Effectiveness of a Third Dose of mRNA Vaccines Against COVID-19–Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance

Abbreviations: ED = emergency department; SMD = standardized mean or proportion difference; UC = urgent care.
*Medical events with a discharge code consistent with COVID-19–like illness were included. COVID-19–like illness diagnoses included acute respiratory illness (e.g., COVID-19, respiratory failure, or pneumonia) or related signs or symptoms (cough, fever, dyspnea, vomiting, or diarrhea) using diagnosis codes from the International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision. Clinician-ordered molecular assays (e.g., real-time reverse transcription–polymerase chain reaction) for SARS-CoV-2 occurring ≤14 days before to <72 hours after the encounter date were included. Recipients of Janssen, 1 or >3 doses of an mRNA vaccine, and those for whom 1–13 days had elapsed since receipt of any dose were excluded.
^†Vaccination was defined as having received the listed number of doses of an mRNA-based COVID-19 vaccine ≥14 days before the medical event index date, which was the date of respiratory specimen collection associated with the most recent positive or negative SARS-CoV-2 test result before the medical event or the admission date if testing only occurred after the admission.
^§Partners contributing data on medical events and estimated dates of Omicron predominance were in California (December 21), Colorado (December 19), Indiana (December 26), Minnesota and Wisconsin (December 25), New York (December 18), Oregon (December 24), Texas (December 16), Utah (December 24), and Washington (December 24). The study period began in September 2021 for partners located in Texas.
^¶The "3 doses" category includes persons who have received a third dose in their primary series or have received an additional dose following their 2-dose primary series; this includes the reduced-dosage Moderna booster.
**An absolute standardized mean or proportion difference ≥0.20 indicates a nonnegligible difference in variable distributions between medical events for vaccinated versus unvaccinated patients; single SMD calculated by averaging pairwise comparisons of each vaccinated category versus unvaccinated and separately for patients with SARS-CoV-2–positive versus SARS-CoV-2–negative test results. For example, the age SMD calculation comparing unvaccinated versus different vaccinated categories was generated by averaging the pairwise SMD calculations for unvaccinated and 2 doses (<180 days earlier), unvaccinated and 2 doses (≥180 days earlier), and unvaccinated and 3 doses.
^††Indicates the reference group used for standardized mean or proportion difference calculations for dichotomous variables.
^§§Other race includes Asian, Hawaiian or Other Pacific islander, American Indian or Alaska Native, Other not listed, and multiple races.
^¶¶Chronic respiratory condition was defined as the presence of discharge code for asthma, chronic obstructive pulmonary disease, or other lung disease using diagnosis codes from the International Classification of Diseases, Ninth Revision and the International Classification of Diseases, Tenth Revision.
***Chronic nonrespiratory condition was defined as the presence of discharge code for heart failure, ischemic heart disease, hypertension, other heart disease, stroke, other cerebrovascular disease, diabetes type I or II, other diabetes, metabolic disease, clinical obesity, clinically underweight, renal disease, liver disease, blood disorder, immunosuppression, organ transplant, cancer, dementia, neurologic disorder, musculoskeletal disorder, or Down syndrome using diagnosis codes from the International Classification of Diseases, Ninth Revision and the International Classification of Diseases, Tenth Revision.

Abbreviations: ED = emergency department; Ref = reference group; UC = urgent care; VE = vaccine effectiveness.
*VE was calculated as ([1−odds ratio] x 100%), estimated using a test-negative design, adjusted for age, geographic region, calendar time (days since August 26, 2021), and local virus circulation (percentage of SARS-CoV-2–positive results from testing within the counties surrounding the facility on the date of the encounter) and weighted for inverse propensity to be vaccinated or unvaccinated (calculated separately for each VE estimate). Generalized boosted regression trees were used to estimate the propensity to be vaccinated based on sociodemographic characteristics, underlying medical conditions, and facility characteristics.
^†Medical events with a discharge code consistent with COVID-19–like illness were included. COVID-19–like illness diagnoses included acute respiratory illness (e.g., COVID-19, respiratory failure, or pneumonia) or related signs or symptoms (cough, fever, dyspnea, vomiting, or diarrhea) using diagnosis codes from the International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision. Clinician-ordered molecular assays (e.g., real-time reverse transcription–polymerase chain reaction) for SARS-CoV-2 occurring ≤14 days before to <72 hours after admission were included. Recipients of Janssen, 1 or >3 doses of an mRNA vaccine, and those for whom 1–13 days had elapsed since receipt of any dose were excluded.
^§Vaccination status was documented in electronic health records and immunization registries and was defined as having received the listed number of doses of an mRNA-based COVID-19 vaccine ≥14 days before the medical event index date. Index date was defined as the date of respiratory specimen collection associated with the most recent positive or negative SARS-CoV-2 test result before the medical event or the admission date if testing only occurred after the admission. Three-dose recipients include persons who received a third dose in their primary series or received an additional (booster) dose after their 2-dose primary series; this includes the reduced-dosage Moderna booster.
^¶Partners contributing data on medical events and estimated dates of Omicron predominance were in California (December 21), Colorado (December 19), Indiana (December 26), Minnesota and Wisconsin (December 25), New York (December 18), Oregon (December 24), Texas (December 16), Utah (December 24), and Washington (December 24). The study period began in September 2021 for partners located in Texas.

Abbreviations: ED = emergency department; SMD = standardized mean or proportion difference; UC = urgent care.
*Medical events with a discharge code consistent with COVID-19–like illness were included. COVID-19–like illness diagnoses included acute respiratory illness (e.g., COVID-19, respiratory failure, or pneumonia) or related signs or symptoms (cough, fever, dyspnea, vomiting, or diarrhea) using diagnosis codes from the International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision. Clinician-ordered molecular assays (e.g., real-time reverse transcription–polymerase chain reaction) for SARS-CoV-2 occurring ≤14 days before to <72 hours after admission were included. Recipients of Janssen, 1 or >3 dose of an mRNA vaccine, and those for whom 1–13 days had elapsed since receipt of any dose were excluded.
^†Vaccination was defined as having received the listed number of doses of an mRNA-based COVID-19 vaccine ≥14 days before the medical event index date, which was the date of respiratory specimen collection associated with the most recent positive or negative SARS-CoV-2 test result before the medical event or the admission date if testing only occurred after the admission.
^§Partners contributing data on medical events and estimated dates of Omicron predominance were in California (December 21), Colorado (December 19), Indiana (December 26), Minnesota and Wisconsin (December 25), New York (December 18), Oregon (December 24), Texas (December 16), Utah (December 24), and Washington (December 24). The study period began in September 2021 for partners located in Texas.
^¶The "3 doses" category includes persons who have received a third dose in their primary series or received an additional dose following their 2-dose primary series; this includes the reduced-dosage Moderna booster.
**An absolute standardized mean or proportion difference ≥0.20 indicates a nonnegligible difference in variable distributions between medical events for vaccinated versus unvaccinated patients. First, a single SMD was calculated by averaging pairwise comparisons of each vaccinated category versus unvaccinated, and then, a second SMD was calculated separately for SARS-CoV-2–positive versus SARS-CoV-2–negative patients. For example, the age SMD calculation comparing unvaccinated versus different vaccinated categories was generated by averaging the pairwise SMD calculations for unvaccinated and 2 doses (<180 days earlier), unvaccinated and 2 doses (≥180 days earlier), and unvaccinated and 3 doses.
^††Indicates the reference group used for standardized mean or proportion difference calculations for dichotomous variables.
^§§Other race includes Asian, Hawaiian or Other Pacific islander, American Indian or Alaska Native, Other not listed, and multiple races.
^¶¶Chronic respiratory condition was defined as the presence of discharge code for asthma, chronic obstructive pulmonary disease, or other lung disease using diagnosis codes from the International Classification of Diseases, Ninth Revision and the International Classification of Diseases, Tenth Revision.
***Chronic nonrespiratory condition was defined as the presence of discharge code for heart failure, ischemic heart disease, hypertension, other heart disease, stroke, other cerebrovascular disease, diabetes type I or II, other diabetes, metabolic disease, clinical obesity, clinically underweight, renal disease, liver disease, blood disorder, immunosuppression, organ transplant, cancer, dementia, neurologic disorder, musculoskeletal disorder, or Down syndrome using diagnosis codes from the International Classification of Diseases, Ninth Revision and the International Classification of Diseases, Tenth Revision.

Authors and Disclosures

Mark G. Thompson, PhD¹, Karthik Natarajan, PhD^2,3, Stephanie A. Irving, MHS⁴, Elizabeth A. Rowley, DrPH⁵, Eric P. Griggs, MPH¹, Manjusha Gaglani, MBBS^6,7, Nicola P. Klein, MD⁸, Shaun J. Grannis, MD^9,10, Malini B. DeSilva, MD¹¹, Edward Stenehjem, MD¹², Sarah E. Reese, PhD⁵, Monica Dickerson¹, Allison L. Naleway, PhD⁴, Jungmi Han², Deepika Konatham⁶, Charlene McEvoy, MD¹¹, Suchitra Rao, MBBS¹³, Brian E. Dixon, PhD^9,14, Kristin Dascomb, MD¹², Ned Lewis, MPH⁸, Matthew E. Levy, PhD⁵, Palak Patel, MBBS¹, I-Chia Liao, MPH⁶, Anupam B. Kharbanda, MD¹⁵, Michelle A. Barron, MD¹³, William F. Fadel, PhD^9,14, Nancy Grisel, MPP¹², Kristin Goddard, MPH⁸, Duck-Hye Yang, PhD⁵, Mehiret H. Wondimu, MPH¹, Kempapura Murthy, MPH⁶, Nimish R. Valvi, DrPH⁹, Julie Arndorfer, MPH¹², Bruce Fireman, MA⁸, Margaret M. Dunne, MSc⁵, Peter Embi, MD^9,16, Eduardo Azziz-Baumgartner, MD¹, Ousseny Zerbo, PhD⁸, Catherine H. Bozio, PhD¹, Sue Reynolds, PhD¹, Jill Ferdinands, PhD¹, Jeremiah Williams, MPH¹, Ruth Link-Gelles, PhD¹, Stephanie J. Schrag, DPhil¹, Jennifer R. Verani, MD¹, Sarah Ball, ScD⁴ and Toan C. Ong, PhD<sup>13

1</sup>CDC COVID-19 Response Team; ²Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York; ³New York Presbyterian Hospital, New York, New York; ⁴Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon; ⁵Westat, Rockville, Maryland; ⁶Baylor Scott & White Health, Temple, Texas; ⁷Texas A&M University College of Medicine, Temple, Texas; ⁸Kaiser Permanente Vaccine Study Center, Kaiser Permanente Northern California, Oakland, California; ⁹Center for Biomedical Informatics, Regenstrief Institute, Indianapolis, Indiana; ¹⁰Indiana University School of Medicine, Indianapolis, Indiana; ¹¹HealthPartners Institute, Minneapolis, Minnesota; ¹²Division of Infectious Diseases and Clinical Epidemiology, Intermountain Healthcare, Salt Lake City, Utah; ¹³Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado; ¹⁴Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana; ¹⁵Children's Minnesota, Minneapolis, Minnesota; ¹⁶Vanderbilt University, Nashville, Tennessee.

Corresponding author
Mark G. Thompson, isq8@cdc.gov.

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Stephanie A. Irving reports institutional support from Westat. Nicola P. Klein reports institutional support from Pfizer, Merck, GlaxoSmithKline, Sanofi Pasteur, and Protein Scient (unrelated to the current work), and institutional support from Pfizer for COVID-19 vaccine clinical trials. Allison L. Naleway reports institutional support from Pfizer for a study of meningococcal B vaccine safety during pregnancy (unrelated to the current work). Charlene McEvoy reports institutional support from AztraZeneca for an AZD1222 COVID-19 vaccine trial. Suchitra Rao reports grant support from GlaxoSmithKline, Biofire Diagnostics. No other potential conflicts of interest were disclosed.

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Summary

What is already known about this topic?

COVID-19 mRNA vaccine effectiveness (VE) in preventing COVID-19 might decline because of waning of vaccine-induced immunity or variant immune evasion.

What is added by this report?

VE was significantly higher among patients who received their second mRNA COVID-19 vaccine dose <180 days before medical encounters compared with those vaccinated ≥180 days earlier. During both Delta- and Omicron-predominant periods, receipt of a third vaccine dose was highly effective at preventing COVID-19–associated emergency department and urgent care encounters (94% and 82%, respectively) and preventing COVID-19–associated hospitalizations (94% and 90%, respectively).

What are the implications for public health practice?

All unvaccinated persons should start vaccination as soon as possible. All adults who have received mRNA vaccines during their primary COVID-19 vaccination series should receive a third dose when eligible, and eligible persons should stay up to date with COVID-19 vaccinations.