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Importance: Little is known about COVID vaccine breakthrough infections and their risk factors., Objective: To identify risk factors associated with COVID-19 breakthrough infections among vaccinated individuals and to reassess the effectiveness of COVID-19 vaccination against severe outcomes using real-world data., Design Setting and Participants: We conducted a series of observational retrospective analyses using the electronic health records (EHRs) of Columbia University Irving Medical Center/New York Presbyterian (CUIMC/NYP) up to September 21, 2021. New York adult residence with PCR test records were included in this analysis., Main Outcomes and Measures: Poisson regression was used to assess the association between breakthrough infection rate in vaccinated individuals and multiple risk factors - including vaccine brand, demographics, and underlying conditions - while adjusting for calendar month, prior number of visits and observational days. Logistic regression was used to assess the association between vaccine administration and infection rate by comparing a vaccinated cohort to a historically matched cohort in the pre-vaccinated period. Infection incident rate was also compared between vaccinated individuals and longitudinally matched unvaccinated individuals. Cox regression was used to estimate the association of the vaccine and COVID-19 associated severe outcomes by comparing breakthrough cohort and two matched unvaccinated infection cohorts., Results: Individuals vaccinated with Pfizer/BNT162b2 (IRR against Moderna/mRNA-1273 [95% CI]: 1.66 [1.17 - 2.35]); were male (1.47 [1.11 - 1.94%]); and had compromised immune systems (1.48 [1.09 - 2.00]) were at the highest risk for breakthrough infections. Vaccinated individuals had a significant lower infection rate among all subgroups. An increased incidence rate was found in both vaccines over the time. Among individuals infected with COVID-19, vaccination significantly reduced the risk of death (adj. HR: 0.20 [0.08 - 0.49])., Conclusion and Relevance: While we found both mRNA vaccines were effective, Moderna/mRNA-1273 had a lower incidence rate of breakthrough infections. Both vaccines had increased incidence rates over the time. Immunocompromised individuals were among the highest risk groups experiencing breakthrough infections. Given the rapidly changing nature of the SARS-CoV-2, continued monitoring and a generalizable analysis pipeline are warranted to inform quick updates on vaccine effectiveness in real time., Key Points: Question: What risk factors contribute to COVID-19 breakthrough infections among mRNA vaccinated individuals? How do clinical outcomes differ between vaccinated but still SARS-CoV-2 infected individuals and non-vaccinated, infected individuals? Findings: This retrospective study uses CUIMC/NYP EHR data up to September 21, 2021. Individuals who were vaccinated with Pfizer/BNT162b2, male, and had compromised immune systems had significantly higher incidence rate ratios of breakthrough infections. Comparing demographically matched pre-vaccinated and unvaccinated individuals, vaccinated individuals had a lower incidence rate of SARS-CoV-2 infection among all subgroups. Meaning: Leveraging real-world EHR data provides insight on who may optimally benefit from a booster COVID-19 vaccination.