Interim Effectiveness of Updated 2023–2024 (Monovalent XBB.1.5) COVID-19 Vaccines Against COVID-19–Associated Hospitalization Among Adults Aged ≥18 Years with Immunocompromising Conditions — VISION Network, September 2023–February 2024

Objective To compare the efficacy of covid-19 vaccines between immunocompromised and immunocompetent people. Design Systematic review and meta-analysis. Data sources PubMed, Embase, Central Register of Controlled Trials, COVID-19 Open Research Dataset Challenge (CORD-19), and WHO covid-19 databases for studies published between 1 December 2020 and 5 November 2021. ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched in November 2021 to identify registered but as yet unpublished or ongoing studies. Study selection Prospective observational studies comparing the efficacy of covid-19 vaccination in immunocompromised and immunocompetent participants. Methods A frequentist random effects meta-analysis was used to separately pool relative and absolute risks of seroconversion after the first and second doses of a covid-19 vaccine. Systematic review without meta-analysis of SARS-CoV-2 antibody titre levels was performed after first, second, and third vaccine doses and the seroconversion rate after a third dose. Risk of bias and certainty of evidence were assessed. Results 82 studies were included in the meta-analysis. Of these studies, 77 (94%) used mRNA vaccines, 16 (20%) viral vector vaccines, and 4 (5%) inactivated whole virus vaccines. 63 studies were assessed to be at low risk of bias and 19 at moderate risk of bias. After one vaccine dose, seroconversion was about half as likely in patients with haematological cancers (risk ratio 0.40, 95% confidence interval 0.32 to 0.50, I 2 =80%; absolute risk 0.29, 95% confidence interval 0.20 to 0.40, I 2 =89%), immune mediated inflammatory disorders (0.53, 0.39 to 0.71, I 2 =89%; 0.29, 0.11 to 0.58, I 2 =97%), and solid cancers (0.55, 0.46 to 0.65, I 2 =78%; 0.44, 0.36 to 0.53, I 2 =84%) compared with immunocompetent controls, whereas organ transplant recipients were 16 times less likely to seroconvert (0.06, 0.04 to 0.09, I 2 =0%; 0.06, 0.04 to 0.08, I 2 =0%). After a second dose, seroconversion remained least likely in transplant recipients (0.39, 0.32 to 0.46, I 2 =92%; 0.35, 0.26 to 0.46), with only a third achieving seroconversion. Seroconversion was increasingly likely in patients with haematological cancers (0.63, 0.57 to 0.69, I 2 =88%; 0.62, 0.54 to 0.70, I 2 =90%), immune mediated inflammatory disorders (0.75, 0.69 to 0.82, I 2 =92%; 0.77, 0.66 to 0.85, I 2 =93%), and solid cancers (0.90, 0.88 to 0.93, I 2 =51%; 0.89, 0.86 to 0.91, I 2 =49%). Seroconversion was similar between people with HIV and immunocompetent controls (1.00, 0.98 to 1.01, I 2 =0%; 0.97, 0.83 to 1.00, I 2 =89%). Systematic review of 11 studies showed that a third dose of a covid-19 mRNA vaccine was associated with seroconversion among vaccine non-responders with solid cancers, haematological cancers, and immune mediated inflammatory disorders, although response was variable in transplant recipients and inadequately studied in people with HIV and those receiving non-mRNA vaccines. Conclusion Seroconversion rates after covid-19 vaccination were significantly lower in immunocompromised patients, especially organ transplant recipients. A second dose was associated with consistently improved seroconversion across all patient groups, albeit at a lower magnitude for organ transplant recipients. Targeted interventions for immunocompromised patients, including a third (booster) dose, should be performed. Systematic review registration PROSPERO CRD42021272088.

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.