The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to significant research into its associated health consequences. Evidence suggests an increased risk of acute and post-acute health issues affecting multiple organ systems and increased mortality following infection. While a universal definition of "long COVID" remains elusive, current literature defines complications within 30 days of infection as acute sequelae and those persisting beyond this as post-acute sequelae. Although many recover within 2-4 weeks, increased risks of cardiovascular, neurological, psychiatric diseases, diabetes, and all-cause mortality have been observed for up to two years. The impact of COVID-19 vaccination on these long-term consequences, however, remains unclear. This study addresses this gap by examining the long-term risks of SARS-CoV-2 infection and the protective effects of COVID-19 vaccination using a large, population-based dataset. Understanding this relationship is critical for informing public health strategies and clinical management of COVID-19 patients.

Previous studies have reported on the long-term health consequences of SARS-CoV-2 infection, highlighting increased risks of various complications and mortality. However, inconsistencies exist in the literature regarding the impact of COVID-19 vaccination on these outcomes. Differences in methodological approaches, including variations in the assessment of vaccination status, age, time since infection, and nature of prior infections, contribute to these inconsistencies. This study aims to address these inconsistencies by employing a rigorous methodology and utilizing a large, population-based dataset to evaluate the impact of COVID-19 vaccination on both acute and post-acute health consequences following SARS-CoV-2 infection, offering a more comprehensive and robust analysis of the long-term effects.

This retrospective, territory-wide cohort study leveraged data from the Hong Kong Hospital Authority (HKHA), incorporating electronic medical records, vaccination records from the Department of Health, and death records from the Hong Kong Deaths Registry. The study population comprised 1,175,277 patients with SARS-CoV-2 infection between April 1st, 2020, and October 31st, 2022, stratified by vaccination status (unvaccinated, one dose, two doses, three or more doses). Non-infected controls were also included. The primary outcomes included major cardiovascular events, other clinical sequelae, and all-cause mortality. The researchers assessed the risk of these outcomes over five observation periods (0–30, 31–90, 91–180, 181–270, 271–365 days post-infection). Inverse Probability Treatment Weighting (IPTW) was used to adjust for potential confounders (age, sex, Charlson Comorbidity Index, medication history, and vaccination status). Cox proportional hazards regression models were employed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for each outcome, comparing patients with SARS-CoV-2 infection to controls, stratified by vaccination status and observation period. Sensitivity analyses were also conducted to address potential biases. The study adhered to the RECORD and STROBE guidelines for reporting observational studies.

The study found a graded reduction in the risk of clinical sequelae over time and with increasing numbers of vaccine doses. Compared to non-infected controls, SARS-CoV-2 patients showed a significantly increased risk of cardiovascular diseases and all-cause mortality during the acute phase, regardless of vaccination status. However, this risk decreased significantly in the post-acute phase, particularly in those with complete vaccination or booster doses. Specifically, completely vaccinated individuals showed no significantly increased risk of health consequences from 271 days post-infection, while those with booster doses showed no increased risk from 91 days. Unvaccinated and incompletely vaccinated patients continued to experience a greater risk of sequelae for up to a year. The risk of all-cause mortality also progressively reduced over the year post-infection, with a sharper decline in the post-acute phase for completely vaccinated individuals. While the risk of certain sequelae, like heart failure, remained higher in SARS-CoV-2 patients, even those who were fully vaccinated, the risk significantly decreased over time. Patients aged over 65 or with a CCI of four or above faced greater risks, particularly those unvaccinated or partially vaccinated. The study also observed a moderate increase in the risk of lung cancer and lymphoma during the first 30 days of infection. Detailed hazard ratios and event incidences are provided in the paper's tables for various clinical sequelae across different vaccination statuses and observation periods. The protective effect of vaccination was more pronounced in older patients and those with multiple comorbidities.

This study provides substantial real-world evidence supporting the effectiveness of COVID-19 vaccines in reducing the risk of long-term health consequences following SARS-CoV-2 infection. The findings show a clear reduction in risk across various clinical sequelae, particularly in those who completed their vaccination series and received boosters. The study's large sample size and population-based nature enhance the generalizability of the findings. The observed reduction in risk over time also suggests a gradual shift in the disease burden associated with SARS-CoV-2, potentially related to the emergence of less severe variants and increased vaccination rates. These findings reinforce the importance of COVID-19 vaccination programs in minimizing both acute and long-term health complications associated with SARS-CoV-2 infection. The results can guide public health policies and clinical management strategies, particularly for high-risk populations.

This large-scale retrospective cohort study confirms the significant protective effect of COVID-19 vaccination against long-term health consequences of SARS-CoV-2 infection. Complete vaccination and booster doses substantially reduce risks, even extending beyond the acute phase. While some residual risk persists, particularly in vulnerable populations, the results strongly support the ongoing importance of vaccination programs. Future research should focus on elucidating the mechanisms underlying these long-term effects and exploring further refinements to vaccination strategies to minimize residual risks.

The study acknowledges several limitations. Detection bias is possible due to potential underreporting of pre-existing conditions. Increased healthcare utilization after vaccination might lead to overdiagnosis of conditions pre-existing SARS-CoV-2 infection. The study also notes potential confounding factors related to the emergence of newer SARS-CoV-2 variants and varying vaccination coverage. Residual confounding, despite propensity score weighting, might also be a factor, as unmeasured confounders like obesity and socioeconomic status could influence outcomes. Selection bias from censoring patients upon the occurrence of clinical sequelae may also have influenced the estimates of hazard ratios.