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 — VISION Net – COVID-19

CDC recommends that all persons aged ≥12 years receive a booster dose of COVID-19 mRNA vaccine ≥5 months after completion of a primary mRNA vaccination series and that immunocompromised persons receive a third primary dose.* Waning of vaccine protection after 2 doses of mRNA vaccine has been observed during the period of the SARS-CoV-2 B.1.617.2 (Delta) variant predominance^† (1–5), but little is known about durability of protection after 3 doses during periods of Delta or SARS-CoV-2 B.1.1.529 (Omicron) variant predominance. A test-negative case-control study design using data from eight VISION Network sites^§ examined vaccine effectiveness (VE) against COVID-19 emergency department/urgent care (ED/UC) visits and hospitalizations among U.S. adults aged ≥18 years at various time points after receipt of a second or third vaccine dose during two periods: Delta variant predominance and Omicron variant predominance (i.e., periods when each variant accounted for ≥50% of sequenced isolates).^¶ Persons categorized as having received 3 doses included those who received a third dose in a primary series or a booster dose after a 2 dose primary series (including the reduced-dosage Moderna booster). The VISION Network analyzed 241,204 ED/UC encounters** and 93,408 hospitalizations across 10 states during August 26, 2021–January 22, 2022. VE after receipt of both 2 and 3 doses was lower during the Omicron-predominant than during the Delta-predominant period at all time points evaluated. During both periods, VE after receipt of a third dose was higher than that after a second dose; however, VE waned with increasing time since vaccination. During the Omicron period, VE against ED/UC visits was 87% during the first 2 months after a third dose and decreased to 66% among those vaccinated 4–5 months earlier; VE against hospitalizations was 91% during the first 2 months following a third dose and decreased to 78% ≥4 months after a third dose. For both Delta- and Omicron-predominant periods, VE was generally higher for protection against hospitalizations than against ED/UC visits. 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.

VISION Network methods have been previously published (6). Eligible medical encounters were defined as those among adults aged ≥18 years with a COVID-19–like illness diagnosis^†† who had received molecular testing (primarily reverse transcription–polymerase chain reaction assay) for SARS-CoV-2, the virus that causes COVID-19, during the 14 days before through 72 hours after the medical encounter. The study period began on August 26, 2021, 14 days after the first U.S. recommendation for a third mRNA COVID-19 vaccine dose.^§§ The date when the Omicron variant accounted for ≥50% of sequenced isolates was determined for each study site based on state and national surveillance data. Recipients of Ad.26.COV2.S (Janssen [Johnson & Johnson]) vaccine, 1 or >3 doses of an mRNA vaccine, and those for whom <14 days had elapsed since receipt of any dose were excluded.

VE was estimated using a test-negative design, comparing the odds of a positive SARS-CoV-2 test result between vaccinated and unvaccinated patients using logistic regression models conditioned on calendar week and geographic area and adjusting for age, local virus circulation, immunocompromised status, additional patient comorbidities, and other patient and facility characteristics.^¶¶ Immunocompromised status was identified by previously published diagnosis codes.*** Vaccination status was categorized based on the number of vaccine doses received and number of days between receipt of the most recent vaccine dose and the index medical encounter date (referred to as time since vaccination).^††† Patients with no record of mRNA vaccination before the index date were considered unvaccinated. Persons categorized as having received 3 doses included those who received a third dose in a primary series or a booster dose after a 2 dose primary series (including the reduced-dosage Moderna booster).

A standardized mean or proportion difference ≥0.2 indicated a nonnegligible difference in distributions of vaccination or infection status. The most remote category of time since vaccination was either ≥4 months or ≥5 months, depending on data availability (no hospitalizations were observed ≥5 months after receipt of a third dose during either period). To test for a trend in waning, time since vaccination categories were specified as an ordinal variable (<2 months = 0; 2–3 months = 1; 4 months = 2; ≥5 months = 3), with statistically significant waning indicated by a p-value <0.05 for the resulting regression coefficient. SAS (version 9.4, SAS Institute) and R software (version 4.1.2, R Foundation) were used to prepare data and perform statistical analysis.

For illustration purposes, the earliest and latest VE estimates for the trend are described. The overall trend can be statistically significant even though the precision of each estimate might be low, with the 95% CIs of estimates including zero. Analyses were stratified by two periods: Delta variant predominance and Omicron variant predominance. This study was reviewed and approved by the institutional review boards at participating sites and under a reliance agreement with the Westat, Inc. Institutional Review Board.^§§§

Among 241,204 eligible ED/UC encounters, 185,652 (77%) and 55,552 (23%) occurred during the Delta- and Omicron-predominant periods, respectively (Table 1). Among persons with COVID-19–like illness seeking care at ED/UC facilities, 46% were unvaccinated, 44% had received 2 doses of vaccine, and 10% had received 3 doses. The median interval since receipt of the most recent dose before the ED/UC encounter was 214 days (IQR = 164–259 days) among those who had received 2 doses and 49 days (IQR = 30–73) among those who had received 3 doses (CDC, unpublished data, 2022).

During the Delta-predominant period, VE against laboratory-confirmed COVID-19–associated ED/UC encounters was higher after receipt of a third dose than after a second dose; however, VE declined with increasing time since vaccination (Table 2). Among recipients of 3 doses, VE was 97% within 2 months of vaccination and declined to 89% among those vaccinated ≥4 months earlier (p<0.001 for test of trend in waning VE).

During the Omicron-predominant period, VE against COVID-19–associated ED/UC encounters was lower overall compared with that during the Delta-predominant period and waned after the second dose, from 69% within 2 months of vaccination to 37% at ≥5 months after vaccination (p<0.001). Protection increased after a third dose, with VE of 87% among those vaccinated within the past 2 months; however, VE after 3 doses declined to 66% among those vaccinated 4–5 months earlier and 31% among those vaccinated ≥5 months earlier, although the latter estimate is imprecise because few data were available on persons vaccinated for ≥5 months after a third dose. The decreasing trend of VE with increasing time since vaccination was significant (p<0.001).

Among 93,408 eligible hospitalizations, 83,045 (89%) and 10,363 (11%) occurred during the Delta- and Omicron-predominant periods, respectively (Table 3). Among persons hospitalized with COVID-19–like illness, 43% were unvaccinated, 45% had received 2 vaccine doses, and 12% had received 3 doses. The median interval since receipt of the most recent dose before hospitalization was 216 days (IQR = 175–257 days) among those who had received 2 doses and 46 days (IQR = 29–67 days) among those who had received 3 doses, (CDC, unpublished data, 2022).

During the Delta-predominant period, 2-dose VE against laboratory-confirmed COVID-19–associated hospitalizations declined with increasing time since vaccination and increased after a third dose (Table 2). Among recipients of 3 doses during the Delta-predominant period, VE against COVID-19–associated hospitalizations declined from 96% within 2 months of vaccination to 76% among those vaccinated ≥4 months earlier although the latter estimate is imprecise because few data were available on persons vaccinated for ≥4 months after a third dose during the Delta-predominant period (p<0.001 for test of trend in waning VE).

During the period of Omicron predominance, VE against COVID-19–associated hospitalizations was lower overall and waned with time since vaccination: VE after a second dose declined from 71% within 2 months of vaccination to 54% among those vaccinated ≥5 months earlier (p = 0.01). Among recipients of 3 doses, VE against COVID-19–associated hospitalizations declined from 91% among those vaccinated within the past 2 months to 78% among those vaccinated ≥4 months earlier (p<0.001).

¹CDC 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.

References

1. Fowlkes A, Gaglani M, Groover K, Thiese MS, Tyner H, Ellingson K; HEROES-RECOVER Cohorts. Effectiveness of COVID-19 vaccines in preventing SARS-CoV-2 infection among frontline workers before and during B.1.617.2 (Delta) variant predominance—eight U.S. locations, December 2020–August 2021. MMWR Morb Mortal Wkly Rep 2021;70:1167–9. https://doi.org/10.15585/mmwr.mm7034e4external icon PMID:34437521external icon
2. Thompson MG, Natarajan K, Irving SA, et al. 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—VISION Network, 10 States, August 2021–January 2022. MMWR Morb Mortal Wkly Rep 2022;71:139–45. https://doi.org/10.15585/mmwr.mm7104e3external icon PMID:35085224external icon
3. Tartof SY, Slezak JM, Fischer H, et al. Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study. Lancet 2021;398:1407–16. https://doi.org/10.1016/S0140-6736(21)02183-8external icon PMID:34619098external icon
4. Tenforde MW, Self WH, Naioti EA, et al.; IVY Network Investigators; IVY Network. Sustained effectiveness of Pfizer-BioNTech and Moderna vaccines against COVID-19 associated hospitalizations among adults—United States, March–July 2021. MMWR Morb Mortal Wkly Rep 2021;70:1156–62. https://doi.org/10.15585/mmwr.mm7034e2external icon PMID:34437524external icon
5. Bruxvoort KJ, Sy LS, Qian L, et al. Effectiveness of mRNA-1273 against
   Delta, Mu, and other emerging variants of SARS-CoV-2: test negative case-control study. BMJ 2021;375:e068848. https://doi.org/10.1136/bmj-2021-068848external icon PMID:34911691external icon
6. Thompson MG, Stenehjem E, Grannis S, et al. Effectiveness of Covid-19 vaccines in ambulatory and inpatient care settings. N Engl J Med 2021;385:1355–71. https://doi.org/10.1056/NEJMoa2110362external icon PMID:34496194external icon
7. Accorsi EK, Britton A, Fleming-Dutra KE, et al. Association between 3 doses of mRNA COVID-19 vaccine and symptomatic infection caused by the SARS-CoV-2 Omicron and Delta variants. JAMA 2022. https://doi.org/10.1001/jama.2022.0470external icon PMID:35060999external icon
8. Barda N, Dagan N, Cohen C, et al. Effectiveness of a third dose of the BNT162b2 mRNA COVID-19 vaccine for preventing severe outcomes in Israel: an observational study. Lancet 2021;398:2093–100. https://doi.org/10.1016/S0140-6736(21)02249-2external icon PMID:34756184external icon

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.