Characteristics of SARS-CoV-2 breakthrough infections tracked in large US study

Characteristics of SARS-CoV-2 breakthrough infections tracked in large US study

As a result of widespread COVID-19 vaccination and high levels of SARS-CoV-2 in communities across the U.S., many breakthrough SARS-CoV-2 infections have been reported.

However, a breakthrough infection in an individual who has been fully vaccinated is generally less severe than an infection in an unvaccinated individual. Still, severe COVID-19 disease leading to hospitalization and/or death can occur.

Although the risk of breakthrough SARS-CoV-2 infection and COVID-19 mortality has recently been reported by vaccine type, there is scant information regarding the risk of hospitalization for breakthrough infections.

Furthermore, prior SARS-CoV-2 infection is associated with a lower risk of breakthrough infection, but it is unknown how significant an effect prior infection has on the severity of breakthrough COVID-19 infections.

COVID-19 vaccinations began in the United States in late December 2020. By late February 2021, the Pfizer-BioNTech (Pfizer), Moderna, and Johnson & Johnson / J&J (Janssen) vaccines were all approved for emergency use authorization (EUA) by regulatory bodies.

Researchers from Microsoft Corporation, Fred Hutch Cancer Research Center, and the University of Washington recently published a report on the preprint server medRxiv* wherein they studied a de-identified cohort from the United States medical claims records from Change Healthcare to estimate the risk of hospitalization and death, by vaccine type and by previous SARS-CoV2 infection, among SARS-CoV-2 breakthrough infections in fully vaccinated individuals.

Study: Risk of hospitalization and mortality after breakthrough SARS-CoV-2 infection by vaccine type and previous SARS-CoV-2 infection utilizing medical claims data. Image Credit: Skylines / Shutterstock

About the study

Researchers collected data from March 1, 2020, to September 30, 2021. This dataset encompassed over 100 million records from over 8 million patients, including all COVID-19 positive patients, identified by the ICD-10 diagnosis codes of U07.1 (COVID-19, virus identified, lab-confirmed) as the principal diagnosis.

From this cohort of 8.18 million patients, fully vaccinated individuals were identified by looking for procedure codes encoding the second doses of Pfizer (0002A) and Moderna (0012A), and the first dose of Janssen (0031A).

The date of complete vaccination was ascertained as 14 days after: 1) a single Janssen vaccine; 2) the second Moderna vaccine dose; or 3) the second Pfizer vaccine dose. Amongst these individuals, breakthrough patients were defined as those who had a COVID-19 diagnosis at least 14 days after the date of vaccination.

Researchers compared the risks of hospitalization (n=1121) and mortality (n=138) in a cohort of 17,881 breakthrough SARS-CoV-2 infections for the Pfizer, Moderna, and Janssen vaccines for those with and without SARS-CoV-2 infections prior to vaccination.

Statistical analysis showed breakthrough cases receiving the Janssen vaccine were younger than those receiving Pfizer or Moderna and were slightly more likely to be male. Breakthrough cases receiving Moderna were more likely to have had COVID-19 prior to vaccination.

Further analysis showed a lower hazard ratio for those receiving the Moderna vaccine but a significantly higher hazard ratio for those receiving Janssen than those receiving Pfizer doses. More importantly, the risk of hospitalization (P<0.001) and death (P<0.05) were significantly lower among individuals who had a SARS-CoV-2 infection prior to vaccination, independent of age, sex, comorbidities, and vaccine type.

It was also noteworthy that the risk of hospitalization and mortality among breakthrough cases increased with older age and was higher for male patients. In addition, there was an eventual increase in the rate of hospitalization starting ∼110-125 days after complete vaccination for all three vaccines depending on age group, with a steeper rise for Janssen.


The current study findings add to the growing literature regarding SARS-CoV-2 breakthrough infections and protection provided by previous SARS-CoV-2 infections against severe disease.

This study reinforces the need for booster vaccination shots to protect against more severe COVID-19 among those initially receiving the Janssen vaccine and provides new information regarding the role of prior SARS-CoV-2 infection and lower risk of more severe breakthrough infections.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Kshirsagar M, Mukherjee S, Nasir M, et al. (2021); Risk of hospitalization and mortality after breakthrough SARS-CoV-2 infection by vaccine type and previous SARS-CoV-2 infection utilizing medical claims data, medRxiv, doi:,

Posted in: Medical Research News | Disease/Infection News

Tags: Cancer, Coronavirus Disease COVID-19, Healthcare, Mortality, Research, SARS, SARS-CoV-2, Vaccine, Virus

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Sreetama Dutt

Sreetama Dutt has completed her B.Tech. in Biotechnology from SRM University in Chennai, India and holds an M.Sc. in Medical Microbiology from the University of Manchester, UK. Initially decided upon building her career in laboratory-based research, medical writing and communications happened to catch her when she least expected it. Of course, nothing is a coincidence.

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