Risk Factors Associated With SARS-CoV-2 Breakthrough Infections in Fully mRNA-Vaccinated Individuals: Retrospective Analysis

Cong Liu, Junghwan Lee, Casey Ta, Ali Soroush, James R. Rogers, Jae Hyun Kim, Karthik Natarajan, Jason Zucker, Yehoshua Perl, Chunhua Weng

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Background: COVID-19 messenger RNA (mRNA) vaccines have demonstrated efficacy and effectiveness in preventing symptomatic COVID-19, while being relatively safe in trial studies. However, vaccine breakthrough infections have been reported. Objective: This study aims to identify risk factors associated with COVID-19 breakthrough infections among fully mRNA-vaccinated individuals. Methods: We conducted a series of observational retrospective analyses using the electronic health records (EHRs) of the Columbia University Irving Medical Center/New York Presbyterian (CUIMC/NYP) up to September 21, 2021. New York City (NYC) adult residences with at least 1 polymerase chain reaction (PCR) record were included in this analysis. Poisson regression was performed to assess the association between the 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 in the EHR. Results: The overall estimated breakthrough infection rate was 0.16 (95% CI 0.14-0.18). Individuals who were vaccinated with Pfizer/BNT162b2 (incidence rate ratio [IRR] against Moderna/mRNA-1273=1.66, 95% CI 1.17-2.35) were male (IRR against female=1.47, 95% CI 1.11-1.94) and had compromised immune systems (IRR=1.48, 95% CI 1.09-2.00) were at the highest risk for breakthrough infections. Among all underlying conditions, those with primary immunodeficiency, a history of organ transplant, an active tumor, use of immunosuppressant medications, or Alzheimer disease were at the highest risk. Conclusions: Although we found both mRNA vaccines were effective, Moderna/mRNA-1273 had a lower incidence rate of breakthrough infections. Immunocompromised and male individuals were among the highest risk groups experiencing breakthrough infections. Given the rapidly changing nature of the SARS-CoV-2 pandemic, continued monitoring and a generalizable analysis pipeline are warranted to inform quick updates on vaccine effectiveness in real time.

Original languageEnglish (US)
Article numbere35311
JournalJMIR Public Health and Surveillance
Issue number5
StatePublished - May 1 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Health Informatics
  • Public Health, Environmental and Occupational Health


  • COVID-19
  • electronic health records
  • medical informatics
  • real-word evidence
  • vaccination


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