consultations from in- and outpatient hospitals and emergency visits, thus allowing timely capture of all medical records of all users of the public health services in HK. Records were obtained from the Hong Kong Deaths Registry to identify mortality in this study. Information on vaccination status was provided by the Department of Health, The Government of Hong Kong Special Administrative Region whilst records of confirmed cases of SARS-CoV-2 infection were obtained from the Centre for Health Protection of the Government, the Hong Kong Special Administrative Region and HKHA. Anonymized unique patient identifiers were used to integrate these databases. These population-based databases have been used in previous studies on the long-term sequelae of COVID-19 infection, COVID-19 vaccines safety surveillance and effectiveness3,6,38,39,40,41,42.

Study design and population

Individuals with data linkage to electronic medical records of Hong Kong Hospital Authority from January 1, 2018 to January 23, 2023 were eligible for this study. A cohort study was conducted to evaluate the risk of health consequences between patients with and without SARS-CoV-2 infection aged 18 years or above. Patients with an incident SARS-CoV-2 infection (confirmed by rapid antigen test [RAT] or polymerase chain reaction [PCR] test in throat swab, nasopharyngeal aspirate, or deep throat sputum specimens) between April 1, 2020 and October 31, 2022 were matched to non-infected controls without a positive SARS-CoV-2 test record throughout the study period with the exact birth-year and sex. All individuals without a record of positive test record of the same birth-year and sex were selected as matched controls. Patients with SARS-CoV-2 infection were further stratified into (1) unvaccinated (0 dose), (2) incompletely vaccinated (1 dose), (3) completely (2 doses), and (4) vaccinated with booster doses ( ≥ 3 doses) according to the number of BioNtech or CoronaVac vaccines received prior to first SARS-CoV-2 infection. The index date of patients with SARS-CoV-2 infection was defined as the date of first diagnosis date of SARS-CoV-2 infection. The identical index date was assigned to randomly selected corresponding matched controls as the pseudo-index date.

All subjects were followed up from the index date until the date of death, the occurrence of outcome, SARS-CoV-2 re-infection or the end of the separate observation periods at 30, 90, 180, 270, and 365 days after the index date or the end of the study period January 31, 2023, whichever occurred earlier.

Anonymized longitudinal clinical healthcare data since 2016 and the earliest date of data availability were obtained for all subjects from HKHA. Relevant data included baseline demographic (sex, age and Charlson Comorbidity Index); pre-existing morbidities captured by clinical diagnosis codes (cardiovascular, cerebrovascular, respiratory, chronic kidney, liver diseases, rheumatoid arthritis and malignancy; Supplementary Table 1), history of long-term medication (renin–angiotensin-system agents, beta-blockers, calcium channel blockers, diuretics, nitrates, lipid-lowering agents, insulins, antidiabetic drugs, oral anticoagulants, antiplatelets and immunosuppressants) and COVID-19 vaccination status before index date.

This study was reported according to the Reporting of studies Conducted using Observational Routinely-collected Data (RECORD), extended from the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline.

Outcomes of clinical diagnosis

The outcomes of this study were selected based on previous evidence on the risk of clinical sequelae associated with SARS-CoV-2 infection which includes incidences of major cardiovascular diseases (a composite outcome of stroke, heart failure and coronary heart disease), stroke, myocardial infarction (MI), heart failure, atrial fibrillation, coronary artery disease, deep vein thrombosis (DVT), chronic pulmonary disease, acute respiratory distress syndrome, seizure, end-stage renal disease, acute kidney injury, pancreatitis, cardiovascular and all-cause mortality1,8,9,10,43. Outcomes were identified based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM; Supplementary Table 1).

Statistical analyses

Inverse Probability Treatment Weighting (IPTW)44 based on age, sex, Charlson Comorbidity index (CCI), history of separate class of medication (renin–angiotensin system agents, beta-blockers, calcium channel blockers, diuretics, nitrates, lipid-lowering agents, insulins, antidiabetic drugs, oral anticoagulants, antiplatelets and immunosuppressants), the number of hospital admission and doctor consultation within one year of index date was applied to account for potential confounding factors. Standardized mean difference (SMD) between cases and controls was estimated, SMD ≤ 0.1 was regarded as sufficient balance between case and control groups45. Subjects with a history of outcome of interest were excluded from the analysis of the specific conditions whilst continued to be considered at risk for other disease outcomes. The incidence rate (per 1000 person-years), hazard ratio (HR) and 95% confidence interval (CI) of each outcome were estimated between COVID and non-COVID-19 cohorts separately for each of the observation period using Cox proportional hazard regressions. Sensitivity analysis was performed by only including individuals with a positive PCR SARS-CoV-2 screening test results, cases of SARS-CoV-2 infection from the Omicron wave in Hong Kong46, unvaccinated patients with COVID-19 and matched control with the same vaccination status, adjusting for the likely variant of SARS-CoV-2 responsible for the infection, excluding patients who received their last dose of vaccine more than 6 months before SARS-CoV-2 infection owing to the waning of immunity following vaccination47,48, and controlling for the false discovery rate at 0.05 through Benjamin-Hochberg procedure49. Lung cancer, brain cancer, and lymphoma which were considered to have a prolonged latent period for their development were included as negative control outcomes to detect possible testing bias. Subgroup analyses were predefined taking account of the risk factors of post-COVID-19 condition50. Patients were stratified by (1) age (≤65, >65), (2) sex, (3) Charlson Comorbidity index (CCI; <4, ≥4).

All statistical analyses were performed using R version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria). All significance tests were two‐tailed. A P value less than 0.05 or 95% CI excluding 1.0 were taken to indicate statistical significance. At least two investigators (ICHL, RZ, and EYFW) conducted each of the statistical analyses independently for quality assurance.

Data access

EYFW and ICKW had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis.

Ethical approval

Ethical approval for this study was granted by the Institutional Review Board of the University of HK/HA HK West Cluster (UW20-556 and UW21-149) and Department of Health, HK (L/M21/2021 and L/M175/2022) with an exemption for informed consent from participants as patients’ confidentiality was maintained in this retrospective cohort study.

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.


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