Six-month sequelae of post-vaccination SARS-CoV-2 infection: A retrospective cohort study of 10,024 breakthrough infections

Abstract

Vaccination has proven effective against infection with SARS-CoV-2, as well as death and hospitalisation following COVID-19 illness. However, little is known about the effect of vaccination on other acute and post-acute outcomes of COVID-19. Data were obtained from the TriNetX electronic health records network (over 81 million patients mostly in the USA). Using a retrospective cohort study and time-to-event analysis, we compared the incidences of COVID-19 outcomes between individuals who received a COVID-19 vaccine (approved for use in the USA) at least 2 weeks before SARS-CoV-2 infection and propensity score-matched individuals unvaccinated for COVID-19 but who had received an influenza vaccine. Outcomes were ICD-10 codes representing documented COVID-19 sequelae in the 6 months after a confirmed SARS-CoV-2 infection (recorded between January 1 and August 31, 2021, i.e. before the emergence of the Omicron variant). Associations with the number of vaccine doses (1 vs. 2) and age (<60 vs. ≥ 60 years-old) were assessed. Among 10,024 vaccinated individuals with SARS-CoV-2 infection, 9479 were matched to unvaccinated controls. Receiving at least one COVID-19 vaccine dose was associated with a significantly lower risk of respiratory failure, ICU admission, intubation/ventilation, hypoxaemia, oxygen requirement, hypercoagulopathy/venous thromboembolism, seizures, psychotic disorder, and hair loss (each as composite endpoints with death to account for competing risks; HR 0.70-0.83, Bonferroni-corrected p < 0.05), but not other outcomes, including long-COVID features, renal disease, mood, anxiety, and sleep disorders. Receiving 2 vaccine doses was associated with lower risks for most outcomes. Associations between prior vaccination and outcomes of SARS-CoV-2 infection were marked in those <60 years-old, whereas no robust associations were observed in those ≥60 years-old. In summary, COVID-19 vaccination is associated with lower risk of several, but not all, COVID-19 sequelae in those with breakthrough SARS-CoV-2 infection. The findings may inform service planning, contribute to forecasting public health impacts of vaccination programmes, and highlight the need to identify additional interventions for COVID-19 sequelae.

Keywords: COVID-19 outcomes; Cohort studies; Electronic health records; Vaccine.

Fig. 1

Hazard ratios for the outcome within 6 months of infection with SARS-CoV-2 between individuals vaccinated vs. unvaccinated against COVID-19. HR lower than 1 indicate outcomes less common among vaccinated individuals. Horizontal bars represent 95% confidence intervals. Each outcome is a composite outcome with death as a component to address competing risks. The contribution of the outcome of interest to the overall incidence of the composite endpoint is encoded by the colour.

Fig. 2

Kaplan-Meier estimates for the incidence of outcomes of SARS-CoV-2 infection between vaccinated and unvaccinated individuals in the whole cohort (top) and for the incidence of death in different subgroups (bottom). Shaded areas are 95% CIs. For Kaplan-Meier curves of all other outcomes of the whole cohort, see Appendix Fig. A1-A4. DVT = Deep vein thrombosis. PE = Pulmonary embolism. ICU = Intensive care unit.

Fig. 3

Hazard ratios for the outcomes within 6 months of infection with SARS-CoV-2 between individuals who received one dose of the vaccine (vs. unvaccinated individuals), those who received two doses of the vaccine (vs. unvaccinated individuals), vaccinated vs. unvaccinated individuals under the age of 60, and vaccinated vs. unvaccinated individuals over the age of 60. HR lower than 1 indicate outcomes less common among vaccinated individuals. Horizontal bars represent 95% confidence intervals. Each outcome is a composite outcome with death as a component to address competing risks. The contribution of the outcome of interest to the overall incidence of the composite endpoint is encoded by the colour. Only a subset of representative outcomes is displayed. The same figures with all outcomes are presented in the Appendix Fig. A6-A9.