Effectiveness of 2, 3, and 4 COVID-19 mRNA Vaccine Doses Among Immunocompetent Adults During Periods when SARS-CoV-2 Omicron BA.1 and BA.2/BA.2.12.1 Sublineages Predominated — VISION Network, 10 States, December 2021–June 2022

The Omicron variant (B.1.1.529) of SARS-CoV-2, the virus that causes COVID-19, was first identified in the United States in November 2021, with the BA.1 sublineage (including BA.1.1) causing the largest surge in COVID-19 cases to date. Omicron sublineages BA.2 and BA.2.12.1 emerged later and by late April 2022, accounted for most cases.* Estimates of COVID-19 vaccine effectiveness (VE) can be reduced by newly emerging variants or sublineages that evade vaccine-induced immunity (1), protection from previous SARS-CoV-2 infection in unvaccinated persons (2), or increasing time since vaccination (3). Real-world data comparing VE during the periods when the BA.1 and BA.2/BA.2.12.1 predominated (BA.1 period and BA.2/BA.2.12.1 period, respectively) are limited. The VISION network^† examined 214,487 emergency department/urgent care (ED/UC) visits and 58,782 hospitalizations with a COVID-19–like illness^§ diagnosis among 10 states during December 18, 2021–June 10, 2022, to evaluate VE of 2, 3, and 4 doses of mRNA COVID-19 vaccines (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) compared with no vaccination among adults without immunocompromising conditions. VE against COVID-19–associated hospitalization 7–119 days and ≥120 days after receipt of dose 3 was 92% (95% CI = 91%–93%) and 85% (95% CI = 81%–89%), respectively, during the BA.1 period, compared with 69% (95% CI = 58%–76%) and 52% (95% CI = 44%–59%), respectively, during the BA.2/BA.2.12.1 period. Patterns were similar for ED/UC encounters. Among adults aged ≥50 years, VE against COVID-19–associated hospitalization ≥120 days after receipt of dose 3 was 55% (95% CI = 46%–62%) and ≥7 days (median = 27 days) after a fourth dose was 80% (95% CI = 71%–85%) during BA.2/BA.2.12.1 predominance. Immunocompetent persons should receive recommended COVID-19 booster doses to prevent moderate to severe COVID-19, including a first booster dose for all eligible persons and second booster dose for adults aged ≥50 years at least 4 months after an initial booster dose. Booster doses should be obtained immediately when persons become eligible.^¶

A 2-dose primary COVID-19 mRNA vaccination series followed by a third (booster) dose at least 5 months after dose 2 is recommended for adults aged ≥18 years without immunocompromising conditions. On March 29, 2022, an additional booster dose (dose 4) was authorized for immunocompetent adults aged ≥50 years at least 4 months after dose 3 (4). The VISION Network evaluated the effectiveness of 2, 3, or 4 mRNA vaccine doses during December 2021–June 2022, a period during which different sublineages of Omicron circulated in the United States. VISION methods have been described previously (5); briefly, eligible medical encounters include ED/UC visits and hospitalizations among adults with COVID-19–like illness and a SARS-CoV-2 molecular test during the 14 days before through 72 hours after the encounter. Variant predominance was defined as the period when a variant accounted for ≥75% of all sequenced specimens at a site (i.e., BA.1, December 2021–March 2022** and BA.2/BA.2.12.1, March–June 2022^††). Dates when the prevalence of BA.1 declined to <75% of sequenced specimens and the prevalence of BA.2/BA.2.12.1 had not yet reached 75% were considered a “washout” period; encounters through June 10, 2022, were included unless BA.2/BA.2.12.1 prevalence declined to <75% at a site before that date. Patients were excluded if 1) a medical event occurred during the washout period; 2) a likely immunocompromising condition was present; 3) an mRNA vaccine dose was received before it was recommended^§§; 4) any doses of a non–mRNA vaccine such as JNJ-78436735 (Janssen [Johnson & Johnson]) were received; 5) <14 days had elapsed since receipt of dose 2 or <7 days since receipt of dose 3 or dose 4; or 6) a previous SARS-CoV-2 infection was documented in the patient’s medical record before the index encounter (to reduce the influence of protection from previous infection).^¶¶ VE was estimated using a test-negative case-control design, comparing the odds of being vaccinated (receipt of 2 doses ≥14 days before the encounter, 3 doses ≥7 days before the encounter, or 4 doses ≥7 days before the encounter) versus being unvaccinated (zero doses received) between persons with positive and negative SARS-CoV-2 test results, using multivariable logistic regression, weighted for inverse propensity to be vaccinated, and adjusted for age, calendar time of index date (days since January 1, 2021),*** study site, and local virus circulation. VE for 4 vaccine doses was assessed only for adults aged ≥50 years during the BA.2/BA.2.12.1 period, aligning with the March 29, 2022, authorization for the fourth dose. Nonoverlapping 95% CIs were considered statistically significant. Analyses were conducted using R software (version 4.1.2; R Foundation). The study was reviewed and approved by institutional review boards at participating sites or under reliance agreement with the institutional review board of Westat, Inc. This activity was conducted consistent with applicable federal law and CDC policy.^†††

Among 214,487 ED/UC encounters with a COVID-19–like illness diagnosis that met inclusion criteria, 124,033 (57.8%) occurred during the BA.1 period, during which 40,801 (32.9%) patients had a positive SARS-CoV-2 test result; 90,454 (42.2%) occurred during the BA.2/BA.2.12.1 period, during which 10,177 (11.3%) had a positive SARS-CoV-2 test result. During the BA.1 period, 51,359 (41.4%) ED/UC patients were unvaccinated, 40,026 (32.3%) had received 2 mRNA vaccine doses, and 32,648 (26.3%) had received 3 doses (Table 1). During the BA.2/BA.2.12.1 period, 27,907 (30.9%) ED/UC patients were unvaccinated; 22,657 (25.0%) had received 2 mRNA vaccine doses, 35,796 (39.6%) had received 3 doses; and 4,094 (4.5%) had received 4 doses. Receipt of 3 versus 2 doses was associated with a higher VE against an ED/UC encounter during both periods, and VE was higher during the BA.1 period than the BA.2/BA.2.12.1 period (Table 2). During the BA.1 period, VE declined to 73% ≥120 days (median = 132 days) after the third vaccine dose; during the BA.2/BA.12.1 period, VE declined to 26% at ≥120 days (median = 166 days) after the third dose.

Among 58,782 hospitalizations with a COVID-19–like illness diagnosis that met inclusion criteria, 35,399 (60.2%) occurred during the BA.1 period, during which 10,534 (29.8%) patients had a positive SARS-CoV-2 test result; 23,383 (17.9%) occurred during the BA.2/BA.2.12.1 period, during which 1,564 (6.7%) patients had a positive test result (Table 3). During the BA.1 period, 14,742 (41.6%) patients hospitalized with COVID-19–like illness were unvaccinated, 10,086 (28.5%) had received 2 mRNA vaccine doses, and 10,571 (29.9%) had received 3 doses. During the BA.2/BA.2.12.1 period, 6,682 (28.6%) patients hospitalized with COVID-19–like illness were unvaccinated, and 5,461 (23.4%), 10,036 (42.9%), and 1,204 (5.1%) had received 2, 3, and 4 mRNA vaccine doses, respectively. VE against COVID-19–associated hospitalization was 61% ≥150 days after dose 2 during the BA.1 period (median = 289 days) compared with 24% during the BA.2/BA.2.12.1 period (median = 371 days) (Table 2). VE associated with a third mRNA vaccine dose was higher than that associated with a second vaccine dose but declined during both periods at ≥120 days to 85% during the BA.1 period (median = 132 days) and 52% during the BA.2/BA.2.12.1 period (median = 168 days).

Among adults aged ≥50 years eligible to receive a fourth mRNA vaccine dose, VE for COVID-19–associated ED/UC encounters during the BA.2/BA.2.12.1 period was 32% at ≥120 days after the third dose (median interval = 170 days) but increased to 66% ≥7 days after the fourth dose (median interval = 28 days). VE against COVID-19–associated hospitalization was 55% ≥120 days after the third dose but increased to 80% ≥7 days after the fourth dose.

Acknowledgments

Rebecca Kondor, Manish Patel, Tamara Pilishvili, Heather Scobie, CDC.

Corresponding author: Ruth Link-Gelles, media@cdc.gov.

¹CDC COVID-19 Emergency Response Team; ²Westat, Rockville, Maryland.; ³Baylor Scott & White Health, Temple, Texas; ⁴Texas A&M University College of Medicine, Temple, Texas; ⁵Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon; ⁶Division of Child and Adolescent Health, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York; ⁷Department of Population and Family Health, Columbia University Mailman School of Public Health, New York, New York; ⁸New York Presbyterian Hospital, New York, New York; ⁹Division of Infectious Diseases and Clinical Epidemiology, Intermountain Healthcare, Salt Lake City, Utah; ¹⁰HealthPartners Institute, Minneapolis, Minnesota; ¹¹School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; ¹²Center for Biomedical Informatics, Regenstrief Institute, Indianapolis, Indiana; ¹³School of Medicine, Indiana University, Indianapolis, Indiana; ¹⁴Kaiser Permanente Vaccine Study Center, Kaiser Permanente Northern California Division of Research, Oakland, California; ¹⁵Paso Del Norte Health Information Exchange, El Paso, Texas; ¹⁶Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York; ¹⁷Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana; ¹⁸Children’s Minnesota, Minneapolis, Minnesota; ¹⁹Brigham Young University Department of Public Health, Provo, Utah.

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Abbreviations: ED = emergency department; ICD-9 = International Classification of diseases, Ninth Revision; ICD-10 = International Classification of diseases, Tenth Revision; KPNC = Kaiser Permanente Northern California; KPNW = Kaiser Permanente Northwest; N/A = not applicable; NH = non-Hispanic; PHIX = Paso del Norte Health Information Exchange; RT-PCR = reverse transcription–polymerase reaction; SMD = standardized mean or proportion difference; UC = urgent care.
* Medical events with a discharge code consistent with COVID-19–like illness were included; using ICD-9 and ICD-10 codes, COVID-19–like illness diagnoses included acute respiratory illness (e.g., respiratory failure or pneumonia) or related signs or symptoms (e.g., cough, fever, dyspnea, vomiting, or diarrhea). Clinician-ordered molecular assays (e.g., real-time RT-PCR) for SARS-CoV-2 occurring ≤14 days before to <72 hours after the encounter date were included.
^† Partners contributing data on medical events during dates of estimated ≥75% Omicron BA.1 predominance were in California (Dec 21, 2021–Mar 6, 2022), Colorado (Dec 25, 2021–Mar 12, 2022), Indiana (Dec 31, 2021–Mar 4, 2022), Minnesota and Wisconsin (Jan 1–Mar 5, 2022), New York (Dec 18, 2021–Feb 26, 2022), Oregon and Washington (Jan 1–Mar 12, 2022), Texas (Baylor Scott & White Health [Dec 18, 2021–Mar 5, 2022] and PHIX [Jan 8–Mar 19, 2022]), and Utah (Dec 27, 2021–Mar 19, 2022).
^§ Partners contributing data on medical events during dates of estimated ≥75% Omicron BA.2/BA.2.12.1 predominance were in California (Mar 25–Jun 10, 2022), Colorado (Apr 9–Jun 4, 2022), Indiana (Mar 19–Jun 10, 2022), Minnesota and Wisconsin (Apr 9–Jun 4, 2022), New York (Mar 26–Jun 10, 2022), Oregon and Washington (Apr 9–Jun 10, 2022), Texas (Baylor Scott & White Health [Mar 26–Jun 4, 2022] and PHIX [Apr 23–Jun 10, 2022]), and Utah (Mar 28–Jun 10, 2022).
^¶ Vaccination was defined as having received the listed number of doses of an mRNA-based COVID-19 vaccine within the specified range of number of 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.
** An absolute SMD ≥0.20 indicates a nonnegligible difference in variable distributions between medical events for vaccinated versus unvaccinated patients or for patients with SARS-CoV-2–positive test result versus those with SARS-CoV-2–negative results. For mRNA COVID-19 vaccination status, a single SMD was calculated by averaging the absolute SMDs obtained from pairwise comparisons of each vaccinated category versus unvaccinated; more specifically as the average of the absolute value of the SMDs for 1) vaccinated with 2 doses 14–149 days earlier versus unvaccinated, 2) vaccinated with 2 doses ≥150 days earlier versus unvaccinated, 3) vaccinated with 3 doses 7–119 days earlier versus unvaccinated, 4) vaccinated with 3 doses ≥120 days earlier versus unvaccinated, and 5) vaccinated with 4 doses ≥7 days earlier versus unvaccinated.
^†† Other race includes Asian, Native Hawaiian or other Pacific islander, American Indian or Alaska Native, Other, 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 ICD-9 or ICD-10 diagnosis codes.
^¶¶ 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 ICD-9 and ICD-10 diagnosis codes.

Abbreviations: ED = emergency department; ICD-9 = International Classification of Diseases, Ninth Revision; ICD-10 = International Classification of Diseases, Tenth Revision; N/A = not applicable; PHIX = Paso Del Norte Health Information Exchange; Ref = referent group; RT-PCR = reverse transcription–polymerase chain reaction; 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 January 1, 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 set of VE estimates among ED or UC encounters and hospitalizations by Omicron–predominant period and age group). 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., respiratory failure or pneumonia) or related signs or symptoms (e.g., cough, fever, dyspnea, vomiting, or diarrhea) using ICD-9 and ICD-10 codes. Clinician-ordered molecular assays (e.g., real-time RT-PCR) for SARS-CoV-2 occurring ≤14 days before to <72 hours after the encounter date were included.
^§ Vaccination was defined as having received the listed number of doses of an mRNA-based COVID-19 vaccine within the specified range of number of 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 during dates of estimated ≥75% Omicron BA.1 predominance were in California (Dec 21, 2021–Mar 6, 2022), Colorado (Dec 25, 2021–Mar 12, 2022), Indiana (Dec 31, 2021–Mar 4, 2022), Minnesota and Wisconsin (Jan 1–Mar 5, 2022), New York (Dec 18, 2021–Feb 26, 2022), Oregon and Washington (Jan 1–Mar 12, 2022), Texas (Baylor Scott & White Health [Dec 18, 2021–Mar 5, 2022] and PHIX [Jan 8–Mar 19, 2022]), and Utah (Dec 27, 2021–Mar 19, 2022).
** Partners contributing data on medical events during dates of estimated ≥75% Omicron BA.2/BA.2.12.1 predominance were in California (Mar 25–Jun 10, 2022), Colorado (Apr 9–Jun 4, 2022), Indiana (Mar 19–Jun 10, 2022), Minnesota and Wisconsin (Apr 9–Jun 4, 2022), New York (Mar 26–Jun 10, 2022), Oregon and Washington (Apr 9–Jun 10, 2022), Texas (Baylor Scott & White Health [Mar 6–Jun 4, 2022 and PHIX [Apr 23–Jun 10, 2022]), and Utah (Mar 28–Jun 10, 2022).
^†† For estimation of 4-dose mRNA VE among patients aged ≥50 years during the Omicron BA.2/BA.2.12.1–predominant period, unvaccinated patients whose medical event index date was before Apr 5, 2022 were excluded from the referent group (1,836 ED or UC encounters and 999 hospitalizations excluded among unvaccinated patients) because the earliest medical event index date included among 4-dose mRNA-vaccinated patients was 7 days after Mar 29, 2022 when a second booster mRNA vaccine dose (fourth dose) was first included in recommendations for adults aged ≥50 years (at least 4 months after receiving a third mRNA dose).
^§§ VE estimates with 95% CIs >50 percentage points are not shown because of imprecision.

Abbreviations: ICD-9 = International Classification of Diseases, Ninth Revision; ICD-10 = International Classification of Diseases, Tenth Revision; KPNC = Kaiser Permanente of Northern California; KPNW = Kaiser Permanente Northwest; N/A = not applicable; NH = non-Hispanic; PHIX = Paso del Norte Health Information Exchange; RT-PCR = reverse transcription–polymerase chain reaction; SMD = standardized mean or proportion difference.
* Hospitalizations with a discharge code consistent with COVID-19–like illness were included. COVID-19–like illness diagnoses included acute respiratory illness (e.g., respiratory failure or pneumonia) or related signs or symptoms (e.g., cough, fever, dyspnea, vomiting, or diarrhea) using diagnosis ICD-9 and ICD-10 codes. Clinician-ordered molecular assays (e.g., real-time RT-PCR) for SARS-CoV-2 occurring ≤14 days before to <72 hours after the encounter date were included.
^† Partners contributing data on hospitalizations during dates of estimated ≥75% Omicron BA.1 predominance were in California (Dec 21, 2021–Mar 6, 2022), Colorado (Dec 25, 2021–Mar 12, 2022), Indiana (Dec 31, 2021–Mar 4, 2022), Minnesota and Wisconsin (Jan 1–Mar 5, 2022), New York (Dec 18, 2021–Feb 26, 2022), Oregon and Washington (Jan 1–Mar 12, 2022), Texas (Baylor Scott & White Health [Dec 18, 2021–Mar 5, 2022] and PHIX [Jan 8–Mar 19, 2022]), and Utah (Dec 27, 2021–Mar 19, 2022).
^§ Partners contributing data on hospitalizations during dates of estimated ≥75% Omicron BA.2/BA.2.12.1 predominance were in California (Mar 25–Jun 10, 2022), Colorado (Apr 9–Jun 4, 2022), Indiana (Mar 19–Jun 10, 2022), Minnesota and Wisconsin (Apr 9–Jun 4, 2022), New York (Mar 26–Jun 10, 2022), Oregon and Washington (Apr 9–Jun 10, 2022), Texas (Baylor Scott & White Health [Mar 26–Jun 4, 2022] and PHIX [Apr 23–Jun 10, 2022]), and Utah (Mar 28–Jun 10, 2022).
^¶ Vaccination was defined as having received the listed number of doses of an mRNA-based COVID-19 vaccine within the specified range of number of days before the hospitalization 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 hospitalization or the admission date if testing only occurred after the admission.
** An absolute SMD ≥0.20 indicates a nonnegligible difference in variable distributions between hospitalizations for vaccinated versus unvaccinated patients or for patients with SARS-CoV-2–positive results versus those with SARS-CoV-2–negative results. For mRNA COVID-19 vaccination status, a single SMD was calculated by averaging the absolute SMDs obtained from pairwise comparisons of each vaccinated category versus unvaccinated; more specifically, as the average of the absolute value of the SMDs for 1) vaccinated with 2 doses 14–149 days earlier versus unvaccinated, 2) vaccinated with 2 doses ≥150 days earlier versus unvaccinated, 3) vaccinated with 3 doses 7–119 days earlier versus unvaccinated, 4) vaccinated with 3 doses ≥120 days earlier versus unvaccinated, and 5) vaccinated with 4 doses ≥7 days earlier versus unvaccinated.
^†† Other race includes Asian, Native Hawaiian or other Pacific islander, American Indian or Alaska Native, Other, 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 ICD-9 and ICD-10 diagnosis codes.
^¶¶ 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 ICD-9 and ICD-10 diagnosis.