Protection with a third dose of mRNA vaccine against SARS-CoV-2 variants in frontline workers

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Data are needed on the efficacy of a third dose of messenger RNA (mRNA) vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant B.1.1.529 (Omicron), based on scientifically rigorous, Population level surveillance. Health care workers, first responders and other essential and frontline workers being evaluated in the HEROES-RECOVER cohorts at eight sites in six states across the United States underwent weekly reverse transcriptase polymerase chain reaction (RT-PCR) testing independently of the presence or absence of symptoms of coronavirus disease 2019 (Covid-19).1-3 Here we report the vaccine efficacy of two or three doses of an mRNA vaccine against infections caused by the Omicron and B.1.617.2 (Delta) variants.

Methods for the HEROES-RECOVER studies have been published previously (with details in the Supplementary Appendixavailable with the full text of this letter at The vaccinations were documented by the workers through vaccination cards and medical records or state vaccination information systems. Cohort participants could have received three doses of BNT162b2 vaccine (Pfizer-BioNTech) (administered in 74%), mRNA-1273 vaccine (Moderna) (in 24%), or a combination of the two vaccines (in 2%); Ad26.COV2.S vaccine recipients (Johnson & Johnson-Janssen) were excluded from the analysis.

The study period began on August 26, 2021, shortly after the Food and Drug Administration recommended that recipients of the first two-dose mRNA vaccine course should receive a third dose (booster). Hazard ratios were estimated using the Andersen-Gill extension of the Cox proportional hazards model, which accounts for time-varying vaccination status. We adjusted vaccine efficacy estimates using inverse slope weighting. We performed SARS-CoV-2 whole genome sequencing using published protocols. The study was reviewed and approved by the institutional review board at each participating study site or under confidentiality agreements.

Efficacy of two or three doses of an mRNA vaccine against SARS-CoV-2 infection among frontline workers at eight study sites (August 26, 2021 to January 22, 2022).

From the start of the study to January 22, 2022, we detected 202 Delta variant and 419 Omicron variant infections in samples from 3241 participants. In unvaccinated adults, the percentage of asymptomatic infections (no reported symptoms) was higher for Omicron variant infections than for Delta variant infections (21% and [CI], 0.96 to 9.70). Participants with symptomatic Covid-19 were less likely to seek medical help for Omicron variant infection than for Delta variant infection (22% and 0.94, respectively). The adjusted efficacy of the vaccine against Delta infection was 65% (95% CI, 49 to 76) after two doses and 91% (95% CI, 84 to 95) after three doses (Table 1). The relative vaccine efficacy of three doses versus two doses against the delta variant was 86% (95% CI, 69 to 94). After adjustment, vaccine efficacy against Omicron infection was 46% (95% CI, 25 to 61) after two doses and 60% (95% CI, 42 to 72) after three doses, for a relative efficacy of 60% ( 95% CI, 40 to 73) for three doses versus two doses.

In this prospective cohort of frontline workers, a third dose of the mRNA vaccine provided strong (91%) protection against Delta infection, similar to the results of a study that reported 89 to 94% efficacy for three doses of the mRNA vaccine. vaccine against medically supervised Covid-19 infections. 19 during a time when the Delta variant was dominant.4 In contrast, our estimate of 60% vaccine efficacy for three doses against Omicron infection was lower than the equivalent efficacy of three doses against medically managed Covid-19 (82 to 90%) in the same study. Although in our study a third dose improved protection against Omicron infection (relative vaccine efficacy, 60%), relative protection against Delta infection was much higher (86%). The lower vaccine efficacy against mild or asymptomatic Omicron infections is consistent with recent data showing lower protection in outpatient care settings and in adults tested for SARS-CoV-2 during the circulating periods of the Delta and Omicron variants became.5 Although these results indicate a decrease in vaccine efficacy, they demonstrate sustained efficacy against clinically serious outcomes associated with both variants.

Sarang K. Yoon, DO, MOH
Kurt T. Hegman, MD, MPH
Matthew S. Thiese, Ph.D., MSPH
University of Utah Health, Salt Lake City, UT

Jefferey L. Citizen, MD, MPH
Katherine Ellingson, Ph.D.
Karen Lutrick, Ph.D.
University of Arizona, Tucson, AZ

Lauren EW Olsho, Ph.D.
Laura J. Edwards, MPH
Brian Sokol, MSPA
Abt Associates, Rockville, MD

Alberto J. Caban-Martinez, DO, Ph.D.
Natasha Schaefer-Solle, RN, Ph.D.
John M Jones, B.S
University of Miami, Miami, FL

Harmony Tyner, MD
Angela Hunt, MLT, ASCP
Karley Respet, B.S
St. Luke’s Regional Health Care System, Duluth, MN

Manjusha Gaglani, MB, BS
Kayan Dunnigan, MPH
Spencer Rose, B.S
Baylor Scott and White Health, Temple, TX

Allison Naleway, Ph.D.
Holly Groom, MPH
Jennifer Kuntz, Ph.D.
Kaiser Permanente Northwest, Portland, OR

Ashley L. Fowlkes, Sc.D.
Mark G. Thompson, Ph.D.
Young M. Yoo, MSPH
Centers for Disease Control and Prevention, Atlanta, GA

for the investigators of the HEROES RECOVER network

Disclosure Forms provided by the authors, along with the full text of this letter, are available at

The findings and conclusions in this letter are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

This letter was published on on April 6, 2022.

A list of HEROES RECOVER Network investigators can be found at Supplementary Appendixavailable at

  1. 1. Thompson MG, Burgess JL, Naleway AL, et al. Prevention and mitigation of Covid-19 with the BNT162b2 and mRNA-1273 vaccines. N Engl. J Med 2021;385:320329.

  2. 2. Edwards LJ, Fowlkes AL, Wesley M.G, et al. Research on the Epidemiology of SARS-CoV-2 in Essential Response Personnel (RECOVER): Protocol for a Multisite Longitudinal Cohort Study. JMIR Res Protoc 2021;10(12):e31574e31574.

  3. 3. Lutrick K, Ellingson KD, Baccam Z, et al. COVID-19 infection, reinfection, and vaccine efficacy in a prospective cohort of Arizona Frontline/Essential Workers: the AZ HEROES research protocol. JMIR Res Protoc 2021;10(6):e28925e28925.

  4. 4. Thompson MG, Natarajan K, Irving S.A, et al. Efficacy of a third dose of mRNA vaccines against COVID-19-associated emergency department and emergency care encounters and hospitalizations in adults during times when Delta and Omicron variants are predominant – VISION Network, 10 states, August 2021-January 2022. MMWR Morb Mortal Wkly Rep 2022;71:139145.

  5. 5. I crashed EK, Britton A, Fleming-Dutra KE, et al. Association between 3 doses of mRNA-COVID-19 vaccine and symptomatic infection caused by the Omicron and Delta variants of SARS-CoV-2. JAMA 2022;327:639651.

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