Waning 2-dose and 3-dose Effectiveness 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; ICD-9 = International Classification of Diseases, Ninth Revision; ICD-10 = International Classification of Diseases, Tenth Revision 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 ICD-9 and ICD-10 diagnosis codes. 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 vaccine, 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 medical event or the admission date if testing only occurred after the admission.
^§California, Colorado, Indiana, Minnesota, New York, Oregon, Texas, Utah, Washington, and Wisconsin.
^¶Partners contributing data on medical events and estimated date 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 "Vaccinated (3 doses)" category includes persons who have received a third dose in their primary series or have received a booster dose following their 2-dose primary series; the third dose could have been either a 100-μg or 50-μg dose of Moderna vaccine or a 30-μg dose of the Pfizer-BioNTech vaccine.
^††An absolute SMD ≥0.20 indicates a nonnegligible difference in variable distributions between medical events for vaccinated versus unvaccinated patients. When calculating SMDs for differences in characteristics across mRNA COVID-19 vaccination status, the SMD was calculated as the average of the absolute value of the SMD for unvaccinated versus vaccinated with 2 doses and the absolute value of the SMD for unvaccinated versus vaccinated with 3 doses. All SMDs are reported as the absolute SMD.
^§§ED data at Columbia University Irving Medical Center and HealthPartners exclude encounters that were transferred to an inpatient setting
^¶¶Referent group used for SMD calculations for dichotomous variables.
***Other race includes Asian, Native Hawaiian or other Pacific islander, American Indian or Alaska Native, Other not listed, and multiple races.
^†††Chronic respiratory condition was defined using ICD-9 and ICD-10 as the presence of discharge codes for asthma, chronic obstructive pulmonary disease, or other lung disease.
^§§§Chronic nonrespiratory condition was defined using ICD-9 and ICD-10 as the presence of discharge codes 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.
^¶¶¶Immunocompromised status was defined using ICD-9 and ICD-10 as the presence of discharge codes for solid malignancy, hematologic malignancy, rheumatologic or inflammatory disorder, other intrinsic immune condition or immunodeficiency, or organ or stem cell transplant.

Abbreviations: ED = emergency department; ICD-9 = International Classification of Diseases, Ninth Revision; ICD-10 = International Classification of Diseases, Tenth Revision; Ref = referent group; UC = urgent care; VE = vaccine effectiveness.
*VE was calculated as [1 − odds ratio] x 100%, estimated using a test-negative design, conditioned on calendar week and geographic area, and adjusted for age, local virus circulation (percentage of SARS-CoV-2–positive results from testing within the counties surrounding the facility on the date of the encounter), propensity to be vaccinated (calculated separately for each VE estimate), and other factors. Generalized boosted regression tree methods 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 ICD-9 and ICD-10 diagnosis codes. 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 vaccine, 1 or >3 doses of an mRNA vaccine, and those for whom <14 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. Persons categorized as having received 3 vaccine doses include those who received a third dose in their primary series or received a booster dose after their 2 dose primary series; the third dose could have been either a 100-μg or 50-μg dose of Moderna vaccine or a 30-μg dose of the Pfizer-BioNTech vaccine.
^¶California, Colorado, Indiana, Minnesota, New York, Oregon, Texas, Utah, Washington, and Wisconsin.
**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.
^††p-value for test of linear trendline fitted to VE estimates across ordinal categories of time since vaccination (<2 months = 0; 2–3 months = 1, 4 months = 2, ≥5 months = 3).

Abbreviations: ICD-9 = International Classification of Diseases, Ninth Revision; ICD-10 = International Classification of Diseases, Tenth Revision; SMD = standardized mean or proportion difference.
*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 ICD-9 and ICD-10 diagnosis codes. 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 vaccine, 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 medical event or the admission date if testing only occurred after the admission.
^§California, Colorado, Indiana, Minnesota, New York, Oregon, Texas, Utah, Washington, and Wisconsin.
^¶Partners contributing data on medical events and estimated date 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.
**Persons categorized as having received 3 vaccine doses include those who have received a third dose in their primary series or have received a booster dose following their 2-dose primary series; the third dose could have been either a 100-μg or 50-μg dose of Moderna vaccine or a 30-μg dose of the Pfizer-BioNTech vaccine.
^††An absolute SMD ≥0.20 indicates a nonnegligible difference in variable distributions between medical events for vaccinated versus unvaccinated patients. When calculating SMDs for differences of characteristics across mRNA COVID-19 vaccination status, the SMD was calculated as the average of the absolute value of the SMD for unvaccinated versus vaccinated with 2 doses and the absolute value of the SMD for unvaccinated versus vaccinated with 3 doses. All SMDs are reported as the absolute SMD.
^§§Indicates the referent group used for SMD calculations for dichotomous variables.
^¶¶Other race includes Asian, Native Hawaiian or other Pacific islander, American Indian or Alaska Native, Other not listed, and multiple races.
***Chronic respiratory condition was defined using ICD-9 and ICD-10 as the presence of discharge codes for asthma, chronic obstructive pulmonary disease, or other lung disease.
^†††Chronic nonrespiratory condition was defined using ICD-9 and ICD-10 as the presence of discharge codes 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.
^§§§Immunocompromised status was defined using ICD-9 and ICD-10 as the presence of discharge codes for solid malignancy, hematologic malignancy, rheumatologic or inflammatory disorder, other intrinsic immune condition or immunodeficiency, or organ or stem cell transplant.

Authors and Disclosures

Jill M. Ferdinands, PhD¹, Suchitra Rao, MBBS², Brian E. Dixon, PhD^3,4, Patrick K. Mitchell, ScD⁵, Malini B. DeSilva, MD⁶, Stephanie A. Irving, MHS⁷, Ned Lewis, MPH⁸, Karthik Natarajan, PhD^9,10, Edward Stenehjem, MD¹¹, Shaun J. Grannis, MD^3,12, Jungmi Han⁹, Charlene McEvoy, MD⁶, Toan C. Ong, PhD², Allison L. Naleway, PhD⁷, Sarah E. Reese, PhD⁵, Peter J. Embi, MD^3,12,13, Kristin Dascomb, MD¹¹, Nicola P. Klein, MD⁸, Eric P. Griggs, MPH¹, Deepika Konatham¹⁴, Anupam B. Kharbanda, MD¹⁵, Duck-Hye Yang, PhD⁵, William F. Fadel, PhD^3,4, Nancy Grisel, MPP¹¹, Kristin Goddard, MPH⁸, Palak Patel, MBBS¹, I-Chia Liao MPH¹⁴, Rebecca Birch, MPH⁵, Nimish R. Valvi, DrPH³, Sue Reynolds, PhD¹, Julie Arndorfer, MPH¹¹, Ousseny Zerbo, PhD⁸, Monica Dickerson¹, Kempapura Murthy, MBBS¹⁴, Jeremiah Williams, MPH¹, Catherine H. Bozio, PhD¹, Lenee Blanton, MPH¹, Jennifer R. Verani, MD¹, Stephanie J. Schrag, DPhil¹, Alexandra F. Dalton, PhD¹, Mehiret H. Wondimu, MPH¹, Ruth Link-Gelles, PhD¹, Eduardo Azziz-Baumgartner, MD¹, Michelle A. Barron, MD², Manjusha Gaglani, MBBS^14,16, Mark G. Thompson, PhD¹ and Bruce Fireman<sup>8

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

Corresponding author
Jill M. Ferdinands, zdn5@cdc.gov.

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Nicola P. Klein reports institutional support from Pfizer, Merck, GlaxoSmithKline, Sanofi Pasteur, and Protein Sciences (now Sanofi Pasteur) for unrelated studies and institutional support from Pfizer for a COVID-19 vaccine trial. Charlene McEvoy reports institutional support from AstraZeneca for a COVID-19 vaccine trial. Allison L. Naleway reports institutional support from Pfizer for an unrelated study of meningococcal B vaccine safety during pregnancy. Suchitra Rao reports grant funding from GlaxoSmithKline and Biofire Diagnostics. No other potential conflicts of interest were disclosed.

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Summary

What is already known about this topic?

Protection against COVID-19 after 2 doses of mRNA vaccine wanes, but little is known about durability of protection after 3 doses.

What is added by this report?

Vaccine effectiveness (VE) against COVID-19–associated emergency department/urgent care (ED/UC) visits and hospitalizations was higher after the third dose than after the second dose but waned with time since vaccination. During the Omicron-predominant period, VE against COVID-19–associated ED/UC visits and hospitalizations was 87% and 91%, respectively, during the 2 months after a third dose and decreased to 66% and 78% by the fourth month after a third dose. Protection against hospitalizations exceeded that against ED/UC visits.

What are the implications for public health practice?

All eligible persons should remain up to date with recommended COVID-19 vaccinations to best protect against COVID-19–associated hospitalizations and ED/UC visits.