On February 11, 2022, this report was posted online as an MMWR Early Release.
Jill M. Ferdinands, PhD1; Suchitra Rao, MBBS2; Brian E. Dixon, PhD3,4; Patrick K. Mitchell, ScD5; Malini B. DeSilva, MD6; Stephanie A. Irving, MHS7; Ned Lewis, MPH8; Karthik Natarajan, PhD9,10; Edward Stenehjem, MD11; Shaun J. Grannis, MD3,12; Jungmi Han9; Charlene McEvoy, MD6; Toan C. Ong, PhD2; Allison L. Naleway, PhD7; Sarah E. Reese, PhD5; Peter J. Embi, MD3,12,13; Kristin Dascomb, MD11; Nicola P. Klein, MD8; Eric P. Griggs, MPH1; Deepika Konatham14; Anupam B. Kharbanda, MD15; Duck-Hye Yang, PhD5; William F. Fadel, PhD3,4; 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, MBBS14,16; Mark G. Thompson, PhD1; Bruce Fireman8 (View author affiliations)
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.
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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).
In a multistate analysis of 241,204 ED/UC encounters and 93,408 hospitalizations among adults with COVID-19–like illness during August 26, 2021–January 22, 2022, estimates of VE against laboratory-confirmed COVID-19 were lower during the Omicron-predominant than during the Delta-predominant period, after accounting for both number of vaccine doses received and time since vaccination. During both periods, VE after receipt of a third dose was always higher than VE following a second dose; however, VE waned with increasing time since vaccination. During the Omicron-predominant period, mRNA vaccination was highly effective against both COVID-19–associated ED/UC encounters (VE = 87%) and COVID-19 hospitalizations (VE = 91%) within 2 months after a third dose, but effectiveness waned, declining to 66% for prevention of COVID-19–associated ED/UC encounters by the fourth month after receipt of a third dose and to 78% for hospitalizations by the fourth month after receipt of a third dose. The finding of lower VE for 2 or 3 doses during the Omicron-predominant period is consistent with previous reports from the VISION network and others¶¶¶,**** (2,7). Waning of VE after receipt of a third dose of mRNA vaccine has also been observed in Israel (8) and in preliminary reports from the VISION Network (2). This analysis enhances an earlier VISION Network report (2) by extending the Omicron study period to January 22, 2022, providing a more detailed breakdown of time since vaccination, and using an analytic technique that better controls for potential confounding by calendar week and geographic area. By comparing COVID-19 test-positive case-patients with COVID-19 test-negative control patients in the same geographic area and for whom encounter index dates occurred within the same week, bias in VE estimates resulting from temporal and spatial variations in virus circulation and vaccine coverage was reduced.
The findings in this report are subject to at least seven limitations. First, because this study was designed to estimate VE against COVID-19–associated ED/UC visits or hospitalizations, VE estimates from this study do not include COVID-19 infections that were not medically attended. Second, the median interval from receipt of a third dose to medical encounters was 49 days; thus, the observed performance of a third dose is limited to a relatively short period after vaccination. Third, the small number of COVID-19 test-positive patients in the most remote time-since-vaccination groups reduced the precision of the VE estimates for those groups (e.g., ≥5 months). Fourth, variations in waning of VE by age group, immunocompromised status, other indicators of underlying health status, or vaccine product have not yet been examined. This study could not distinguish whether a third dose was received as an additional dose as part of a primary series (as recommended for immunocompromised persons) or as a booster dose after completion of a primary series. Further research should evaluate waning VE of a third primary dose among immunocompromised adults compared with waning of VE after a booster dose among immunocompetent adults. Fifth, despite adjustments to account for differences between unvaccinated and vaccinated persons, VE estimates might have been biased by residual differences between these groups with respect to immunocompromised status and other health conditions, as well as from unmeasured behaviors (e.g., mask use and close contact with persons with COVID-19). For example, insufficient adjustment for immunocompromised status might have biased the estimates of VE downward among persons most remote from receipt of a third dose. Sixth, genetic characterization of patients’ viruses was not available, and analyses relied on dates when the Omicron variant became locally predominant based on surveillance data; therefore, the Omicron period of predominance in this study likely includes some medical encounters associated with the Delta variant. Finally, although the facilities in this study serve heterogeneous populations in 10 states, the findings might not be generalizable to the U.S. population.
These findings underscore the importance of receiving a third dose of mRNA COVID-19 vaccine to prevent both COVID-19–associated ED/UC encounters and COVID-19 hospitalizations among adults. The finding that protection conferred by mRNA vaccines waned in the months after receipt of a third vaccine dose reinforces the importance of further consideration of additional doses to sustain or improve protection against COVID-19–associated ED/UC encounters and COVID-19 hospitalizations. 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.
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.
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Suggested citation for this article: Ferdinands JM, Rao S, Dixon BE, et al. 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 Network, 10 States, August 2021–January 2022. MMWR Morb Mortal Wkly Rep 2022;71:255–263. DOI: http://dx.doi.org/10.15585/mmwr.mm7107e2external icon.
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