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

Our take —

This preprint, which has yet to undergo peer-review, used a large-scale network of electronic health records in the US to evaluate the risk of various post- COVID-19 symptoms within 6 months following infection among those vaccinated and not vaccinated for COVID-19. To account for potential differences between those who were and were not vaccinated, the investigators compared those vaccinated against COVID-19 with a comparison group of unvaccinated individuals but who had been vaccinated for influenza in a prior year. These data show that having at least one dose of a COVID-19 vaccine prior to infection was associated with a significantly lower risk of numerous clinical outcomes (each a composite outcome with death), including ICU admission (hazard ratio [HR] 0.75), respiratory failure (HR 0.70), and intubation/ventilation (HR 0.72), seizures (HR 0.73), hypercoagulopathy/venous thromboembolism (HR 0.81), especially among those younger than 60, but not a lower risk of various long-COVID symptoms, including mood, sleep, or anxiety disorders. Fewer benefits of one dose were observed among those 60 or older, however, which supports calls for additional vaccine doses among older individuals. These findings should be interpreted with caution given the observational nature of the study and the measurement uncertainty inherent to electronic health record data.

Study design

Retrospective Cohort

Study population and setting

This study used data from the TriNetX electronic health records network to compare the incidence of COVID-19 sequelae within 6 months following SARS-CoV-2 infection between those who received at least one dose of a COVID-19 vaccine and individuals unvaccinated for COVID-19 but who had received an influenza vaccine. TriNetX Analytics maintains a network of 59 healthcare organizations with data on approximately 81 million people in the US, both insured and uninsured. All study participants had a confirmed SARS-CoV-2 infection (either laboratory-confirmed or by clinical diagnosis) between January 1, 2021 and August 31, 2021. Among the exposed group, infection must have occurred at least 14 days after documented COVID-19 vaccination. To capture individuals who were not vaccine-averse (and thus might be considerably different from the vaccinated individuals in unknown ways), investigators included individuals without a COVID-19 vaccine but who had previously received at least one influenza vaccine in the comparison group. Outcomes consisted of numerous acute and post-acute ICD-10 codes previously associated with COVID-19, including hospitalization, ICU admission, respiratory failure, ventilation, and death, as well as several conditions associated with long-COVID. To achieve balance in baseline characteristics, 1:1 propensity score matching was employed, and Cox proportional survival methods were stratified by 2-month periods to account for potential changes in diagnostics and other temporal variations. Analyses accounted for death as a competing risk. Secondary analyses assessed potential effect modification by age at the time of infection and the impact of 1 versus 2 vaccine doses. Bonferroni corrections were utilized to account for multiple testing.

Summary of Main Findings

10,024 individuals were identified as having had a SARS-CoV-2 infection at least 2 weeks after documented COVID-19 vaccine (mean age: 57 years; 59.4% female). Of these, 9,479 were matched to individuals without a COVID-19 vaccine prior to their infection but who had had at least one previous influenza vaccine. Individuals who received a COVID-19 vaccine prior to infection were significantly less likely to experience deleterious acute outcomes, including death and respiratory failure (composite outcome; hazard ratio [HR] 0.70; Bonferonni-corrected, p<0.0001), ventilation (HR 0.72, p=0.0024), ICU admission (HR 0.75, p<0.0001), venous thromboembolism (HR 0.81, p=0.014), and an oxygen requirement (HR 0.83, p=0.011), than those who hadn’t received a COVID-19 vaccine. No differences between the study groups were observed for the following outcomes: composite of death and any long-COVID symptom, Type 2 diabetes, or mood or anxiety disorders. In secondary analyses, lower risks among those who received 2 doses of a COVID-19 vaccine were observed for additional outcomes, including myocarditis, cerebral hemorrhage, interstitial lung disease, and death, compared to the unvaccinated, although these risks were not statistically different from those who had received only 1 dose. These associations were generally stronger (i.e., vaccines were associated with noticeably lower risks) among those younger than 60 years old compared to those 60 or older. 

Study Strengths

This study examined an extensive list of outcomes, both acute and post-acute, previously reported with COVID-19 and their apparent association with SARS-CoV-2 among those who had and had not been vaccinated against COVID-19 using data from a large-scale electronic health records network. 


As noted in the study, electronic health records may be limited by missing data, incomplete and non-standardized records, and inadequate information on contextual factors, such as socioeconomic status and key behavioral factors. Moreover, the investigators were not able to consider the role of variants of concern, compare the different vaccine types on the likelihood of breakthrough infections or their sequelae, or how booster vaccines impact these outcomes. While including death as a composite for each outcome reduced the risk of survivorship bias from competing risks, it made it difficult to assess how SARS-CoV-2 vaccination impacted rare COVID-19 sequelae, such as those related to long-COVID. To account for potential confounding by both known and unknown behavioral factors, the investigators utilized a control group that had been vaccinated for influenza in a prior year but not for COVID-19. While this likely removed some unobserved differences between vaccinated and unvaccinated individuals, given the politicization of vaccines during the COVID-19 pandemic, influenza vaccination in any previous year is an imperfect proxy of openness to vaccination. Finally, this study only included individuals who sought healthcare for their infection and may therefore not generalize to those who did not get tested or seek healthcare assistance. 

Value added

This is one of the first and largest studies to compare the likelihood of a broad array of acute and post-acute sequelae of COVID-19 six months following SARS-CoV-2 infection, between those who were vaccinated vs. those who were not vaccinated for COVID-19. 

This review was posted on: 5 January 2022