Estimates of Bivalent mRNA Vaccine Durability in Preventing COVID-19–Associated Hospitalization and Critical Illness Among Adults with and Without Immunocompromising Conditions — VISION Network, September 2022–April 2023

Persons with moderate-to-severe immunocompromising conditions might have reduced protection after COVID-19 vaccination, compared with persons without immunocompromising conditions ( 1 – 3 ). On August 13, 2021, the Advisory Committee on Immunization Practices (ACIP) recommended that adults with immunocompromising conditions receive an expanded primary series of 3 doses of an mRNA COVID-19 vaccine. ACIP followed with recommendations on September 23, 2021, for a fourth (booster) dose and on September 1, 2022, for a new bivalent mRNA COVID-19 vaccine booster dose, containing components of the BA.4 and BA.5 sublineages of the Omicron (B.1.1.529) variant ( 4 ). Data on vaccine effectiveness (VE) of monovalent COVID-19 vaccines among persons with immunocompromising conditions since the emergence of the Omicron variant in December 2021 are limited. In the multistate VISION Network, § monovalent 2-, 3-, and 4-dose mRNA VE against COVID-19–related hospitalization were estimated among adults with immunocompromising conditions ¶ hospitalized with COVID-19–like illness,** using a test-negative design comparing odds of previous vaccination among persons with a positive or negative molecular test result (case-patients and control-patients) for SARS-CoV-2 (the virus that causes COVID-19). During December 16, 2021–August 20, 2022, among SARS-CoV-2 test-positive case-patients, 1,815 (36.3%), 1,387 (27.7%), 1,552 (31.0%), and 251 (5.0%) received 0, 2, 3, and 4 mRNA COVID-19 vaccine doses, respectively. Among test-negative control-patients during this period, 6,928 (23.7%), 7,411 (25.4%), 12,734 (43.6%), and 2,142 (7.3%) received these respective doses. Overall, VE against COVID-19–related hospitalization among adults with immunocompromising conditions hospitalized for COVID-like illness during Omicron predominance was 36% ≥14 days after dose 2, 69% 7–89 days after dose 3, and 44% ≥90 days after dose 3. Restricting the analysis to later periods when Omicron sublineages BA.2/BA.2.12.1 and BA.4/BA.5 were predominant and 3-dose recipients were eligible to receive a fourth dose, VE was 32% ≥90 days after dose 3 and 43% ≥7 days after dose 4. Protection offered by vaccination among persons with immunocompromising conditions during Omicron predominance was moderate even after a 3-dose monovalent primary series or booster dose. Given the incomplete protection against hospitalization afforded by monovalent COVID-19 vaccines, persons with immunocompromising conditions might benefit from updated bivalent vaccine booster doses that target recently circulating Omicron sublineages, in line with ACIP recommendations. Further, additional protective recommendations for persons with immunocompromising conditions, including the use of prophylactic antibody therapy, early access to and use of antivirals, and enhanced nonpharmaceutical interventions such as well-fitting masks or respirators, should also be considered. VISION Network methods to assess VE have been previously described ( 3 , 5 ). For this analysis, among adults aged ≥18 years, eligible medical encounters were defined as hospitalizations of patients with one or more immunocompromising conditions and a COVID-19–like illness diagnosis who underwent SARS-CoV-2 molecular testing ≤14 days before to 4 doses, dose 2 0.20 indicates a nonnegligible difference in variable distributions between hospitalizations 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 2 doses ≥14 days earlier versus unvaccinated, 2) vaccinated with 3 doses 7–89 days earlier versus unvaccinated, 3) vaccinated with 3 doses ≥90 days earlier versus unvaccinated, and 4) vaccinated with 4 doses ≥7 days earlier versus unvaccinated. ** Partners contributing data on hospitalizations during dates of estimated ≥50% Omicron BA.1 predominance were in California (December 21, 2021–March 20, 2022), Colorado (December 19, 2021–March 20, 2022), Indiana (December 26, 2021–March 20, 2022), Minnesota and Wisconsin (December 25, 2021–March 21, 2022), New York (December 18, 2021–March 16, 2022), Oregon and Washington (December 24, 2021–March 23, 2022), Texas (Baylor Scott & White Health: December 16, 2021–March 18, 2022; PHIX: December 29, 2021–March 29, 2022), and Utah (December 24, 2021–March 18, 2022). †† Partners contributing data on hospitalizations during dates of estimated ≥50% Omicron BA.2/BA.2.12.1 predominance were in California (March 21–June 24, 2022), Colorado (March 21–June 18, 2022), Indiana (March 21–June 18, 2022), Minnesota and Wisconsin (March 22–June 21, 2022), New York (March 17–June 28, 2022), Oregon and Washington (March 24–June 28, 2022), Texas (Baylor Scott & White Health: March 19–June 21, 2022; PHIX: March 30–June 21, 2022), and Utah (March 19–June 22, 2022). §§ Partners contributing data on hospitalizations during dates of estimated ≥50% Omicron BA.4/BA.5 predominance were in California (June 25–August 20, 2022), Colorado (June 19–August 20, 2022), Indiana (June 19–August 20, 2022), Minnesota and Wisconsin (June 22–August 20, 2022), New York (June 29–August 20, 2022), Oregon and Washington (June 29–August 20, 2022), Texas (Baylor Scott & White Health: June 22–August 20, 2022; PHIX: June 22–August 20, 2022), and Utah (June 23–August 20, 2022). ¶¶ Other race includes American Indian or Alaska Native, Asian, Native Hawaiian or other Pacific islander, other not listed, and multiple races. These categories were combined because of small numbers. *** 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. ††† Chronic respiratory condition was defined by corresponding discharge codes for asthma, chronic obstructive pulmonary disease, or other lung disease using ICD-9 and ICD-10 diagnosis codes. §§§ In-hospital death was defined as death while hospitalized within 28 days after admission. TABLE 2 Vaccine effectiveness* of 2-, 3-, and 4-dose mRNA COVID-19 vaccination against COVID-19–associated † hospitalizations among immunocompromised § adults aged ≥18 years, by Omicron (and Omicron sublineage) predominance period ¶ and mRNA COVID-19 vaccination status ** — VISION Network, 10 states, December 2021–August 2022 Omicron predominance period/vaccination status Total SARS-CoV-2 positive test result, no. (%) Median interval since last dose, days (IQR) VE % (95% CI) Omicron predominance period Unvaccinated (Ref) 8,743 1,815 (20.8) NA NA 2 doses (≥14 days earlier) 8,798 1,387 (15.8) 316 (250–387) 36 (30–41) 3 doses (≥7 days earlier) 14,286 1,552 (10.9) 147 (96–202) 57 (53–61) 3 doses (7–89 days earlier) 3,198 335 (10.5) 59 (38–76) 69 (63–74) 3 doses (≥90 days earlier) 11,088 1,217 (11.0) 169 (131–218) 44 (37–49) BA.1 sublineage predominance†† Unvaccinated (Ref) 4,422 1,373 (31.1) NA NA 2 doses (≥14 days earlier) 4,486 1,008 (22.5) 283 (222–321) 40 (34–46) 3 doses (≥7 days earlier) 6,141 809 (13.2) 99 (65–133) 67 (63–71) 3 doses (7–89 days earlier) 2,638 302 (11.4) 59 (38–75) 75 (71–79) 3 doses (≥90 days earlier) 3,503 507 (14.5) 128 (109–152) 49 (41–7) BA.2/BA.2.12.1 sublineage predominance§§ Unvaccinated (Ref) 2,807 190 (6.8) NA NA 2 doses (≥14 days earlier) 2,892 204 (7.1) 371 (286–414) 7 (–16–25) 3 doses (≥7 days earlier) 5,648 372 (6.6) 172 (134–210) 32 (16–46) 3 doses (7–89 days earlier) —¶¶ — — — 3 doses (≥90 days earlier) 5,172 351 (6.8) 179 (145–214) 32 (15–45) BA.4/BA.5 sublineage predominance*** Unvaccinated (Ref) 1,514 252 (16.6) NA NA 2 doses (≥14 days earlier) 1,420 175 (12.3) 445 (336–488) 38 (23–50) 3 doses (≥7 days earlier) 2,497 371 (14.9) 239 (199–276) 35 (21–47) 3 doses (7–89 days earlier) — — — — 3 doses (≥90 days earlier) 2,413 359 (14.9) 241 (204–278) 36 (22–47) BA.2/BA.2.12.1/BA.4/BA.5 sublineage predominance††† Unvaccinated (Ref) 4,321 442 (10.2) NA NA 2 doses (≥14 days earlier) 4,312 379 (8.8) 386 (305–441) 22 (10–33) 3 doses (≥7 days earlier) 8,145 743 (9.1) 190 (147–234) 33 (22–42) 3 doses (7–89 days earlier) — — — — 3 doses (≥90 days earlier) 7,585 710 (9.4) 196 (156–238) 32 (21–42) 4 doses (≥7 days earlier) 2,393 251 (10.5) 61 (34–91) 43 (27–56) Abbreviations: ICD-9 = International Classification of Diseases, Ninth Revision; ICD-10 = International Classification of Diseases, Tenth Revision; NA = not applicable; PHIX = Paso del Norte Health Information Exchange; Ref = referent group; 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 VE estimate). Generalized boosted regression trees were used to estimate the propensity to be vaccinated based on sociodemographic characteristics, underlying medical conditions, and facility characteristics. † Hospitalizations with a discharge code consistent with COVID-19–like illness and molecular testing for SARS-CoV-2 ≤14 days before to <72 hours after the encounter date were included. COVID-19–like illness diagnoses included acute respiratory illness (e.g., respiratory failure or pneumonia) or related signs or symptoms (cough, fever, dyspnea, vomiting, or diarrhea) using ICD-9 and ICD-10 diagnosis codes. § Immunocompromised status was defined as the presence of at least one discharge diagnosis using ICD-9 and ICD-10 diagnosis codes for solid malignancy (ICD-10 codes: C00–C80, C7A, C7B, D3A, Z51.0, and Z51.1), hematologic malignancy (ICD-10 codes: C81–C86, C88, C90–C96, D46, D61.0, D70.0, D61.2, D61.9, and D71), rheumatologic or inflammatory disorder (ICD-10 codes: D86, E85 [except E85.0], G35, J67.9, L40.54, L40.59, L93.0, L93.2, L94, M05–M08, M30, M31.3, M31.5, M32–M34, M35.3, M35.8, M35.9, M46, and T78.40), other intrinsic immune condition or immunodeficiency (ICD-10 codes: D27.9, D61.09, D72.89, D80, D81 [except D81.3], D82–D84, D89 [except D89.2], K70.3, K70.4, K72, K74.3–K74.6 [except K74.60 and K74.69], N04, and R18), or organ or stem cell transplant (ICD-10 codes: T86 [except T86.82–T86.84, T86.89, and T86.9], D47.Z1, Z48.2, Z94, and Z98.85). ¶ Based on ≥50% of sequenced specimens yielding a specific Omicron sublineage. ** mRNA COVID-19 vaccination status was defined as having received the listed number of doses of an mRNA COVID-19 vaccine within the specified range of number of days before the encounter 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 hospital admission or the admission date if testing only occurred after the admission. †† Partners contributing data on hospitalizations during dates of estimated ≥50% Omicron BA.1 predominance were in California (December 21, 2021–March 20, 2022), Colorado (December 19, 2021–March 20, 2022), Indiana (December 26, 2021–March 20, 2022), Minnesota and Wisconsin (December 25, 2021–March 21, 2022), New York (December 18, 2021–March 16, 2022), Oregon and Washington (December 24, 2021–March 23, 2022), Texas (Baylor Scott & White Health: December 16, 2021–March 18, 2022; PHIX: December 29, 2021–March 29, 2022), and Utah (December 24, 2021–March 18, 2022). §§ Partners contributing data on hospitalizations during dates of estimated ≥50% Omicron BA.2/BA.2.12.1 predominance were in California (March 21–June 24, 2022), Colorado (March 21–June 18, 2022), Indiana (March 21–June 18, 2022), Minnesota and Wisconsin (March 22–June 21, 2022), New York (March 17–June 28, 2022), Oregon and Washington (March 24–June 28, 2022), Texas (Baylor Scott & White Health: March 19–June 21, 2022; PHIX: March 30–June 21, 2022), and Utah (March 19–June 22, 2022). ¶¶ Dashes indicate that estimated VE had a CI width ≥50%. Estimates with CI widths ≥50% are not shown here due to imprecision. The associated data (total number of tests, number of SARS-CoV-2 positive tests, and median interval since last dose) are also omitted. *** Partners contributing data on hospitalizations during dates of estimated ≥50% Omicron BA.4/BA.5 predominance were in California (June 25–August 20, 2022), Colorado (June 19–August 20, 2022), Indiana (June 19–August 20, 2022), Minnesota and Wisconsin (June 22–August 20, 2022), New York (June 29–August 20, 2022), Oregon and Washington (June 29–August 20, 2022), Texas (Baylor Scott & White Health: June 22–August 20, 2022; PHIX: June 22–August 20, 2022), and Utah (June 23–August 20, 2022). ††† Partners contributing data on hospitalizations during dates of estimated ≥50% Omicron BA.2/BA.2.12.1/BA.4/BA.5 predominance were in California (March 21–August 20, 2022), Colorado (March 21–August 20, 2022), Indiana (March 21–August 20, 2022), Minnesota and Wisconsin (March 22–August 20, 2022), New York (March 17–August 20, 2022), Oregon and Washington (March 24–August 20, 2022), Texas (Baylor Scott & White Health: March 19–August 20, 2022; PHIX: March 30–August 20, 2022), and Utah (March 19–August 20, 2022). VE ≥7 days after receipt of dose 3 varied by immunocompromising condition, ranging from 43% among persons with an organ or stem cell transplant (with or without another condition) to 70% among those with a solid malignancy only (Table 3). TABLE 3 Vaccine effectiveness* of 2- and 3-dose mRNA COVID-19 vaccination against COVID-19–associated † hospitalization among immunocompromised § adults aged ≥18 years by immunocompromising condition category and mRNA COVID-19 vaccination status, ¶ during period of Omicron predominance** — VISION Network, 10 states, December 2021–August 2022 Immunocompromising condition Total SARS-CoV-2 positive test result, no. (%) Median interval since last dose, days (IQR) VE % (95% CI) Solid malignancy only Unvaccinated (Ref) 2,467 411 (16.7) NA NA 2 doses (≥14 days earlier) 2,574 282 (11.0) 322 (257–390) 47 (36–55) 3 doses (≥7 days earlier) 4,523 296 (6.5) 148 (96–203) 70 (64–76) 3 doses (7–89 days earlier) 991 55 (5.5) 57 (37–75) 81 (72–87) 3 doses (≥90 days earlier) 3,532 241 (6.8) 171 (131–219) 61 (52–69) Hematologic malignancy only Unvaccinated (Ref) 562 117 (20.8) NA NA 2 doses (≥14 days earlier) —†† — — — 3 doses (≥7 days earlier) 1,209 162 (13.4) 147 (94–204) 58 (40–70) 3 doses (7–89 days earlier)†† — — — — 3 doses (≥90 days earlier) 924 104 (11.3) 171 (131–219) 63 (45–75) Rheumatologic or inflammatory disorder only Unvaccinated (Ref) 1,549 378 (24.4) NA NA 2 doses (≥14 days earlier) 1,528 281 (18.4) 321 (249–394) 38 (24–49) 3 doses (≥7 days earlier) 2,395 253 (10.6) 141 (90–195) 61 (51–69) 3 doses (7–89 days earlier) 599 57 (9.5) 61 (38–76) 76 (63–84) 3 doses (≥90 days earlier) 1,796 196 (10.9) 166 (129–212) 48 (34–60) Other intrinsic immune condition or immunodeficiency only Unvaccinated (Ref) 2,334 465 (19.9) NA NA 2 doses (≥14 days earlier) 1,852 279 (15.1) 304 (239–375) 40 (28–51) 3 doses (≥7 days earlier) 2,222 210 (9.4) 140 (87–196) 64 (54–72) 3 doses (7–89 days earlier) 576 46 (8.0) 59 (37–76) 76 (62–85) 3 doses (≥90 days earlier) 1,646 164 (10.0) 168 (129–215) 45 (27–58) Organ or stem cell transplant only Unvaccinated (Ref) 151 47 (31.1) NA NA 2 doses (≥14 days earlier) — — — — 3 doses (≥7 days earlier) — — — — 3 doses (7–89 days earlier) — — — — 3 doses (≥90 days earlier) — — — — Organ or stem cell transplant (not mutually exclusive of other conditions) §§ Unvaccinated (Ref) 509 151 (29.7) NA NA 2 doses (≥14 days earlier) 747 178 (23.8) 310 (248–378) 40 (17–56) 3 doses (≥7 days earlier) 1,413 326 (23.1) 153 (107–210) 43 (22–58) 3 doses (7–89 days earlier) — — — — 3 doses (≥90 days earlier) 1,150 265 (23.0) 170 (134–223) 30 (4–49) Any immunocompromising condition, except organ or stem cell transplant ¶¶ Unvaccinated (Ref) 8,234 1,664 (20.2) NA NA 2 doses (≥14 days earlier) 8,051 1,209 (15.0) 317 (250–387) 37 (31–42) 3 doses (≥7 days earlier) 12,873 1,226 (9.5) 146 (95–201) 60 (56–64) 3 doses (7–89 days earlier) 2,935 274 (9.3) 60 (39–76) 70 (64–75) 3 doses (≥90 days earlier) 9,938 952 (9.6) 169 (130–217) 47 (41–53) Abbreviations: ICD-9 = International Classification of Diseases, Ninth Revision; ICD-10 = International Classification of Diseases, Tenth Revision; NA = not applicable; Ref = referent group; 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 VE estimate). Generalized boosted regression trees were used to estimate the propensity to be vaccinated based on sociodemographic characteristics, underlying medical conditions, and facility characteristics. † Hospitalizations with a discharge code consistent with COVID-19–like illness and molecular testing for SARS-CoV-2 ≤14 days before to <72 hours after the encounter date were included. COVID-19–like illness diagnoses included acute respiratory illness (e.g., respiratory failure or pneumonia) or related signs or symptoms (cough, fever, dyspnea, vomiting, or diarrhea) using ICD-9 and ICD-10 diagnosis codes. § Immunocompromised status was defined as the presence of at least one discharge diagnosis using ICD-9 and ICD-10 diagnosis codes (ICD-10 codes: C00–C80, C7A, C7B, D3A, Z51.0, and Z51.1), hematologic malignancy (ICD-10 codes: C81–C86, C88, C90–C96, D46, D61.0, D70.0, D61.2, D61.9, and D71), rheumatologic or inflammatory disorder (ICD-10 codes: D86, E85 [except E85.0], G35, J67.9, L40.54, L40.59, L93.0, L93.2, L94, M05–M08, M30, M31.3, M31.5, M32–M34, M35.3, M35.8, M35.9, M46, and T78.40), other intrinsic immune condition or immunodeficiency (ICD-10 codes: D27.9, D61.09, D72.89, D80, D81 [except D81.3], D82–D84, D89 [except D89.2], K70.3, K70.4, K72, K74.3–K74.6 [except K74.60 and K74.69], N04, and R18), or organ or stem cell transplant (ICD-10 codes: T86 [except T86.82–T86.84, T86.89, and T86.9], D47.Z1, Z48.2, Z94, and Z98.85). ¶ mRNA COVID-19 vaccination status was defined as having received the listed number of doses of an mRNA COVID-19 vaccine within the specified range of number of days before the encounter 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 hospital admission or the admission date if testing only occurred after the admission. ** Based on ≥50% of sequenced specimens yielding an Omicron variant or sublineage. †† Dashes indicated that estimated VE had a CI width ≥50%. Estimates with CI widths ≥50% are not shown here due to imprecision. The associated data (total number of tests, number of SARS-CoV-2 positive tests, and median interval since last dose) are also omitted. §§ Category includes persons with at least organ or stem cell transplant, but these categories are not mutually exclusive (i.e., persons might have one or more additional immunocompromising conditions). ¶¶ Category includes persons with one or more immunocompromising conditions: solid malignancy, hematologic malignancy, rheumatologic or inflammatory disorder, and other intrinsic immune condition or immunodeficiency; all persons with organ or stem cell transplant were excluded. Discussion In this multistate analysis of over 34,000 hospitalizations for COVID-19–like illness among adults with immunocompromising conditions, 2 doses of monovalent mRNA COVID-19 vaccine were 36% effective against COVID-19–associated hospitalization during a period of Omicron variant predominance. VE increased to 67% with the addition of a third dose of monovalent vaccine during BA.1 predominance but declined during the combined BA.2/BA.2.12.1 and BA.4/BA.5 periods to 32% ≥90 days after dose 3 and 43% ≥7 days after a monovalent fourth dose. These results suggest that monovalent COVID-19 vaccination among persons with immunocompromising conditions conferred moderate protection against COVID-19–associated hospitalization during Omicron circulation, with lower protection during BA.2/BA.2.12.1 and BA.4/BA.5 sublineage predominance periods. Although protection increased after receipt of a third monovalent vaccine dose (compared with 2 doses), estimated 3-dose VE was lower in this study than in other similar studies among immunocompetent persons during Omicron predominance, including recent VISION Network analyses ( 6 , 7 ). Consistent with previous studies restricted to persons with immunocompromising conditions, VE in this study was lower among persons with certain immunocompromising conditions that might be associated with being more severely immunocompromised, particularly solid organ or stem cell transplant recipients. Estimated VE among persons with immunocompromising conditions during Omicron predominance was lower than VE in comparable studies during Delta variant predominance ( 2 ). Protection was also lower during Omicron BA.2/BA.2.12.1 and BA.4/BA.5 than during BA.1 predominance, although the median interval since receipt of last vaccine dose was lower during BA.1, and waning effectiveness over time might have also contributed to the lower VE observed during these later sublineage periods. In either case, these findings suggest that the newly authorized bivalent booster vaccines, which target BA.4/BA.5 might offer additional benefit to persons with immunocompromising conditions ( 8 ). Given the moderate protection observed even after monovalent booster doses, persons with immunocompromising conditions might also benefit from other recommended protective measures including preexposure prophylaxis with the antibody treatment tixagevimab/cilgavimab (Evusheld), ¶¶¶¶ which was authorized in December 2021 for persons with moderate-to-severe immunocompromising conditions and was associated with a reduction in risk for both symptomatic and severe COVID-19 in clinical trials ( 9 ). However, recent in vitro data suggest protection against emerging Omicron sublineages might be reduced and additional clinical data are needed ( 10 ). The findings in this report are subject to at least four limitations. First, immunocompromising conditions were based on discharge diagnosis codes and a range of immune suppression is associated with each code. Second, residual confounding in VE models is possible. For example, history of previous infection could not be accurately ascertained, but might have differed between vaccinated and unvaccinated persons, which could affect VE estimates. Third, data on the use of outpatient treatments such as nirmatelvir/ritonavir (Paxlovid) or prophylaxis with Evusheld were not available. Finally, SARS-CoV-2 genomic sequencing data were unavailable for individual encounters, and date of testing was used to assign likely sublineage ecologically. Persons with immunocompromising conditions have been disproportionately affected by the COVID-19 pandemic. Whereas monovalent vaccination remains moderately protective in persons with immunocompromising conditions, VE has decreased compared with that during pre-Omicron periods, most notably during recent Omicron sublineage predominance periods, despite expanded dosing recommendations. Given the incomplete protection against hospitalization afforded by monovalent COVID-19 vaccines, persons with immunocompromising conditions might benefit from updated bivalent boosters that target BA.4/BA.5 sublineages. In addition, other protective measures recommended for persons with immunocompromising conditions, including prophylactic antibody treatments, early access to and use of antivirals, and nonpharmaceutical interventions, such as the use of well-fitting masks or respirators, should also be considered. Further study of VE of updated vaccines in persons with immunocompromising conditions is warranted. Summary What is already known about this topic? COVID-19 vaccine effectiveness (VE) data among immunocompromised persons during SARS-CoV-2 Omicron variant predominance are limited. What is added by this report? Among immunocompromised adults hospitalized with a COVID-like illness, 2-dose monovalent mRNA COVID-19 vaccine VE against COVID-19–associated hospitalization during Omicron predominance was 36%. VE was 67% ≥7 days after a third dose during BA.1 predominance but declined during BA.2/BA.2.12.1 and BA.4/BA.5 predominance to 32% ≥90 days after dose 3 and 43% ≥7 days after dose 4. What are the implications for public health practice? Monovalent COVID-19 vaccine protection among persons with immunocompromising conditions during Omicron predominance was moderate after a 3-dose primary series or booster dose. Persons with immunocompromising conditions might benefit from updated bivalent boosters that target circulating BA.4/BA.5 sublineages.

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, 32% 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 59% compared with no vaccination, 42% compared with monovalent vaccination only with last dose 5–7 months earlier, and 48% 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 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 5,571 5,040 (91) 531 (10) 115 (91–134) Ref BV booster dose, ≥7 days earlier 4,697 4,359 (93) 338 (7) 25 (16–37) 32 (21–42) Only MV doses, last dose 5–7 mos earlier 6,623 5,944 (90) 679 (10) 184 (166–210) Ref BV booster dose, ≥7 days earlier 4,697 4,359 (93) 338 (7) 25 (16–37) 43 (34–50) Only MV doses, last dose 8–10 mos earlier 14,050 12,387 (88) 1,663 (12) 294 (273–311) Ref BV booster dose, ≥7 days earlier 4,697 4,359 (93) 338 (7) 25 (16–37) 54 (48–59) Only MV doses, last dose ≥11 mos earlier 23,099 20,361 (88) 2,738 (12) 463 (366–543) Ref BV booster dose, ≥7 days earlier 4,697 4,359 (93) 338 (7) 25 (16–37) 50 (44–56) Absolute VE Unvaccinated 24,130 21,093 (87) 3,037 (13) NA Ref BV booster dose, ≥7 days earlier 4,697 4,359 (93) 338 (7) 25 (16–37) 56 (50–61) 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 1,780 1,615 (91) 165 (9) 178 (164–201) Ref BV booster dose, ≥7 days earlier 884 828 (94) 56 (6) 23 (14–34) 42 (20–58) Only MV doses, last dose 8–10 mos earlier 2,636 2,405 (91) 231 (9) 294 (273–313) Ref BV booster dose, ≥7 days earlier 884 828 (94) 56 (6) 23 (14–34) 44 (23–59) Only MV doses, last dose ≥11 mos earlier 4,549 4,105 (90) 444 (10) 474 (362–556) Ref BV booster dose, ≥7 days earlier 884 828 (94) 56 (6) 23 (14–34) 48 (30–62) Absolute VE Unvaccinated 4,092 3,658 (89) 434 (11) NA Ref BV booster dose, ≥7 days earlier 884 828 (94) 56 (6) 23 (14–34) 59 (44–70) 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. Among 15,502 hospitalizations with COVID-19–like illness that met inclusion criteria, 1,452 (9%) case-patients and 14,050 (91%) control patients were identified (Table 3). Overall, 4,092 (26%) were unvaccinated. Among those who had not received a bivalent dose, 3,343 (22%), 4,704 (30%), and 2,479 (16%) had received 2, 3, and 4 doses of monovalent mRNA vaccine, respectively. Among the 884 (6%) adults who had received a bivalent booster dose (median interval since receipt of bivalent booster dose = 23 days), 58 (7%) had received 2 monovalent doses, 299 (34%) had received 3 monovalent doses, and 527 (60%) 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 59% (95% CI = 44%–70%) compared with no vaccination and 48% (95% CI = 30%–62%) compared with receipt of last monovalent doses, with last dose ≥11 months earlier (Table 2). 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 2–4 5–7 8–10 ≥11 All hospitalizations 15,502 (100.0) 1,452 (9.4) 14,050 (90.6) — 4,092 (26.4) 1,561 (10.1) 1,780 (11.5) 2,636 (17.0) 4,549 (29.3) 884 (5.7) — Site Baylor Scott & White Health 3,782
(24.4) 331
(8.8) 3,451
(91.2) 0.2 1,545
(40.9) 117
(3.1) 136
(3.6) 433
(11.4) 1,516
(40.1) 35
(0.9) 3.92 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 1,668 (10.8) 218 (13.1) 1,450 (86.9) 506 (30.3) 145 (8.7) 128 (7.7) 266 (15.9) 490 (29.4) 133 (8.0) 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 2,925 (18.9) 160 (5.5) 2,765 (94.5) 0.34 1,315 (45.0) 72 (2.5) 136 (4.6) 502 (17.2) 816 (27.9) 84 (2.9) 2.73 50–64 2,985 (19.3) 212 (7.1) 2,773 (92.9) 1,006 (33.7) 223 (7.5) 280 (9.4) 567 (19.0) 805 (27.0) 104 (3.5) 65–74 3,240 (20.9) 300 (9.3) 2,940 (90.7) 717 (22.1) 385 (11.9) 391 (12.1) 526 (16.2) 1,007 (31.1) 214 (6.6) 75–84 3,615 (23.3) 410 (11.3) 3,205 (88.7) 599 (16.6) 475 (13.1) 551 (15.2) 636 (17.6) 1,072 (29.7) 282 (7.8) ≥85 2,737 (17.7) 370 (13.5) 2,367 (86.5) 455 (16.6) 406 (14.8) 422 (15.4) 405 (14.8) 849 (31.0) 200 (7.3) Sex Female 8,393 (54.1) 747 (8.9) 7,646 (91.1) 0.06 2,147 (25.6) 861 (10.3) 966 (11.5) 1,437 (17.1) 2,500 (29.8) 482 (5.7) 0.19 Male 7,109 (45.9) 705 (9.9) 6,404 (90.1) 1,945 (27.4) 700 (9.8) 814 (11.5) 1,199 (16.9) 2,049 (28.8) 402 (5.7) 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) 247 (13.8) 544 (30.4) 54 (3.0) 1.17 Hispanic or Latino 2,394 (15.4) 178 (7.4) 2,216 (92.6) 696 (29.1) 211 (8.8) 248 (10.4) 488 (20.4) 682 (28.5) 69 (2.9) Other,** NH 1,500 (9.7) 117 (7.8) 1,383 (92.2) 279 (18.6) 197 (13.1) 239 (15.9) 301 (20.1) 379 (25.3) 105 (7.0) Unknown 239 (1.5) 21 (8.8) 218 (91.2) 111 (46.4) 13 (5.4) 24 (10.0) 29 (12.1) 56 (23.4) 6 (2.5) White, NH 9,581 (61.8) 1,020 (10.6) 8,561 (89.4) 2,372 (24.8) 1,002 (10.5) 1,098 (11.5) 1,571 (16.4) 2,888 (30.1) 650 (6.8) Documented prior SARS-CoV-2 infection†† Yes 2,444 (15.8) 141 (5.8) 2,303 (94.2) 0.2 641 (26.2) 213 (8.7) 251 (10.3) 413 (16.9) 819 (33.5) 107 (4.4) 0.18 No 13,058 (84.2) 1,311 (10.0) 11,747 (90.0) 3,451 (26.4) 1,348 (10.3) 1,529 (11.7) 2,223 (17.0) 3,730 (28.6) 777 (6.0) SARS-CoV-2 status Positive test result (case-patient) 1,452 (9.4) 1,452 (100.0) 0
(—) — 434 (29.9) 122 (8.4) 165 (11.4) 231 (15.9) 444 (30.6) 56 (3.9) 0.26 Negative test result (control patient) 14,050 (90.6) 0
(—) 14,050 (100.0) 3,658 (26.0) 1,439 (10.2) 1,615 (11.5) 2,405 (17.1) 4,105 (29.2) 828 (5.9) 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 3,401 (21.9) 322 (9.5) 3,079 (90.5) 0
(—) 48
(1.4) 81 (2.4) 194 (5.7) 3,020 (88.8) 58 (1.7) 3 5,003 (32.3) 442 (8.8) 4,561 (91.2) 0
(—) 213 (4.3) 520 (10.4) 2,442 (48.8) 1,529 (30.6) 299 (6.0) 4 3,006 (19.4) 254 (8.4) 2,752 (91.6) 0
(—) 1,300 (43.2) 1,179 (39.2) 0
(—) 0
(—) 527 (17.5) Most recent dose product manufacturer Pfizer-BioNTech 7,088 (45.7) 622 (8.8) 6,466 (91.2) 0.09 0
(—) 986 (13.9) 1,101 (15.5) 1,439 (20.3) 2,878 (40.6) 684 (9.7) — Moderna 4,322 (27.9) 396 (9.2) 3,926 (90.8) 0
(—) 575 (13.3) 679 (15.7) 1,197 (27.7) 1,671 (38.7) 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 14,649 (94.5) 1,410 (9.6) 13,239 (90.4) 0.14 3,748 (25.6) 1,536 (10.5) 1,743 (11.9) 2,454 (16.8) 4,322 (29.5) 846 (5.8) 0.84 No 853 (5.5) 42
(4.9) 811 (95.1) 344 (40.3) 25
(2.9) 37
(4.3) 182 (21.3) 227 (26.6) 38 (4.5) ≥1 chronic respiratory condition Yes 9,246 (59.6) 921 (10.0) 8,325 (90.0) 0.09 2,324
(25.1) 1,032 (11.2) 1,150 (12.4) 1,527 (16.5) 2,673 (28.9) 540 (5.8) 0.43 No 6,256 (40.4) 531 (8.5) 5,725 (91.5) 1,768 (28.3) 529 (8.5) 630 (10.1) 1,109 (17.7) 1,876 (30.0) 344 (5.5) ≥1 chronic non-respiratory condition Yes 14,119 (91.1) 1,369 (9.7) 12,750 (90.3) 0.13 3,530
(25.0) 1,514 (10.7) 1,707 (12.1) 2,385 (16.9) 4,157 (29.4) 826 (5.9) 1.07 No 1,383 (8.9) 83
(6.0) 1,300 (94.0) 562 (40.6) 47 (3.4) 73 (5.3) 251 (18.1) 392 (28.3) 58 (4.2) ICU admission Yes 2,566 (16.6) 182
(7.1) 2,384 (92.9) 0.13 751 (29.3) 229 (8.9) 298 (11.6) 447 (17.4) 727 (28.3) 114 (4.4) 0.27 No 12,936 (83.4) 1,270 (9.8) 11,666 (90.2) 3,341
(25.8) 1,332 (10.3) 1,482 (11.5) 2,189 (16.9) 3,822 (29.5) 770 (6.0) Receipt of invasive mechanical ventilation Yes 1,579 (10.2) 97
(6.1) 1,482 (93.9) 0.14 567
(35.9) 111 (7.0) 126 (8.0) 226 (14.3) 497
(31.5) 52 (3.3) 0.75 No 13,923 (89.8) 1,355 (9.7) 12,568 (90.3) 3,525
(25.3) 1,450 (10.4) 1,654 (11.9) 2,410 (17.3) 4,052 (29.1) 832 (6.0) In-hospital death§§ Yes 466
(3.0) 51
(10.9) 415
(89.1) 0.03 129
(27.7) 61
(13.1) 57
(12.2) 56 (12.0) 138 (29.6) 25 (5.4) 0.11 No 15,036 (97.0) 1,401 (9.3) 13,635 (90.7) 3,963 (26.4) 1,500 (10.0) 1,723 (11.5) 2,580 (17.2) 4,411 (29.3) 859 (5.7) 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 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. Discussion Analysis of data from the multistate VISION Network found that during September–November 2022, when the BA.5 and other Omicron sublineages were the predominant circulating SARS-CoV-2 variants in the United States, bivalent booster doses (after receipt of 2, 3, or 4 monovalent doses) were effective in preventing medically attended COVID-19 compared with no previous vaccination among immunocompetent adults and provided additional protection when compared with previous monovalent mRNA vaccine doses only. VE was similar against COVID-19–associated ED/UC encounters and hospitalizations, which might reflect changing severity of hospitalized cases over time ( 5 ). Additional studies are needed to evaluate VE against outcomes such as COVID-19–associated severe respiratory illness or death. The IVY Network, an adult inpatient VE network, recently found higher estimated VE in adults aged ≥65 years compared with estimates for those aged ≥18 years included in this analysis ( 6 ). This might reflect differences in population subgroups evaluated. Long-term durability of bivalent booster vaccination protection also could not be assessed because of the short period of observation since bivalent dose receipt. In a recent analysis from VISION, during BA.4/BA.5–predominant circulation, 3-dose monovalent VE against COVID-19–associated hospitalization was observed to wane from 68% at 7–119 days after vaccination to 36% at ≥120 days ( 5 ). This might explain why, among patients who had received 2, 3, or 4 monovalent vaccine doses only, a longer interval since the most recent dose was associated with more relative protection after receipt of the bivalent booster dose. Bivalent COVID-19 booster vaccines were developed to improve protection against circulating Omicron sublineages because of immune escape potentially associated with these subvariants and waning of monovalent vaccine-conferred protection over time ( 7 ). Real-world data suggest that bivalent boosters provide a modest degree of protection against symptomatic infection among adults compared with receipt of 2, 3, or 4 doses of monovalent vaccines only ( 8 ). Results from this study also demonstrate protection against ED/UC encounters and hospitalization during a period when BA.5 and other Omicron sublineage viruses predominated in the United States. With co-circulation of multiple respiratory viruses, including SARS-CoV-2, influenza, and respiratory syncytial virus, vaccination against respiratory diseases for which vaccines are available is especially important to prevent illnesses resulting in health care encounters and to reduce strain on the health care system ( 9 ). Additional studies will be critical to evaluating the durability of added protection, especially with circulation of sublineages of the BA.4/BA.5 Omicron variants such as BQ.1 and BQ.1.1. The findings in this study are subject to at least six limitations. First, previous SARS-CoV-2 infection was not accounted for in this analysis. A large proportion of the population has now experienced SARS-CoV-2 infection which decreases the risk of future medically attended COVID-19 illness and might affect observed VE due to background immunity ( 10 ). Second, although models adjusted for relevant confounders, residual confounding is possible, including by behavioral differences and use of COVID-19 treatments such as nirmatrelvir/ritonavir (Paxlovid). Third, sublineage-specific VE could not be estimated. Fourth, this analysis did not compare product-specific bivalent booster VE estimates. Fifth, relative VE was estimated using the interval since receipt of last monovalent dose; this study was not statistically powered to estimate whether relative VE differed by number of previous monovalent vaccine doses received. Finally, because these data are from nine states, the patients in this analysis might not be representative of the entire population of the United States. Further, this analysis included adults who received bivalent booster doses shortly after authorization who might not be fully representative of the vaccine-eligible population. For example, over one half of bivalent booster recipients had previously received 4 monovalent vaccine doses. Additional VE studies are needed as coverage of bivalent boosters increases. In this early study of immunocompetent adults, significant protection from a booster dose of bivalent mRNA COVID-19 vaccine (after receipt of 2, 3, or 4 monovalent doses) compared with no vaccination was found, as well as significant relative benefits of a bivalent booster dose when compared with previous receipt of monovalent doses only. These findings support efforts to improve coverage with bivalent vaccines, although optimal timing for receipt of bivalent vaccine booster doses needs to be established. All eligible persons should stay up to date with recommended COVID-19 vaccination, including receiving a bivalent booster dose. In addition, persons should consider taking other precautions to avoid respiratory illness this winter season, including masking in public indoor spaces, especially in areas where COVID-19 community levels are high, to protect themselves and others and reduce strain on the health care system during an ongoing surge in multiple respiratory viruses. Summary What is already known about this topic? Bivalent mRNA COVID-19 booster doses containing an Omicron BA.4/BA.5 sublineage component were recommended on September 1, 2022. The effectiveness of these updated vaccines against COVID-19–associated medical encounters has not been established. What is added by this report? Bivalent booster doses provided additional protection against COVID-19–associated emergency department/urgent care encounters and hospitalizations in persons who previously received 2, 3, or 4 monovalent vaccine doses. Because of waning of monovalent vaccine-conferred immunity, relative effectiveness of bivalent vaccines was higher with increased time since the previous monovalent dose. What are the implications for public health practice? All persons should stay up to date with recommended COVID-19 vaccinations, including receiving a bivalent booster dose if eligible.