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Effectiveness of Homologous or Heterologous Covid-19 Boosters in Veterans

Vaccine effectiveness against coronavirus disease 2019 (Covid-19) wanes over time, and boosters are now recommended for residents of the United States starting at the age of 12 years.1 Clinical trials have shown that receipt of a booster that does not match the primary vaccination (heterologous booster) may result in a higher neutralizing-antibody response than the receipt of a matching (homologous) booster, particularly after primary vaccination with an adenoviral-vector vaccine.2-5 Whether the choice of booster affects real-world vaccine effectiveness is poorly understood.

We performed a study involving 4,806,026 veterans and linked their information to the Veterans Affairs Covid-19 Shared Data Resource, a database that was created in response to the Covid-19 pandemic and that contains information on all veterans with a confirmed laboratory diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We created two analysis cohorts based on the primary vaccine that each veteran received (adenoviral-vector or messenger RNA [mRNA]) to compare the effectiveness of heterologous and homologous boosters. (Details regarding the study participants are provided in the Supplementary Appendix, available with the full text of this letter at

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