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

Ruth Link-Gelles, PhD; Matthew E. Levy, PhD; Manjusha Gaglani, MBBS; Stephanie A. Irving, MHS; Melissa Stockwell, MD; Kristin Dascomb, MD, PhD; Malini B. DeSilva, MD; Sarah E. Reese, PhD; I-Chia Liao, MPH; Toan C. Ong, PhD; Shaun J. Grannis, MD; Charlene McEvoy, MD; Palak Patel, MBBS; Nicola P. Klein, MD, PhD; Emily Hartmann, MPP; Edward Stenehjem, MD; Karthik Natarajan, PhD; Allison L. Naleway, PhD; Kempapura Murthy, MBBS; Suchitra Rao, MBBS; Brian E. Dixon, PhD; Anupam B. Kharbanda, MD; Akintunde Akinseye, MSPH; Monica Dickerson; Ned Lewis, MPH; Nancy Grisel, MPP; Jungmi Han; Michelle A. Barron, MD; William F. Fadel, PhD; Margaret M. Dunne, MSc; Kristin Goddard, MPH; Julie Arndorfer, MPH; Deepika Konatham; Nimish R. Valvi, DrPH, MBBS; J. C. Currey; Bruce Fireman, MA; Chandni Raiyani, MPH; Ousseny Zerbo, PhD; Chantel Sloan-Aagard, PhD; Sarah W. Ball, ScD; Mark G. Thompson, PhD; Mark W. Tenforde, MD, PhD

Disclosures

Morbidity and Mortality Weekly Report. 2022;71(29):931-939. 

In This Article

Abstract and Introduction

Introduction

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.

*https://covid.cdc.gov/covid-data-tracker/#variant-proportions
Funded by CDC, the VISION Network includes Baylor Scott & White Health (Texas), Columbia University Irving Medical Center (New York), HealthPartners (Minnesota and Wisconsin), Intermountain Healthcare (Utah), Kaiser Permanente Northern California (California), Kaiser Permanente Northwest (Oregon and Washington), Paso Del Norte Health Information Exchange-PHIX (Texas), Regenstrief Institute (Indiana), and University of Colorado (Colorado).
§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 diagnosis codes from the International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision.
https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html
**Local sequencing data were obtained in the states of participating VISION sites. Partners contributing data on medical events during dates of estimated ≥75% Omicron BA.1 predominance were in California (December 21, 2021–March 6, 2022), Colorado (December 25, 2021–March 12, 2022), Indiana (December 31, 2021–March 4, 2022), Minnesota and Wisconsin (January 1–March 5, 2022), New York (December 18, 2021–February 26, 2022), Oregon and Washington (January 1–March 12, 2022), Texas (Baylor Scott & White Health [December 18, 2021–March 5, 2022] and Paso del Norte Health Information Exchange [January 8–March 19, 2022]), and Utah (December 27, 2021–March 19, 2022).
††Partners contributing data on medical events during dates of estimated ≥75% Omicron BA.2/BA.2.12.1 prevalence were in California (March 25–June 10, 2022), Colorado (April 9–June 4, 2022), Indiana (March 19–June 10, 2022), Minnesota and Wisconsin (April 9–June 4, 2022), New York (March 26–June 10, 2022), Oregon and Washington (April 9–June 10, 2022), Texas (Baylor Scott & White Health [March 26–June 4, 2022] and Paso del Norte Health Information Exchange [April 23–June 10, 2022]), and Utah (March 28–June 10, 2022).
§§A booster (third) mRNA vaccine dose was first recommended by CDC for adults without immunocompromising conditions on September 23, 2021, and is currently recommended for all persons aged ≥5 years at least 5 months after a second mRNA vaccine dose. A second booster mRNA vaccine dose (fourth dose) was authorized for adults aged ≥50 years on March 29, 2022, at least 4 months after receiving a third mRNA vaccine dose. After this authorization CDC stated that adults aged ≥50 years may receive this additional booster dose; on May 19, 2022, CDC strengthened this recommendation to state that all adults aged ≥50 years should receive this additional booster dose. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html
¶¶Among ED/UC encounters and hospitalizations during the BA.1 period, 15,863 (11.3%) and 3,313 (11.8%), patients, respectively, had previous infection documented in their medical record and were excluded from analysis. Among ED/UC encounters and hospitalizations during the BA.2/BA.2.12.1 period, 17,293 (16.0%) and 3,829 (14.1%), patients, respectively, had previous infection documented in their medical record and were excluded from analysis.
***The index date for each medical visit was defined as either the date of collection of a respiratory specimen associated with the most recent positive or negative SARS-CoV-2 test result before the medical visit or the date of the medical visit (if testing occurred only after the admission or visit date).
†††45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. 3501 et seq.

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