Immunocompromised persons, defined as those with suppressed humoral or cellular immunity resulting from health conditions or medications, account for approximately 3% of the US adult population.1 Immunocompromised adults are at increased risk for severe COVID-19 outcomes2 and might not acquire the same level of protection from COVID-19 mRNA vaccines as do immunocompetent adults.3, 4 To evaluate vaccine effectiveness (VE) among immunocompromised adults, data from the VISION Network1 on hospitalizations among persons aged ≥18 years with COVID-19–like illness from 187 hospitals in nine states during January 17–September 5, 2021 were analyzed. Using selected discharge diagnoses,2 VE against COVID-19–associated hospitalization conferred by completing a two-dose series of an mRNA COVID-19 vaccine ≥14 days before the index hospitalization date3 (i.e., being fully vaccinated) was evaluated using a test-negative design comparing 20,101 immunocompromised adults (10,564 [53%] of whom were fully vaccinated) and 69,116 immunocompetent adults (29,456 [43%] of whom were fully vaccinated). VE of two doses of mRNA COVID-19 vaccine against COVID-19–associated hospitalization was lower among immunocompromised patients (77%; 95% confidence interval [CI] = 74%–80%) than among immunocompetent patients (90%; 95% CI = 89%–91%). This difference persisted irrespective of mRNA vaccine product, age group, and timing of hospitalization relative to SARS-CoV-2 (the virus that causes COVID-19) B.1.617.2 (Delta) variant predominance in the state of hospitalization. VE varied across immunocompromising condition subgroups, ranging from 59% (organ or stem cell transplant recipients) to 81% (persons with a rheumatologic or inflammatory disorder). Immunocompromised persons benefit from mRNA COVID-19 vaccination but are less protected from severe COVID-19 outcomes than are immunocompetent persons, and VE varies among immunocompromised subgroups. Immunocompromised persons receiving mRNA COVID-19 vaccines should receive three doses and a booster, consistent with CDC recommendations,5 practice nonpharmaceutical interventions, and, if infected, be monitored closely and considered early for proven therapies that can prevent severe outcomes.

Data came from the VISION Network, a collaboration between CDC and seven US health-care systems and research centers with integrated medical, laboratory, and vaccination records that was established to assess the effectiveness of COVID-19 vaccines.6 Eligible hospitalizations were defined as those among adults aged ≥18 years with SARS-CoV-2 molecular testing (from 14 days before through 72 h after admission) and a COVID-19–like illness discharge diagnosis.4 Encounters without molecular testing were excluded from this analysis. Immunocompromised patients were defined by the presence of at least one selected discharge diagnosis for immunocompromising conditions using the International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision. Diagnoses across five categories of immunocompromising conditions were derived from lists used in previous studies of large hospital-based or administrative databases and included the following conditions: (1) solid malignancies, (2) hematologic malignancies, (3) rheumatologic or inflammatory disorders, (4) other intrinsic immune conditions or immunodeficiencies, and (5) organ or stem cell transplants.7-9 Immunosuppressive medication use data were not available for these analyses. Vaccination status was documented in electronic health records or state immunization registries.6 Full vaccination was defined as receipt of the second in a two-dose series of Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccines ≥14 days before the index hospitalization date; unvaccinated patients had not received any COVID-19 vaccine doses and were considered the referent group. Patients who received (1) only one mRNA vaccine dose, (2) ≥3 mRNA vaccine doses, (3) the second dose <14 days before index hospitalization date, or (4) the Janssen (Johnson & Johnson [Ad26.COV2]) vaccine were excluded from the analysis.

Vaccine effectiveness was estimated using a test-negative design comparing the odds of a positive test result for SARS-CoV-2 between fully vaccinated and unvaccinated patients using multivariable logistic regression models. VE was adjusted for age, geographic region, calendar time (days from January 1 to hospitalization), and local virus circulation in the community where each partner site was located 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, known previous SARS-CoV-2 infection, and hospital characteristics. VE estimates were stratified by immunocompromised status, mRNA COVID-19 vaccine product received, age group, and network partner (representing different health-care systems and geographic regions). Among immunocompromised patients, VE was also calculated separately among subgroups of patients with each of the five categories of immunocompromising diagnoses (subgroups that were not mutually exclusive). VE was also calculated separately for hospitalizations occurring before and after the period when the Delta variant accounted for ≥50% of sequenced isolates within each site's state.10 VE estimates with 95% CIs that did not overlap were considered statistically different, which is a conservative approach. This study was reviewed and approved by Westat, Inc. institutional review board.5

Among 69,116 immunocompetent adults and 20,101 immunocompromised adults hospitalized with COVID-19–like illness and with available molecular testing results for SARS-CoV-2, 29,456 (43%) and 10,564 (53%), respectively, were fully vaccinated (Table 1). The median ages of immunocompetent and immunocompromised patients were 68 years (interquartile range [IQR] = 52–79 years) and 70 years (IQR = 60–78 years), respectively. Among immunocompetent patients, 42% had received the Moderna vaccine and 58% had received the Pfizer-BioNTech vaccine, and among immunocompromised patients, 41% and 59% had received Moderna and Pfizer-BioNTech vaccines, respectively. Among immunocompetent patients, the median interval from receipt of the second vaccine dose to hospital admission was 89 days (IQR = 52–129 days) among Moderna vaccine recipients and 90 days (IQR = 52–131 days) among Pfizer-BioNTech vaccine recipients; among immunocompromised patients, the intervals were 89 days (IQR = 52–128 days) and 89 days (IQR = 53–128 days) for Moderna vaccine and Pfizer-BioNTech vaccine recipients, respectively.

TABLE 1. Characteristics of COVID-19–like illness hospitalizations among immunocompetent and immunocompromised adults aged ≥18 years and proportions of two-dose mRNA COVID-19 vaccine recipients with laboratory-confirmed SARS-CoV-2 infection—nine states, January–September 2021 Characteristic Immunocompetent Immunocompromised§ Total Vaccinated¶ SARS-CoV-2–positive test result Total Vaccinated¶ SARS-CoV-2–positive test result No. (column %) No. (row %) SMD** No. (row %) SMD†† No. (column %) No. (row %) SMD** No. (row %) SMD†† All hospitalizations 69,116 (100) 29,456 (43) — 10,961 (16) — 20,101 (100) 10,564 (53) — 1,537 (8) — Site Columbia University 4,221 (6) 1,338 (32) 0.70 673 (16) 0.39 1,615 (8) 645 (40) 0.86 149 (9) 0.50 HealthPartners 1,695 (2) 1,022 (60) 100 (6) 721 (4) 467 (65) 24 (3) Intermountain Healthcare 6,937 (10) 2,501 (36) 1,925 (28) 1,479 (7) 659 (45) 292 (20) Kaiser Permanente Northern California 22,331 (32) 14,222 (64) 3,253 (15) 7,518 (37) 5,707 (76) 461 (6) Kaiser Permanente Northwest 3,531 (5) 1,716 (49) 347 (10) 1,117 (6) 614 (55) 47 (4) Regenstrief Institute 19,099 (28) 6,188 (32) 3,562 (19) 3,000 (15) 1,121 (37) 320 (11) University of Colorado 11,302 (16) 2,469 (22) 1,101 (10) 4,651 (23) 1,351 (29) 244 (5) Age group, years 18–49 15,891 (23) 3,469 (22) 0.62 3,542 (22) 0.43 2,291 (11) 709 (31) 0.47 241 (11) 0.21 50–64 13,669 (20) 4,597 (34) 2,989 (22) 4,524 (23) 1,874 (41) 411 (9) 65–74 15,715 (23) 7,477 (48) 2,101 (13) 6,149 (31) 3,429 (56) 431 (7) 75–84 14,421 (21) 8,270 (57) 1,491 (10) 5,064 (25) 3,201 (63) 341 (7) ≥85 9,420 (14) 5,643 (60) 838 (9) 2,073 (10) 1,351 (65) 113 (5) Sex Men§§ 30,625 (44) 13,106 (43) –0.01 5,406 (18) –0.12 9,552 (48) 5,082 (53) –0.02 762 (8) –0.04 Women 38,491 (56) 16,350 (42) 5,555 (14) 10,549 (52) 5,482 (52) 775 (7) Race (regardless of ethnicity) White 45,206 (65) 20,094 (44) 0.28 6,512 (14) 0.20 13,834 (69) 7,344 (53) 0.23 985 (7) 0.16 Black 7,204 (10) 2,107 (29) 1,274 (18) 1,821 (9) 819 (45) 182 (10) Other 5,382 (8) 3,126 (58) 722 (13) 1,725 (9) 1,164 (67) 110 (6) Unknown 11,324 (16) 4,129 (36) 2,453 (22) 2,721 (14) 1,237 (45) 260 (10) Ethnicity Hispanic 9,415 (14) 3,464 (37) 0.10 2,069 (22) 0.26 2,786 (14) 1,366 (49) 0.09 271 (10) 0.14 Non-Hispanic 48,146 (70) 20,753 (43) 6,498 (13) 14,448 (72) 7,544 (52) 1,020 (7) Unknown 11,555 (17) 5,239 (45) 2,394 (21) 2,867 (14) 1,654 (58) 246 (9) Chronic respiratory condition¶¶ Has chronic respiratory condition 44,264 (64) 19,788 (45) 0.11 6,891 (16) –0.03 13,652 (68) 7,331 (54) 0.07 1,084 (8) 0.06 No chronic respiratory condition§§ 24,852 (36) 9,668 (39) 4,070 (16) 6,449 (32) 3,233 (50) 453 (7) ICU admission Admitted to ICU 10,939 (16) 4,278 (39) –0.06 1,700 (16) –0.01 4,285 (21) 1,977 (46) –0.13 361 (8) 0.06 Not admitted to ICU§§ 58,177 (84) 25,178 (43) 9,261 (16) 15,816 (79) 8,587 (54) 1,176 (7) COVID-19 vaccination status Unvaccinated 39,660 (57) 0 (—) — 9,853 (25) 0.94 9,537 (47) 0 (—) — 1,127 (12) 0.60 Moderna (mRNA-1273) 12,341 (18) 12,341 (100) 357 (3) 4,337 (22) 4,337 (100) 138 (3) Pfizer-BioNTech (BNT162b2) 17,115 (25) 17,115 (100) 751 (4) 6,227 (31) 6,227 (100) 272 (4) Abbreviations: ICD-10, International Classification of Diseases, Tenth Revision; ICD-9, International Classification of Diseases, Ninth Revision; ICU, intensive care unit; SMD, standardized mean or proportion difference.

Among immunocompetent patients, SARS-CoV-2 infection was laboratory-confirmed in 9,853 (24.8%) unvaccinated and 1,108 (3.8%) fully vaccinated persons, compared with 1,127 (11.8%) unvaccinated and 410 (3.9%) fully vaccinated immunocompromised patients (Table 2). VE of two doses of mRNA vaccine against COVID-19 hospitalization was lower among immunocompromised patients (77%) than among immunocompetent patients (90%). Differences persisted when analyzed among patients aged 18–64 years and aged ≥65 years, and among Moderna and Pfizer-BioNTech vaccine recipients. Among immunocompromised patients, VE was 81% for the Moderna vaccine and 71% for the Pfizer-BioNTech vaccine; however, CIs slightly overlapped between these two estimates. VE was similarly lower among immunocompromised than among immunocompetent patients both before the period of Delta variant predominance (76%; 95% CI = 69%–81% vs 91%; 95% CI = 90%–93%) and during the period of Delta variant predominance (79%; 95% CI = 74%–83% vs 90%; 95% CI = 89%–91%). Across network partners, VE point estimates varied more for immunocompromised patients (57%–85%) than for immunocompetent patients (84%–94%).

TABLE 2. Two-dose mRNA COVID-19 vaccine effectiveness against laboratory-confirmed COVID-19–associated hospitalization among immunocompetent and immunocompromised adults aged ≥18 years, by age group and vaccine—nine states, January–September 2021 Age group, years, vaccine Total no. of adults SARS-CoV-2–positive test result, no. (row %) VE,¶ % (95% CI) ≥18, any mRNA COVID-19 vaccine Immunocompetent (n = 69,116) Unvaccinated 39,660 9,853 (24.8) Ref Vaccinated with two doses** 29,456 1,108 (3.8) 90 (89–91) Immunocompromised†† (n = 20,101) Unvaccinated 9,537 1,127 (11.8) Ref Vaccinated with two doses** 10,564 410 (3.9) 77 (74–80) 18–64, any mRNA COVID-19 vaccine Immunocompetent (n = 29,560) Unvaccinated 21,494 6,243 (29.1) Ref Vaccinated with two doses** 8,066 288 (3.6) 93 (92–94) Immunocompromised†† (n = 6,815) Unvaccinated 4,232 544 (12.8) Ref Vaccinated with two doses** 2,583 108 (4.2) 80 (74–84) ≥65, any mRNA COVID-19 vaccine Immunocompetent (n = 39,556) Unvaccinated 18,166 3,610 (19.9) Ref Vaccinated with two doses** 21,390 820 (3.8) 87 (86–88) Immunocompromised†† (n = 13,286) Unvaccinated 5,305 583 (11) Ref Vaccinated with two doses** 7,981 302 (3.8) 75 (70–79) ≥18, Moderna (mRNA-1273) vaccine Immunocompetent (n = 52,001) Unvaccinated 39,660 9,853 (24.8) Ref Vaccinated with two doses** 12,341 357 (2.9) 93 (92–94) Immunocompromised†† (n = 13,874) Unvaccinated 9,537 1,127 (11.8) Ref Vaccinated with two doses** 4,337 138 (3.2) 81 (76–85) ≥18, Pfizer-BioNTech (BNT162b2) vaccine Immunocompetent (n = 56,775) Unvaccinated 39,660 9,853 (24.8) Ref Vaccinated with two doses** 17,115 751 (4.4) 88 (86–89) Immunocompromised†† (n = 15,764) Unvaccinated 9,537 1,127 (11.8) Ref Vaccinated with two doses** 6,227 272 (4.4) 71 (65–76) Abbreviations: CI, confidence interval; ICD-10, International Classification of Diseases, Tenth Revision; ICD-9, International Classification of Diseases, Ninth Revision; Ref, referent group; VE, vaccine effectiveness.

Among immunocompromised patients, 8,887 (44%) had a solid malignancy (range across network partners = 34%–47%), 2,790 (14%) had a hematologic malignancy (range = 11%–19%), 5,024 (25%) had a rheumatologic or inflammatory disorder (range = 22%–30%), 6,380 (32%) had another intrinsic immune condition or immunodeficiency (range = 29%–37%), and 1,416 (7%) had received an organ or stem cell transplant (range = 4%–10%). VE point estimates ranged from 59% (organ or stem cell transplant patients) to 81% (patients with a rheumatologic or inflammatory disorder) across these subgroups (Table 3). Subgroup VE point estimates were generally higher for the Moderna vaccine than for the Pfizer-BioNTech vaccine but were the same among patients with a rheumatologic or inflammatory disorder.

TABLE 3. Two-dose mRNA COVID-19 vaccine effectiveness against laboratory-confirmed COVID-19–associated hospitalization among subgroups of adults aged ≥18 years with specific types of conditions and presumed to be immunocompromised (20,101)—nine states, January–September 2021 Condition (no. of adults) Total SARS-CoV-2–positive tests, no. (row %) VE,** % (95% CI) Solid malignancy†† (8,887) Unvaccinated 3,986 304 (7.6) Ref Vaccinated with any two mRNA vaccine doses§§ 4,901 106 (2.2) 79 (73–84) Vaccinated with two Moderna (mRNA-1273) vaccine doses§§ 2,053 30 (1.5) 85 (76–91) Vaccinated with two Pfizer-BioNTech (BNT162b2) vaccine doses§§ 2,848 76 (2.7) 72 (62–80) Hematologic malignancy¶¶ (2,790) Unvaccinated 1,156 130 (11.2) Ref Vaccinated with any two mRNA vaccine doses§§ 1,634 86 (5.3) 74 (62–83) Vaccinated with two Moderna vaccine doses§§ 660 26 (3.9) 85 (74–92) Vaccinated with two Pfizer-BioNTech vaccine doses§§ 974 60 (6.2) 62 (42–75) Rheumatologic or inflammatory disorder*** (5,024) Unvaccinated 2,380 383 (16.1) Ref Vaccinated with any two mRNA vaccine doses§§ 2,644 123 (4.6) 81 (75–86) Vaccinated with two Moderna vaccine doses