Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19–Associated Emergency Department or Urgent Care Encounters and Hospitalizations Among Immunocompetent Adults

VISION Network, Nine States, September-November 2022

Mark W. Tenforde, MD, PhD; Zachary A. Weber, PhD; Karthik Natarajan, PhD; Nicola P. Klein, MD, PhD; Anupam B. Kharbanda, MD; Edward Stenehjem, MD; Peter J. Embi, MD; Sarah E. Reese, PhD; Allison L. Naleway, PhD; Shaun J. Grannis, MD; Malini B. DeSilva, MD; Toan C. Ong, PhD; Manjusha Gaglani, MBBS; Jungmi Han; Monica Dickerson; Bruce Fireman, MA; Kristin Dascomb, MD, PhD; Stephanie A. Irving, MHS; Gabriela Vazquez-Benitez, PhD; Suchitra Rao, MBBS; Deepika Konatham; Palak Patel, MBBS; Kristin E. Schrader, MA; Ned Lewis, MPH; Nancy Grisel, MPP; Charlene McEvoy, MD; Kempapura Murthy, MBBS; Eric P. Griggs, MPH; Elizabeth A. K. Rowley, DrPH; Ousseny Zerbo, PhD; Julie Arndorfer, MPH; Margaret M. Dunne, MSc; Kristin Goddard, MPH; Caitlin Ray, MPH; Yan Zhuang, PhD; Julius Timbol, MS; Morgan Najdowski, MPH; Duck-Hye Yang, PhD; John Hansen, MPH; Sarah W. Ball, ScD; Ruth Link-Gelles, PhD

Disclosures

Morbidity and Mortality Weekly Report. 2022;71(5152):1616-1624.

Abstract and Introduction

Introduction

During June–October 2022, the SARS-CoV-2 Omicron BA.5 sublineage accounted for most of the sequenced viral genomes in the United States, with further Omicron sublineage diversification through November 2022.* Bivalent mRNA vaccines contain an ancestral SARS-CoV-2 strain component plus an updated component of the Omicron BA.4/BA.5 sublineages. On September 1, 2022, a single bivalent booster dose was recommended for adults who had completed a primary vaccination series (with or without subsequent booster doses), with the last dose administered ≥2 months earlier.^[1] During September 13–November 18, the VISION Network evaluated vaccine effectiveness (VE) of a bivalent mRNA booster dose (after 2, 3, or 4 monovalent doses) compared with 1) no previous vaccination and 2) previous receipt of 2, 3, or 4 monovalent-only mRNA vaccine doses, among immunocompetent adults aged ≥18 years with an emergency department/urgent care (ED/UC) encounter or hospitalization for a COVID-19–like illness.^† VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against COVID-19–associated ED/UC encounters was 56% compared with no vaccination, 31% compared with monovalent vaccination only with last dose 2–4 months earlier, and 50% compared with monovalent vaccination only with last dose ≥11 months earlier. VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against COVID-19–associated hospitalizations was 57% compared with no vaccination, 38% compared with monovalent vaccination only with last dose 5–7 months earlier, and 45% compared with monovalent vaccination only with last dose ≥11 months earlier. Bivalent vaccines administered after 2, 3, or 4 monovalent doses were effective in preventing medically attended COVID-19 compared with no vaccination and provided additional protection compared with past monovalent vaccination only, with relative protection increasing with time since receipt of the last monovalent dose. All eligible persons should stay up to date with recommended COVID-19 vaccinations, including receiving a bivalent booster dose. Persons should also consider taking additional precautions to avoid respiratory illness this winter season, such as masking in public indoor spaces, especially in areas where COVID-19 community levels are high.

Monovalent COVID-19 mRNA vaccines were developed against the spike protein of the ancestral SARS-CoV-2 virus and were found to provide cross-reactive immune protection against Alpha and Delta SARS-CoV-2 variants.^[2] The SARS-CoV-2 Omicron variant emerged in November 2021 and diversified into sublineages. These Omicron sublineages were associated with decreased protection from vaccination with monovalent vaccine.^[3] A single booster dose of bivalent mRNA vaccine (Pfizer-BioNTech or Moderna) containing an updated BA.4/BA.5 component was recommended by CDC on September 1, 2022,^[1] for adults who had completed a primary series with any Food and Drug Administration–approved or –authorized monovalent vaccine or who had previously received a monovalent booster dose ≥2 months earlier.^§

The VISION Network^¶ evaluated the effectiveness of a bivalent booster dose among immunocompetent adults during September 13–November 18, 2022, a period during which the Omicron BA.5 sublineage predominated and additional Omicron sublineages emerged. Seven health systems in nine states contributed data for this analysis. VISION methods have been described.^[3] Briefly, ED/UC encounters and hospitalizations associated with a COVID-19–like illness among adults who received a SARS-CoV-2 molecular test result during the 14 days before through 72 hours after the encounter were included.** Patients were classified as unvaccinated (zero doses received), vaccinated with 2, 3, or 4 doses of a monovalent-only mRNA vaccine, or vaccinated with 2, 3, or 4 monovalent doses plus a bivalent booster dose ≥60 days after receipt of their last monovalent dose. Encounters were excluded if 1) the patient likely had an immunocompromising condition;^[4] 2) only one mRNA monovalent vaccine dose was received, a second monovalent vaccine dose was received <14 days before the encounter date, or a third or fourth monovalent vaccine dose or a bivalent booster dose was received <7 days before the encounter date; 3) any dose of a non-mRNA vaccine (e.g., Janssen [Johnson & Johnson]) was received; or 4) a vaccine dose was received before being recommended by CDC.^†† VE was estimated using a test-negative case-control design, comparing the odds of having received versus having not received a bivalent booster dose among case-patients (those who received a positive SARS-CoV-2 test result) and control patients (those who received a negative SARS-CoV-2 test result).

Odds ratios and 95% CIs were calculated using multivariable logistic regression, adjusting for age, race and ethnicity, sex, calendar day (days since January 1, 2021), geographic region, and local SARS-CoV-2 circulation (percentage of SARS-CoV-2–positive results from testing within the counties surrounding the facility on the date of the encounter). Age, calendar day, and local circulation were modeled as natural cubic splines. A single, combined model was fit for each outcome (ED/UC encounters and hospitalizations) with those who had received a bivalent booster dose (after 2, 3, or 4 monovalent doses) as the referent group with the following vaccination groups: those who had received no vaccine doses (unvaccinated) (i.e., absolute VE) and those who had received 2, 3, or 4 monovalent doses but not a bivalent booster dose (i.e., relative VE). Varying time intervals between the last dose and the index date (2–4, 5–7, 8–10, or ≥11 months)^§§ were used to calculate relative VE. Analyses were conducted using R (version 4.2.2; R Foundation). This study was conducted consistent with applicable federal law and CDC policy and was reviewed and approved by Institutional Review Boards at participating sites or under reliance agreement with the Institutional Review Board of Westat, Inc.^¶¶

Among 78,303 ED/UC encounters with COVID-19–like illness that met inclusion criteria, 9,009 (12%) case-patients and 69,294 (89%) control patients were identified (Table 1). Overall, 24,142 (31%) were unvaccinated. Among persons who had not received a bivalent dose, 18,812 (24%), 23,042 (29%), and 8,402 (11%) had received 2, 3, and 4 doses of monovalent mRNA vaccine, respectively. Among the 3,905 (5%) adults who had received a bivalent booster dose (median interval since receipt of bivalent booster dose = 25 days), 216 (6%) had received 2 monovalent doses, 1,679 (43%) had received 3 monovalent doses, and 2,010 (51%) had received 4 monovalent vaccine doses. Bivalent booster dose recipients were older (median age = 68 years) than were those who had not received a bivalent booster dose (median age = 55 years). VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against ED/UC encounters for COVID-19–associated illness was 56% (95% CI = 49%–62%) compared with no vaccination, 31% (95% CI = 19%–41%) compared with receipt of last monovalent dose 2–4 months earlier, and 50% (95% CI = 43%–57%) compared with receipt of last monovalent dose ≥11 months earlier (Table 2).

Among 15,527 hospitalizations with COVID-19–like illness that met inclusion criteria, 1,453 (9%) case-patients and 14,074 (91%) control patients were identified (Table 3). Overall, 4,092 (26%) were unvaccinated. Among those who had not received a bivalent dose, 3,355 (22%), 4,766 (31%), and 2,531 (16%) had received 2, 3, and 4 doses of monovalent mRNA vaccine, respectively. Among the 783 (5%) adults who had received a bivalent booster dose (median interval since receipt of bivalent booster dose = 23 days), 49 (6%) had received 2 monovalent doses, 252 (32%) had received 3 monovalent doses, and 482 (62%) had received 4 monovalent doses. Bivalent booster dose recipients were similar in age to vaccinated adults who had not received a bivalent booster dose (median age = 76 and 73 years, respectively). VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against hospitalization for COVID-19–associated illness was 57% (95% CI = 41%–69%) compared with no vaccination and 45% (95% CI = 25%–60%) compared with receipt of last monovalent doses, with last dose ≥11 months earlier (Table 2).

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Next Section

Abstract and Introduction
Discussion
References
Sidebar

*SARS-CoV-2 variant proportions are monitored by CDC, and available online. https://covid.cdc.gov/covid-data-tracker/#variant-proportions
^†Medical events with a discharge code consistent with COVID-19–like illness were included. COVID-19–like illness diagnoses were obtained from International Classification of Diseases, Tenth Revision (ICD-10) discharge codes. The specific codes used were: COVID-19 pneumonia: J12.81 and J12.82; influenza pneumonia: J09.X1, J10.0, J10.00, J10.01, J10.08, J11.0, J11.00, and J11.08; other viral pneumonia: J12*; bacterial and other pneumonia: J13, J14, J15*, J16*, J17, and J18*; influenza disease: J09*, J10.1, J10.2, J10.8*, J11.1, J11.2, and J11.8*; acute respiratory distress syndrome: J80; chronic obstructive pulmonary disease with acute exacerbation: J44.1; asthma acute exacerbation: J45.21, J45.22, J45.31, J45.32, J45.41, J45.42, J45.51, J45.52, J45.901, and J45.902; respiratory failure: J96.0*, J96.2*, and R09.2; other acute lower respiratory tract infections: J20*, J21*, J22, J40, J44.0, J41*, J42, J43*, J47*, J85, J85.0, J85.2, J85.3, J85.1, and J86*; acute and chronic sinusitis: J01* and J32*; acute upper respiratory tract infections: J00*, J02*, J03*, J04*, J05*, and J06*; acute respiratory illness signs and symptoms: R04.2, R05, R05.1, R05.2, R05.4, R05.8, R05.9, R06.00, R06.02, R06.03, R06.1, R06.2, R06.8, R06.81, R06.82, R06.89, R07.1, R09.0*, R09.01, R09.02, R09.1, R09.2, R09.3, and R09.8*; acute febrile illness signs and symptoms: R50*, R50.81, R50.9, and R68.83; acute nonrespiratory illness signs and symptoms: R19.7, R43*, R43.9, R51*, R51.9, M79.1*, M79.10, M79.18, R65*, R53.81, R53.83, R57.9, R41.82, R40*, R40.0, R40.1, R53.1, R11*, R11.0, R11.1, R11.10, R11.11, R11.15, R11.2, R21*, R10*, R10.0, R10.1*, R10.2, R10.3*, R10.8, R10.81, R10.81*, R10.84, and R10.9. All ICD-10 codes with * include all child codes under the specific parent code.
^§ https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html
^¶Sites from the CDC-funded VISION Network that contributed data for this analysis were 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 Center for Health Research (Oregon and Washington), and University of Colorado (Colorado).
**The encounter date was either the date of collection of a respiratory specimen associated with the most recent positive or negative SARS-CoV-2 test result before the admission or visit date, or the date of the medical visit if testing occurred only after the admission or visit.
^††Encounters were excluded if a first mRNA booster dose (third dose) was received before it was recommended by CDC on September 23, 2021; the interval between the second and third doses was <5 months, a second mRNA booster dose (fourth dose) was received before it was authorized for adults aged ≥50 years on March 29, 2022; the interval between the third and fourth doses was <4 months; a bivalent booster dose was received before recommended and generally available to the public (September 6, 2022); or the interval between the last monovalent vaccine dose (second, third, or fourth dose) and the bivalent booster dose was <2 months. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html
^§§Sixty–149 days was classified as 2–4 months, 150–239 days as 5–7 months, 240–329 days as 8–10 months, and ≥330 days as ≥11 months.
^¶¶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.

Table 1. Characteristics of emergency department and urgent care encounters among immunocompetent adults aged ≥18 years with COVID-19–like illness,* by mRNA COVID-19 vaccination status and SARS-CoV-2 test result — nine states, ^† September–November 2022
Characteristic	Overall, no. (column %)	SARS-CoV-2 test result status, no. (row %)		SMD^¶	mRNA COVID-19 vaccination status,^§ no. (row %)						SMD^¶
		Case-patients (positive)	Control patients (negative)		Unvaccinated	Received 2, 3, or 4 MV doses only, interval since last dose (mos)				Received BV booster dose ≥7 days earlier
		Case-patients (positive)	Control patients (negative)		Unvaccinated	2–4	5–7	8–10	≥11	Received BV booster dose ≥7 days earlier
All ED/UC encounters	78,303	9,009 (11.5)	69,294 (88.5)	—	24,142 (30.8)	5,668 (7.2)	6,891 (8.8)	14,220 (18.2)	23,477 (30.0)	3,905 (5.0)	—
Site
Baylor Scott & White Health	13,516 (17.3)	1,390 (10.3)	12,126 (89.7)	0.37	7,014 (51.9)	288 (2.1)	374 (2.8)	1,244 (9.2)	4,513 (33.4)	83 (0.6)	3.8
Columbia University	3,243 (4.1)	253 (7.8)	2,990 (92.2)		1,421 (43.8)	110 (3.4)	209 (6.4)	508 (15.7)	941 (29.0)	54 (1.7)
HealthPartners	14,214 (18.2)	1,637 (11.5)	12,577 (88.5)		3,523 (24.8)	1,236 (8.7)	1,296 (9.1)	3,006 (21.1)	3,683 (25.9)	1,470 (10.3)
Intermountain Healthcare	16,110 (20.6)	2,746 (17.0)	13,364 (83.0)		5,290 (32.8)	924 (5.7)	1,189 (7.4)	2,933 (18.2)	5,538 (34.4)	236 (1.5)
KPNC	19,484 (24.9)	1,326 (6.8)	18,158 (93.2)		2,431 (12.5)	2,350 (12.1)	3,052 (15.7)	4,787 (24.6)	5,339 (27.4)	1,525 (7.8)
KPCHR	5,840 (7.5)	736 (12.6)	5,104 (87.4)		1,405 (24.1)	617 (10.6)	602 (10.3)	1,190 (20.4)	1,611 (27.6)	415 (7.1)
University of Colorado	5,896 (7.5)	921 (15.6)	4,975 (84.4)		3,058 (51.9)	143 (2.4)	169 (2.9)	552 (9.4)	1,852 (31.4)	122 (2.1)
Age group, yrs
18–49	39,190 (50.0)	4,035 (10.3)	35,155 (89.7)	0.14	16,470 (42.0)	870 (2.2)	1,661 (4.2)	7,211 (18.4)	12,048 (30.7)	930 (2.4)	3.41
50–64	14,692 (18.8)	1,710 (11.6)	12,982 (88.4)		3,903 (26.6)	1,362 (9.3)	1,328 (9.0)	3,085 (21.0)	4,308 (29.3)	706 (4.8)
65–74	10,533 (13.5)	1,311 (12.4)	9,222 (87.6)		1,898 (18.0)	1,362 (12.9)	1,478 (14.0)	1,714 (16.3)	3,100 (29.4)	981 (9.3)
75–84	8,844 (11.3)	1,275 (14.4)	7,569 (85.6)		1,202 (13.6)	1,277 (14.4)	1,536 (17.4)	1,424 (16.1)	2,532 (28.6)	873 (9.9)
≥85	5,044 (6.4)	678 (13.4)	4,366 (86.6)		669 (13.3)	797 (15.8)	888 (17.6)	786 (15.6)	1,489 (29.5)	415 (8.2)
Sex
Female	48,342 (61.7)	5,343 (11.1)	42,999 (88.9)	0.06	14,554 (30.1)	3,431 (7.1)	4,182 (8.7)	9,033 (18.7)	14,819 (30.7)	2,323 (4.8)	0.15
Male	29,961 (38.3)	3,666 (12.2)	26,295 (87.8)	0.06	9,588 (32.0)	2,237 (7.5)	2,709 (9.0)	5,187 (17.3)	8,658 (28.9)	1,582 (5.3)	0.15
Race and ethnicity
Black or African American, NH	9,261 (11.8)	823 (8.9)	8,438 (91.1)	0.17	3,837 (41.4)	516 (5.6)	694 (7.5)	1,421 (15.3)	2,553 (27.6)	240 (2.6)	1.17
Hispanic or Latino	14,703 (18.8)	1,345 (9.1)	13,358 (90.9)		5,119 (34.8)	850 (5.8)	1,096 (7.5)	2,767 (18.8)	4,492 (30.6)	379 (2.6)
Other, NH**	7,417 (9.5)	841 (11.3)	6,576 (88.7)		1,746 (23.5)	659 (8.9)	785 (10.6)	1,743 (23.5)	2,031 (27.4)	453 (6.1)
Unknown	1,255 (1.6)	154 (12.3)	1,101 (87.7)		547 (43.6)	46 (3.7)	73 (5.8)	240 (19.1)	321 (25.6)	28 (2.2)
White, NH	45,667 (58.3)	5,846 (12.8)	39,821 (87.2)		12,893 (28.2)	3,597 (7.9)	4,243 (9.3)	8,049 (17.6)	14,080 (30.8)	2,805 (6.1)
Documented previous SARS-CoV-2 infection^††
Yes	15,750 (20.1)	1,247 (7.9)	14,503 (92.1)	0.19	4,682 (29.7)	1,036 (6.6)	1,351 (8.6)	2,916 (18.5)	5,136 (32.6)	629 (4.0)	0.15
No	62,553 (79.9)	7,762 (12.4)	54,791 (87.6)	0.19	19,460 (31.1)	4,632 (7.4)	5,540 (8.9)	11,304 (18.1)	18,341 (29.3)	3,276 (5.2)	0.15
SARS-CoV-2 status
Positive test result (case-patient)	9,009 (11.5)	9,009 (100.0)	0 (—)	—	3,040 (33.7)	537 (6.0)	725 (8.0)	1,677 (18.6)	2,783 (30.9)	247 (2.7)	0.24
Negative test result (control patient)	69,294 (88.5)	0 (—)	69,294 (100.0)	—	21,102 (30.5)	5,131 (7.4)	6,166 (8.9)	12,543 (18.1)	20,694 (29.9)	3,658 (5.3)	0.24
No. of MV mRNA vaccine doses received
None	24,142 (30.8)	3,040 (12.6)	21,102 (87.4)	0.08	24,142 (100.0)	0 (—)	0 (—)	0 (—)	0 (—)	0 (—)	—
2	19,028 (24.3)	2,158 (11.3)	16,870 (88.7)		0 (—)	277 (1.5)	606 (3.2)	1,391 (7.3)	16,538 (86.9)	216 (1.1)
3	24,721 (31.6)	2,752 (11.1)	21,969 (88.9)		0 (—)	1,006 (4.1)	2,268 (9.2)	12,829 (51.9)	6,939 (28.1)	1,679 (6.8)
4	10,412 (13.3)	1,059 (10.2)	9,353 (89.8)		0 (—)	4,385 (42.1)	4,017 (38.6)	0 (—)	0 (—)	2,010 (19.3)
Most recent dose product manufacturer
Pfizer-BioNTech	34,596 (44.2)	3,821 (11.0)	30,775 (89.0)	0.07	0 (—)	3,610 (10.4)	4,451 (12.9)	8,441 (24.4)	15,290 (44.2)	2,804 (8.1)	—
Moderna	19,565 (25.0)	2,148 (11.0)	17,417 (89.0)		0 (—)	2,058 (10.5)	2,440 (12.5)	5,779 (29.5)	8,187 (41.8)	1,101 (5.6)
None	24,142 (30.8)	3,040 (12.6)	21,102 (87.4)		24,142 (100.0)	0 (—)	0 (—)	0 (—)	0 (—)	0 (—)
Any chronic condition
Yes	23,892 (30.5)	2,311 (9.7)	21,581 (90.3)	0.12	6,782 (28.4)	2,114 (8.8)	2,466 (10.3)	4,056 (17.0)	7,313 (30.6)	1,161 (4.9)	0.46
No	54,411 (69.5)	6,698 (12.3)	47,713 (87.7)	0.12	17,360 (31.9)	3,554 (6.5)	4,425 (8.1)	10,164 (18.7)	16,164 (29.7)	2,744 (5.0)	0.46
≥1 chronic respiratory condition
Yes	12,316 (15.7)	1,060 (8.6)	11,256 (91.4)	0.13	3,606 (29.3)	1,014 (8.2)	1,203 (9.8)	2,067 (16.8)	3,863 (31.4)	563 (4.6)	0.2
No	65,987 (84.3)	7,949 (12.0)	58,038 (88.0)	0.13	20,536 (31.1)	4,654 (7.1)	5,688 (8.6)	12,153 (18.4)	19,614 (29.7)	3,342 (5.1)	0.2
≥1 chronic non-respiratory condition
Yes	17,268 (22.1)	1,836 (10.6)	15,432 (89.4)	0.05	4,869 (28.2)	1,600 (9.3)	1,794 (10.4)	2,853 (16.5)	5,389 (31.2)	763 (4.4)	0.4
No	61,035 (77.9)	7,173 (11.8)	53,862 (88.2)	0.05	19,273 (31.6)	4,068 (6.7)	5,097 (8.4)	11,367 (18.6)	18,088 (29.6)	3,142 (5.1)	0.4

Abbreviations: BV = bivalent; ED/UC = emergency department/urgent care; KPNC = Kaiser Permanente Northern California; KPCHR = Kaiser Permanente Center for Health Research; MV = monovalent; NH = non-Hispanic; SMD = standardized mean or proportion difference.
*ED/UC encounters with a discharge code consistent with COVID-19–like illness were included. COVID-19–like illness diagnoses included acute respiratory illness, respiratory signs or symptoms, or febrile signs or symptoms using diagnosis codes from the International Classification of Diseases, Tenth Revision. 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 the encounter date were included.
^†California (Sep 13–Nov 18, 2022), Colorado (Sep 13–Nov 7, 2022), Minnesota and Wisconsin (Sep 13–Nov 18, 2022), New York (Sep 13–Nov 18, 2022), Oregon and Washington (Sep 13–Nov 14, 2022), Texas (Sep 13–Nov 13, 2022), and Utah (Sep 13–Nov 18, 2022).
^§Vaccination was defined as having received the last monovalent or bivalent dose within the specified range of months or days before the ED/UC encounter date, which was the date of respiratory specimen collection associated with the most recent positive or negative SARS-CoV-2 test result before the encounter start date or the encounter start date if testing only occurred after the admission.
^¶An absolute SMD >0.20 indicates a nonnegligible difference in variable distributions between ED/UC encounters for vaccinated versus unvaccinated patients or for patients with positive SARS-CoV-2 test results versus patients with negative SARS-CoV-2 test 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. Specifically, it was calculated as the average of the absolute value of the SMDs for 1) vaccinated with only monovalent doses, ≥11 months earlier versus unvaccinated, 2) vaccinated with only monovalent doses, 8–10 months earlier versus unvaccinated, 3) vaccinated with only monovalent doses 5–7 months earlier versus unvaccinated, 4) vaccinated with only monovalent doses 2–4 months earlier versus unvaccinated, and 5) vaccinated with bivalent booster ≥7 days earlier versus unvaccinated.
**Other race includes Asian, Hawaiian or other Pacific Islander, American Indian or Alaska Native, other not listed, and multiple races. Because of small numbers, these categories were combined.
^††Previous SARS-CoV-2 infection was defined as having a positive SARS-CoV-2 test result (molecular or antigen) documented in the electronic health record ≥15 days before the hospital admission date. This does not capture previous infections in which testing was not performed or testing was performed but not available in the electronic health record (e.g., at-home testing).

Table 2. Bivalent booster COVID-19 vaccine effectiveness* against laboratory confirmed COVID-19–associated emergency department and urgent care encounters and hospitalizations among immunocompetent adults aged 18 years — nine states, ^† September–November 2022
mRNA dosage pattern	Total	Negative SARS-CoV-2 test result, no. (%)	Positive SARS-CoV-2 test result, no. (%)	Median interval since last dose, days (IQR)	VE % (95% CI)
ED/UC encounters
Relative VE
Only MV doses, last dose 2–4 mos earlier	5,668	5,131 (91)	537 (9)	115 (91–134)	Ref
BV booster dose, ≥7 days earlier	3,905	3,658 (94)	247 (6)	25 (16–37)	31 (19–41)
Only MV doses, last dose 5–7 mos earlier	6,891	6,166 (89)	725 (11)	184 (166–209)	Ref
BV booster dose, ≥7 days earlier	3,905	3,658 (94)	247 (6)	25 (16–37)	42 (32–50)
Only MV doses, last dose 8–10 mos earlier	14,220	12,543 (88)	1,677 (12)	294 (273–312)	Ref
BV booster dose, ≥7 days earlier	3,905	3,658 (94)	247 (6)	25 (16–37)	53 (46–60)
Only MV doses, last dose ≥11 mos earlier	23,477	20,694 (88)	2,783 (12)	459 (365–542)	Ref
BV booster dose, ≥7 days earlier	3,905	3,658 (94)	247 (6)	25 (16–37)	50 (43–57)
Absolute VE
Unvaccinated	24,142	21,102 (87)	3,040 (13)	NA	Ref
BV booster dose, ≥7 days earlier	3,905	3,658 (94)	247 (6)	25 (16–37)	56 (49–62)
Hospitalizations
Relative VE
Only MV doses, last dose 2–4 mos earlier	— ^§	—	—	—	—
BV booster dose, ≥7 days earlier	—	—	—	—	—
Only MV doses, last dose 5–7 mos earlier	1,819	1,652 (91)	167 (9)	178 (164–201)	Ref
BV booster dose, ≥7 days earlier	783	734 (94)	49 (6)	23 (14–34)	38 (13–56)
Only MV doses, last dose 8–10 mos earlier	2,655	2,422 (91)	233 (9)	294 (273–313)	Ref
BV booster dose, ≥7 days earlier	783	734 (94)	49 (6)	23 (14–34)	42 (19–58)
Only MV doses, last dose ≥11 mos earlier	4,595	4,147 (90)	448 (10)	472 (362–556)	Ref
BV booster dose, ≥7 days earlier	783	734 (94)	49 (6)	23 (14–34)	45 (25–60)
Absolute VE
Unvaccinated	4,092	3,658 (89)	434 (11)	NA	Ref
BV booster dose, ≥7 days earlier	783	734 (94)	49 (6)	23 (14–34)	57 (41–69)

Abbreviations: BV = bivalent; ED/UC = emergency department/urgent care; MV = monovalent; NA = not applicable; Ref = referent group; VE = vaccine effectiveness.
*VE was calculated as ([1 − odds ratio] x 100%), estimated using a test-negative case-control design, adjusted for age, sex, race and ethnicity, geographic region, calendar time (days since January 1, 2021), and local virus circulation (percentage of positive SARS-CoV-2 test results from testing within the counties surrounding the facility on the date of the encounter).
^†California (Sep 13, 2022–Nov 18, 2022), Colorado (Sep 13, 2022–Nov 7, 2022), Minnesota and Wisconsin (Sep 13, 2022–Nov 18, 2022), New York (Sep 13, 2022–Nov 18, 2022), Oregon and Washington (Sep 13, 2022–Nov 14, 2022), Texas (Sep 13, 2022–Nov 13, 2022), and Utah (Sep 13, 2022–Nov 18, 2022).
^§Dashes indicate that estimated VE had a CI width ≥50%. Estimates with CI widths ≥50% are not shown here because of imprecision. The associated data are also omitted.

Table 3. Characteristics of hospitalizations among immunocompetent adults aged ≥18 years with COVID-19–like illness,* by mRNA COVID-19 vaccination status and SARS-CoV-2 test result — nine states, ^† September–November 2022
Characteristic	Overall, no. (col %)	SARS-CoV-2 test result status, no. (row %)		SMD^¶	mRNA COVID-19 vaccination status.^§ no. (row %)						SMD^¶
		Case-patients (positive)	Control patients (negative)		Unvaccinated	Received 2, 3, or 4 MV doses only, interval since last dose (mos)				Received BV booster dose ≥7 days earlier
		Case-patients (positive)	Control patients (negative)		Unvaccinated	2–4	5–7	8–10	≥11	Received BV booster dose ≥7 days earlier
All hospitalizations	15,527 (100.0)	1,453 (9.4)	14,074 (90.6)	—	4,092 (26.4)	1,583 (10.2)	1,819 (11.7)	2,655 (17.1)	4,595(29.6)	783(5.0)	—
Site
Baylor Scott & White Health	3,782 (24.4)	331 (8.8)	3,451 (91.2)	0.19	1,545 (40.9)	117 (3.1)	136 (3.6)	433 (11.4)	1,516(40.1)	35(0.9)	3.91
Columbia University	1,125 (7.2)	128 (11.4)	997 (88.6)		432 (38.4)	69 (6.1)	109 (9.7)	200 (17.8)	292(26.0)	23(2.0)
HealthPartners	1,504 (9.7)	165 (11.0)	1,339 (89.0)		311 (20.7)	206 (13.7)	183 (12.2)	267 (17.8)	349(23.2)	188(12.5)
Intermountain Healthcare	1,693 (10.9)	219 (12.9)	1,474 (87.1)		506 (29.9)	167 (9.9)	167 (9.9)	285 (16.8)	536(31.7)	32(1.9)
KPNC	5,489 (35.4)	438 (8.0)	5,051 (92.0)		582 (10.6)	838 (15.3)	1,076 (19.6)	1,193 (21.7)	1,384(25.2)	416(7.6)
KPNW	1,028 (6.6)	82 (8.0)	946 (92.0)		305 (29.7)	135 (13.1)	104 (10.1)	181 (17.6)	238(23.2)	65(6.3)
University of Colorado	906 (5.8)	90 (9.9)	816 (90.1)		411 (45.4)	51 (5.6)	44 (4.9)	96 (10.6)	280(30.9)	24(2.6)
Age group, yrs
18–49	2,928 (18.9)	160 (5.5)	2,768 (94.5)	0.34	1,315 (44.9)	72 (2.5)	138 (4.7)	506 (17.3)	822(28.1)	75(2.6)	2.74
50–64	2,988 (19.2)	212 (7.1)	2,776 (92.9)		1,006 (33.7)	229 (7.7)	284 (9.5)	574 (19.2)	812(27.2)	83(2.8)
65–74	3,244 (20.9)	300 (9.2)	2,944 (90.8)		717 (22.1)	390 (12.0)	404 (12.5)	528 (16.3)	1,016(31.3)	189(5.8)
75–84	3,626 (23.4)	410 (11.3)	3,216 (88.7)		599 (16.5)	482 (13.3)	565 (15.6)	639 (17.6)	1,085(29.9)	256(7.1)
≥85	2,741 (17.7)	371 (13.5)	2,370 (86.5)		455 (16.6)	410 (15.0)	428 (15.6)	408 (14.9)	860(31.4)	180(6.6)
Sex
Female	8,405 (54.1)	748 (8.9)	7,657 (91.1)	0.06	2,147 (25.5)	873 (10.4)	990 (11.8)	1,447 (17.2)	2,525(30.0)	423(5.0)	0.19
Male	7,122 (45.9)	705 (9.9)	6,417 (90.1)	0.06	1,945 (27.3)	710 (10.0)	829 (11.6)	1,208 (17.0)	2,070(29.1)	360(5.1)	0.19
Race and ethnicity
Black or African American, NH	1,788 (11.5)	116 (6.5)	1,672 (93.5)	0.2	634 (35.5)	138 (7.7)	171 (9.6)	248 (13.9)	546(30.5)	51(2.9)	1.18
Hispanic or Latino	2,395 (15.4)	178 (7.4)	2,217 (92.6)		696 (29.1)	212 (8.9)	248 (10.4)	490 (20.5)	683(28.5)	66(2.8)
Other,** NH	1,502 (9.7)	117 (7.8)	1,385 (92.2)		279 (18.6)	197 (13.1)	240 (16.0)	303 (20.2)	381(25.4)	102(6.8)
Unknown	239 (1.5)	21 (8.8)	218 (91.2)		111 (46.4)	13 (5.4)	24 (10.0)	29 (12.1)	58(24.3)	4(1.7)
White, NH	9,603 (61.8)	1,021 (10.6)	8,582 (89.4)		2,372 (24.7)	1,023 (10.7)	1,136 (11.8)	1,585 (16.5)	2,927(30.5)	560(5.8)
Documented prior SARS-CoV-2 infection^††
Yes	2,450 (15.8)	141 (5.8)	2,309 (94.2)	0.2	641 (26.2)	217 (8.9)	253 (10.3)	415 (16.9)	828(33.8)	96(3.9)	0.19
No	13,077 (84.2)	1,312 (10.0)	11,765 (90.0)	0.2	3,451 (26.4)	1,366 (10.4)	1,566 (12.0)	2,240 (17.1)	3,767(28.8)	687(5.3)	0.19
SARS-CoV-2 status
Positive test result (case-patient)	1,453 (9.4)	1,453 (100.0)	0 (—)	—	434 (29.9)	122 (8.4)	167 (11.5)	233 (16.0)	448(30.8)	49(3.4)	0.27
Negative test result (control patient)	14,074 (90.6)	0 (—)	14,074 (100.0)	—	3,658 (26.0)	1,461 (10.4)	1,652 (11.7)	2,422 (17.2)	4,147(29.5)	734(5.2)	0.27
No. of monovalent mRNA vaccine doses received
None	4,092 (26.4)	434 (10.6)	3,658 (89.4)	0.1	4,092 (100.0)	0 (—)	0 (—)	0 (—)	0(—)	0(—)	—
2	3,404 (21.9)	322 (9.5)	3,082 (90.5)		0 (—)	48 (1.4)	82 (2.4)	196 (5.8)	3,029(89.0)	49(1.4)
3	5,018 (32.3)	443 (8.8)	4,575 (91.2)		0 (—)	216 (4.3)	525 (10.5)	2,459 (49.0)	1,566(31.2)	252(5.0)
4	3,013 (19.4)	254 (8.4)	2,759 (91.6)		0 (—)	1,319 (43.8)	1,212 (40.2)	0 (—)	0(—)	482(16.0)
Most recent dose product manufacturer
Pfizer-BioNTech	7,085 (45.6)	620 (8.8)	6,465 (91.2)	0.09	0 (—)	1,006 (14.2)	1,132 (16.0)	1,450 (20.5)	2,914(41.1)	583(8.2)	—
Moderna	4,350 (28.0)	399 (9.2)	3,951 (90.8)		0 (—)	577 (13.3)	687 (15.8)	1,205 (27.7)	1,681(38.6)	200(4.6)
None	4,092 (26.4)	434 (10.6)	3,658 (89.4)		4,092 (100.0)	0 (—)	0 (—)	0 (—)	0(—)	0(—)
Any chronic condition
Yes	14,671 (94.5)	1,411 (9.6)	13,260 (90.4)	0.14	3,748 (25.5)	1,558 (10.6)	1,782 (12.1)	2,472 (16.8)	4,363(29.7)	748(5.1)	0.83
No	856 (5.5)	42 (4.9)	814 (95.1)	0.14	344 (40.2)	25 (2.9)	37 (4.3)	183 (21.4)	232(27.1)	35(4.1)	0.83
≥1 chronic respiratory condition
Yes	9,261 (59.6)	921 (9.9)	8,340 (90.1)	0.08	2,324 (25.1)	1,049 (11.3)	1,174 (12.7)	1,540 (16.6)	2,700(29.2)	474(5.1)	0.44
No	6,266 (40.4)	532 (8.5)	5,734 (91.5)	0.08	1,768 (28.2)	534 (8.5)	645 (10.3)	1,115 (17.8)	1,895(30.2)	309(4.9)	0.44
≥1 chronic non-respiratory condition
Yes	14,141 (91.1)	1,370 (9.7)	12,771 (90.3)	0.14	3,530 (25.0)	1,535 (10.9)	1,745 (12.3)	2,402 (17.0)	4,197(29.7)	732(5.2)	1.07
No	1,386 (8.9)	83 (6.0)	1,303 (94.0)	0.14	562 (40.5)	48 (3.5)	74 (5.3)	253 (18.3)	398(28.7)	51(3.7)	1.07
ICU admission
Yes	2,568 (16.5)	182 (7.1)	2,386 (92.9)	0.13	751 (29.2)	232 (9.0)	300 (11.7)	449 (17.5)	729(28.4)	107(4.2)	0.29
No	12,959 (83.5)	1,271 (9.8)	11,688 (90.2)	0.13	3,341 (25.8)	1,351 (10.4)	1,519 (11.7)	2,206 (17.0)	3,866(29.8)	676(5.2)	0.29
Receipt of invasive mechanical ventilation
Yes	1,580 (10.2)	97 (6.1)	1,483 (93.9)	0.14	567 (35.9)	112 (7.1)	128 (8.1)	227 (14.4)	497(31.5)	49(3.1)	0.75
No	13,947 (89.8)	1,356 (9.7)	12,591 (90.3)	0.14	3,525 (25.3)	1,471 (10.5)	1,691 (12.1)	2,428 (17.4)	4,098(29.4)	734(5.3)	0.75
In-hospital death^§§
Yes	466 (3.0)	51 (10.9)	415 (89.1)	0.03	129 (27.7)	61 (13.1)	57 (12.2)	58 (12.4)	139(29.8)	22(4.7)	0.11
No	15,061 (97.0)	1,402 (9.3)	13,659 (90.7)	0.03	3,963 (26.3)	1,522 (10.1)	1,762 (11.7)	2,597 (17.2)	4,456(29.6)	761(5.1)	0.11

Abbreviations: BV = bivalent; ICU = intensive care unit; KPNC = Kaiser Permanente Northern California; KPCHR = Kaiser Permanente Center for Health Research; MV = monovalent; NH = non-Hispanic; 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, respiratory signs or symptoms or febrile signs or symptoms using diagnosis codes from the International Classification of Diseases, Tenth Revision. 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 the encounter date were included.
^†California (Sep 13–Nov 18, 2022), Colorado (Sep 13–Nov 7, 2022), Minnesota and Wisconsin (Sep 13–Nov 18, 2022), New York (Sep 13–Nov 18, 2022), Oregon and Washington (Sep 13–Nov 14, 2022), Texas (Sep 13–Nov 13, 2022), and Utah (Sep 13–Nov 18, 2022).
^§Vaccination was defined as having received the last monovalent or bivalent dose within the specified range of months/days before the hospitalization encounter date, which was the date of respiratory specimen collection associated with the most recent positive or negative SARS-CoV-2 test result before the admission date 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 a positive SARS-Cov-2 test result versus patients with a negative SARS-CoV-2 test result. 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. Specifically, it was calculated as the average of the absolute value of the SMDs for 1) vaccinated with only monovalent doses, ≥11 months earlier versus unvaccinated, 2) vaccinated with only monovalent doses, 8–10 months earlier versus unvaccinated, 3) vaccinated with only monovalent doses 5–7 months earlier versus unvaccinated, 4) vaccinated with only monovalent doses 2–4 months earlier versus unvaccinated, and 5) vaccinated with bivalent booster ≥7 days earlier versus unvaccinated.
**Other race includes Asian, Hawaiian or other Pacific Islander, American Indian or Alaska Native, other not listed, and multiple races. Because of small numbers, these categories were combined.
^††Previous SARS-CoV-2 infection was defined as having a positive SARS-CoV-2 test result (molecular or antigen) documented in the electronic health record ≥15 days before the hospital admission date. This does not capture infections in which testing was not performed or testing was performed but not available in the electronic health record, e.g., at-home testing.
^§§In-hospital death was identified at each individual site and was defined as a death while hospitalized and ≤28 days after admission.

Authors and Disclosures

Mark W. Tenforde, MD, PhD¹, Zachary A. Weber, PhD², Karthik Natarajan, PhD^3,4, Nicola P. Klein, MD, PhD⁵, Anupam B. Kharbanda, MD⁶, Edward Stenehjem, MD⁷, Peter J. Embi, MD^8,9, Sarah E. Reese, PhD², Allison L. Naleway, PhD¹⁰, Shaun J. Grannis, MD^9,11, Malini B. DeSilva, MD¹², Toan C. Ong, PhD¹³, Manjusha Gaglani, MBBS^14,15, Jungmi Han³, Monica Dickerson¹, Bruce Fireman, MA⁵, Kristin Dascomb, MD, PhD⁷, Stephanie A. Irving, MHS¹⁰, Gabriela Vazquez-Benitez, PhD¹², Suchitra Rao, MBBS¹³, Deepika Konatham¹⁶, Palak Patel, MBBS¹, Kristin E. Schrader, MA², Ned Lewis, MPH⁵, Nancy Grisel, MPP⁷, Charlene McEvoy, MD¹², Kempapura Murthy, MBBS¹⁶, Eric P. Griggs, MPH¹, Elizabeth A. K. Rowley, DrPH², Ousseny Zerbo, PhD⁵, Julie Arndorfer, MPH⁷, Margaret M. Dunne, MSc², Kristin Goddard, MPH⁵, Caitlin Ray, MPH¹, Yan Zhuang, PhD², Julius Timbol, MS⁵, Morgan Najdowski, MPH¹⁷, Duck-Hye Yang, PhD², John Hansen, MPH⁵, Sarah W. Ball, ScD² and Ruth Link-Gelles, PhD¹⁷

¹Influenza Division, National Center for Immunization and Respiratory Diseases, CDC; ²Westat Inc., Rockville, Maryland; ³Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York; ⁴New York Presbyterian Hospital, New York, New York; ⁵Kaiser Permanente Vaccine Study Center, Kaiser Permanente Northern California Division of Research, Oakland, California; ⁶Children's Minnesota, Minneapolis, Minnesota; ⁷Division of Infectious Diseases and Clinical Epidemiology, Intermountain Healthcare, Salt Lake City, Utah; ⁸Vanderbilt University Medical Center, Nashville, Tennessee; ⁹Center for Biomedical Informatics, Regenstrief Institute, Indianapolis, Indiana; ¹⁰Kaiser Permanente Center for Health Research, Portland, Oregon; ¹¹School of Medicine, Indiana University, Indianapolis, Indiana; ¹²HealthPartners Institute, Minneapolis, Minnesota; ¹³School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; ¹⁴Department of Pediatrics, Section of Pediatric Infectious Diseases, Baylor Scott & White Health, Temple, Texas; ¹⁵Department of Medical Education, Texas A&M University College of Medicine, Temple, Texas; ¹⁶Department of Research Analytics and Development, Baylor Scott & White Research Institute, Baylor Scott & White Health, Temple Texas; ¹⁷National Center for Immunization and Respiratory Diseases, CDC.

Corresponding author
Mark W. Tenforde, media@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 received grants from Pfizer, Merck, GlaxoSmithKline, and Sanofi Pasteur. Allison L. Naleway received grants from Pfizer and Vir Biotechnology. Suchitra Rao received grants from GlaxoSmithKline. Charlene McEvoy received grants from AztraZeneca. No other potential conflicts of interest were disclosed.