Information for Persons Who Are Immunocompromised Regarding Prevention and Treatment of SARS-CoV-2 Infection in the Context of Currently Circulating Omicron Sublineages — United States, January 2023

To the Editor: Three sublineages of the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have serially transitioned into globally dominant forms — first BA.1, then BA.2, and then BA.5. As of October 2022, most circulating omicron variants belong to BA.5. However, the prevalence of BQ.1.1 (a BA.5 subvariant) and XBB (a BA.2 subvariant) is increasing rapidly in several countries, including the United States and India. BA.2 and BA.5 variants have been shown to have less sensitivity to certain monoclonal antibodies than previously circulating variants of concern. 1-5 Notably, as compared with BA.5 and BA.2, BQ.1.1 and XBB carry additional substitutions in the receptor-binding domain of the spike (S) protein, which is the major target for vaccines and therapeutic monoclonal antibodies for coronavirus disease 2019 (Covid-19). These subvariants may, therefore, be more immune-evasive than BA.5 and BA.2. We assessed the efficacy of therapeutic monoclonal antibodies against omicron BQ.1.1 (hCoV-19/Japan/TY41-796/2022; TY41-796) and XBB (hCoV-19/Japan/TY41-795/2022; TY41-795), which were isolated from patients. The BQ.1.1 isolate had three more substitutions (R346T, K444T, and N460K) in its receptor-binding domain than a BA.5 (hCoV-19/Japan/TY41-702/2022) isolate (Fig. S1A in the Supplementary Appendix, available with the full text of this letter at NEJM.org). The XBB isolate had nine more changes (G339H, R346T, L368I, V445P, G446S, N460K, F486S, F490S, and the wild-type amino acid at position 493) in its receptor-binding domain than a BA.2 (hCoV-19/Japan/UT-NCD1288-2N/2022) isolate (Fig. S1B). To examine the reactivity of monoclonal antibodies against these subvariants, we determined the 50% focus reduction neutralization test (FRNT50) titer of the monoclonal antibodies by using a live-virus neutralization assay. REGN10987 (marketed as imdevimab), REGN10933 (marketed as casirivimab), COV2-2196 (marketed as tixagevimab), COV2-2130 (marketed as cilgavimab), and S309 (the precursor of sotrovimab) did not neutralize the BQ.1.1 or XBB isolates even at the highest FRNT50 value (>50,000 ng per milliliter) tested (Figure 1A and Table S1). LY-CoV1404 (marketed as bebtelovimab), which effectively neutralizes 1,3-5 omicron BA.1, BA.2, BA.4, and BA.5, had no efficacy against BQ.1.1 or XBB. Both combinations of monoclonal antibodies tested (i.e., imdevimab–casirivimab and tixagevimab–cilgavimab) failed to neutralize either BQ.1.1 or XBB. These results suggest that imdevimab–casirivimab, tixagevimab–cilgavimab, sotrovimab, and bebtelovimab may not be effective against BQ.1.1 or XBB in the clinical setting. The Food and Drug Administration approved remdesivir (an inhibitor of the RNA-dependent RNA polymerase [RdRp] of SARS-CoV-2) for the treatment of Covid-19 and issued an emergency use authorization for molnupiravir (an RdRp inhibitor) and nirmatrelvir (an inhibitor of the main protease of SARS-CoV-2). We therefore tested these antiviral drugs by determining the in vitro 50% inhibitory concentration (IC50) of each compound against BQ.1.1 and XBB. Unlike the amino acid sequence of the reference strain Wuhan/Hu-1/2019, the BQ.1.1 and XBB isolates encode the P3395H substitution in their main protease (Fig. S1C and S1D). The BQ.1.1 and XBB isolates also have two (Y264H and P314L) and three (P314L, M659I, and G662S) substitutions in their RdRp, respectively. The susceptibilities of BQ.1.1 and XBB to the three compounds were similar to those of the ancestral strain (SARS-CoV-2/UT-NC002-1T/Human/2020/Tokyo). For BQ.1.1, the IC50 value was lower by a factor of 0.6 with remdesivir and higher by factors of 1.1 and 1.2 with molnupiravir and nirmatrelvir, respectively. For the XBB subvariant, the IC50 value was lower by a factor of 0.8 with remdesivir, lower by a factor of 0.5 with molnupiravir, and higher by a factor of 1.3 with nirmatrelvir (Figure 1B). These results suggest that remdesivir, molnupiravir, and nirmatrelvir are efficacious against both BQ.1.1 and XBB in vitro. Our data suggest that the omicron sublineages BQ.1.1 and XBB have immune-evasion capabilities that are greater than those of earlier omicron variants, including BA.5 and BA.2. The continued evolution of omicron variants reinforces the need for new therapeutic monoclonal antibodies for Covid-19.

On September 1, 2022, bivalent COVID-19 mRNA vaccines, composed of components from the SARS-CoV-2 ancestral and Omicron BA.4/BA.5 strains, were recommended by the Advisory Committee on Immunization Practices (ACIP) to address reduced effectiveness of COVID-19 monovalent vaccines during SARS-CoV-2 Omicron variant predominance ( 1 ). Initial recommendations included persons aged ≥12 years (Pfizer-BioNTech) and ≥18 years (Moderna) who had completed at least a primary series of any Food and Drug Administration–authorized or –approved monovalent vaccine ≥2 months earlier ( 1 ). On October 12, 2022, the recommendation was expanded to include children aged 5–11 years. At the time of recommendation, immunogenicity data were available from clinical trials of bivalent vaccines composed of ancestral and Omicron BA.1 strains; however, no clinical efficacy data were available. In this study, effectiveness of the bivalent (Omicron BA.4/BA.5–containing) booster formulation against symptomatic SARS-CoV-2 infection was examined using data from the Increasing Community Access to Testing (ICATT) national SARS-CoV-2 testing program.* During September 14–November 11, 2022, a total of 360,626 nucleic acid amplification tests (NAATs) performed at 9,995 retail pharmacies for adults aged ≥18 years, who reported symptoms consistent with COVID-19 at the time of testing and no immunocompromising conditions, were included in the analysis. Relative vaccine effectiveness (rVE) of a bivalent booster dose compared with that of ≥2 monovalent vaccine doses among persons for whom 2–3 months and ≥8 months had elapsed since last monovalent dose was 30% and 56% among persons aged 18–49 years, 31% and 48% among persons aged 50–64 years, and 28% and 43% among persons aged ≥65 years, respectively. Bivalent mRNA booster doses provide additional protection against symptomatic SARS-CoV-2 in immunocompetent persons who previously received monovalent vaccine only, with relative benefits increasing with time since receipt of the most recent monovalent vaccine dose. Staying up to date with COVID-19 vaccination, including getting a bivalent booster dose when eligible, is critical to maximizing protection against COVID-19 ( 1 ). The ICATT program was designed to increase access to COVID-19 testing in areas with high social vulnerability † through contracts with retail pharmacy chains to provide SARS-CoV-2 testing at no cost to the recipient at selected sites nationwide ( 2 ). ICATT vaccine effectiveness (VE) methods have been described previously ( 3 ). Briefly, at test registration, adults report their vaccination history § and information on current COVID-19 symptoms, previous SARS-CoV-2 infection, and underlying medical conditions. Adults receiving testing at participating sites during September 14–November 11, 2022, (when Omicron variant BA.4/BA.5 lineages and their sublineages predominated ¶ ) who reported one or more COVID-19–compatible symptoms were included; case-patients were persons who received a positive rapid or laboratory-based NAAT result; control-patients were those who received a negative NAAT result. Tests from persons who reported an immunocompromising condition ( 4 ), who received non-mRNA COVID-19 vaccines, who had received only a single monovalent mRNA vaccine dose or >4 monovalent mRNA doses, or who had received their last monovalent dose 90 days before the current test was more common among persons who received a negative test result (43%) than among those who received a positive test result (22%). TABLE 1 Characteristics of patients with SARS-CoV-2 tests conducted at national pharmacy testing program locations (N = 360,626) — Increasing Community Access to Testing program, United States, September–November 2022 Characteristic SARS-CoV-2 test result
(col. %) Number and type of mRNA COVID-19 vaccine doses received* before test date,
no. (row %) Positive (case-patients) Negative (control-patients) Unvaccinated 2 monovalent doses 3 monovalent doses 4 monovalent doses† ≥2 monovalent doses ≥2 monovalent plus bivalent booster SARS-CoV-2 status § Positive (case-patients) 121,687 (100) 0 (—) 28,874 (24) 36,429 (30) 41,409 (34) 9,175 (8) 87,013 (72) 5,800 (5) Negative (control-patients) 0 (—) 238,939 (100) 72,010 (30) 72,352 (30) 65,122 (27) 12,981 (5) 150,455 (63) 16,474 (7) Time frame of test Sep 14–Oct 29, 2022 98,729 (81) 194,150 (81) 81,876 (28) 88,392 (30) 88,768 (30) 19,425 (7) 196,585 (67) 14,418 (5) Oct 30–Nov 11, 2022 22,958 (19) 44,789 (19) 19,008 (28) 20,389 (30) 17,763 (26) 2,731 (4) 40,883 (60) 7,856 (12) Age group, yrs 18–49 75,012 (62) 171,125 (72) 81,296 (33) 82,488 (34) 71,881 (29) 0 (—) 154,369 (63) 10,472 (4) 50–64 29,896 (25) 43,179 (18) 14,366 (20) 19,688 (27) 22,580 (31) 11,055 (15) 53,323 (73) 5,386 (7) ≥65 16,779 (14) 24,635 (10) 5,222 (13) 6,605 (16) 12,070 (29) 11,101 (27) 29,776 (72) 6,416 (15) Sex Female 68,487 (56) 150,790 (63) 57,988 (26) 66,662 (30) 66,983 (31) 13,661 (6) 147,306 (67) 13,983 (6) Male 53,029 (44) 87,644 (37) 42,818 (30) 41,915 (30) 39,245 (28) 8,486 (6) 89,646 (64) 8,209 (6) Other 171 (0.1) 505 (0.2) 78 (12) 204 (30) 303 (45) 9 (1) 516 (76) 82 (12) Race and ethnicity Black or African American, non-Hispanic 15,881 (13) 39,592 (17) 20,759 (37) 19,729 (36) 11,190 (20) 2,321 (4) 33,240 (60) 1,474 (3) Hispanic or Latino 22,694 (19) 48,109 (20) 22,074 (31) 25,281 (36) 19,408 (27) 2,141 (3) 46,830 (66) 1,899 (3) Other, non-Hispanic 14,583 (12) 25,453 (11) 7,796 (19) 10,552 (26) 16,811 (42) 2,240 (6) 29,603 (74) 2,637 (7) White, non-Hispanic 60,315 (50) 110,191 (46) 40,756 (24) 46,158 (27) 53,483 (31) 14,654 (9) 114,295 (67) 15,455 (9) Unknown 8,214 (7) 15,594 (7) 9,499 (40) 7,061 (30) 5,639 (24) 800 (3) 13,500 (57) 809 (3) HHS testing site region ¶ Region 1 8,705 (7) 15,181 (6) 5,088 (21) 5,653 (24) 9,005 (38) 1,943 (8) 16,601 (70) 2,197 (9) Region 2 13,533 (11) 19,672 (8) 7,698 (23) 8,918 (27) 12,151 (37) 2,199 (7) 23,268 (70) 2,239 (7) Region 3 9,802 (8) 17,519 (7) 7,090 (26) 7,618 (28) 8,564 (31) 1,957 (7) 18,139 (66) 2,092 (8) Region 4 24,059 (20) 57,781 (24) 28,092 (34) 26,615 (33) 18,942 (23) 4,525 (6) 50,082 (61) 3,666 (4) Region 5 25,382 (21) 44,689 (19) 19,072 (27) 20,873 (30) 20,740 (30) 4,403 (6) 46,016 (66) 4,983 (7) Region 6 12,601 (10) 31,708 (13) 14,127 (32) 15,290 (35) 10,892 (25) 2,140 (5) 28,322 (64) 1,860 (4) Region 7 3,451 (3) 6,715 (3) 3,004 (30) 3,318 (33) 2,735 (27) 537 (5) 6,590 (65) 572 (6) Region 8 3,060 (3) 5,423 (2) 1,485 (18) 2,861 (34) 2,973 (35) 527 (6) 6,361 (75) 637 (8) Region 9 18,771 (15) 35,126 (15) 14,080 (26) 15,321 (28) 17,755 (33) 3,433 (6) 36,509 (68) 3,308 (6) Region 10 2,323 (2) 5,125 (2) 1,148 (15) 2,314 (31) 2,774 (37) 492 (7) 5,580 (75) 720 (10) SVI,** mean (SD) 0.5 (0.3) 0.5 (0.3) 0.6 (0.3) 0.5 (0.3) 0.5 (0.3) 0.5 (0.3) 0.5 (0.3) 0.5 (0.3) History of self-reported SARS-CoV-2 positive test result None 95,378 (78) 136,420 (57) 59,380 (26) 63,497 (27) 73,538 (32) 18,420 (8) 155,455 (67) 16,963 (7) Positive >90 days before current test 26,309 (22) 102,519 (43) 41,504 (32) 45,284 (35) 32,993 (26) 3,736 (3) 82,013 (64) 5,311 (4) SARS-CoV-2 test type Rapid NAAT†† 39,729 (33) 84,511 (35) 33,055 (27) 44,280 (36) 34,218 (28) 6,281 (5) 84,779 (68) 6,406 (5) Laboratory-based NAAT§§ 81,958 (67) 154,428 (65) 67,829 (29) 64,501 (27) 72,313 (31) 15,875 (7) 152,689 (65) 15,868 (7) Self-reported one or more chronic underlying condition ¶¶ No 94,236 (77) 187,842 (79) 85,207 (30) 86,234 (31) 81,463 (29) 13,581 (5) 181,278 (64) 15,593 (6) Yes 27,451 (23) 51,097 (21) 15,677 (20) 22,547 (29) 25,068 (32) 8,575 (11) 56,190 (72) 6,681 (9) For persons who received only monovalent mRNA doses, no. of mos since most recent dose 2–3 3,718 (3) 7,540 (3) 0 (—) 1,966 (17) 3,446 (31) 5,846 (52) 11,258 (100) 0 (—) 4–5 7,188 (6) 12,284 (6) 0 (—) 2,907 (15) 5,517 (28) 11,048 (57) 19,472 (100) 0 (—) 6–7 6,110 (5) 11,396 (5) 0 (—) 4,002 (23) 9,061 (52) 4,443 (25) 17,506 (100) 0 (—) ≥8 69,592 (60) 118,304 (53) 0 (—) 99,906 (53) 87,943 (47) 47 (0.03) 187,896 (100) 0 (—) Abbreviations: HHS = U.S. Department of Health and Human Services; ICATT = Increasing Community Access to Testing program; NAAT = nucleic acid amplification test; SVI = social vulnerability index. * Only month and year of receipt were reported for each vaccination dose from some participating pharmacies; therefore, the number of months between a vaccine dose and testing is a whole number calculated as the difference between the month and year of testing and the month and year of the vaccine dose. Persons reporting an mRNA booster dose on or after September 1, 2022, were assumed to have received a bivalent dose because no monovalent mRNA doses were authorized for use as booster doses at that time. For doses received in the same month or the month before SARS-CoV-2 testing, an additional question was asked to specify whether the dose was received ≥2 weeks before testing, and only doses received ≥2 weeks before testing were included. † Persons aged 50 percentage points are not shown because of imprecision. † Total number of monovalent doses received for persons who did and did not receive a bivalent booster dose. § Persons aged 90% of adults have received ≥1 COVID-19 vaccine dose. ††† Therefore, aVE should be interpreted with caution because unvaccinated persons might have different behaviors or a fundamentally different risk for acquiring COVID-19 compared with vaccinated persons. aVE in this study appeared lower in persons aged ≥50 years who received 3 or 4 monovalent doses before a bivalent booster dose compared with those who received only 2 monovalent doses before a bivalent booster dose; this might be because of differential rates of previous infection or differences in behaviors in those who had not previously received a booster dose compared with those who remained up to date with previous booster dose recommendations. The findings in this study are subject to at least six limitations. First, vaccination status, previous infection history, and underlying medical conditions were self-reported and might be subject to recall bias. In particular, if previous infection provides protection against repeat infection, then VE estimates in this study would likely be biased toward the null, because self-reported previous infection differed by vaccination status, and statistical power was not sufficient to stratify VE estimates by presence of previous infection. In addition, previous infection might have been underreported ( 7 ). Second, acceptance of bivalent booster doses to date has been low (approximately 10% of persons aged ≥5 years as of November 15, 2022), §§§ which could bias the results if persons getting vaccinated early are systematically different from those vaccinated later. Third, important data including SARS-CoV-2 exposure risk and mask use were not collected, which might result in residual confounding. Fourth, the circulating variants in the United States continue to change, and results of this study might not be generalizable to future variants. Fifth, tests used in this study were collected predominantly (although not exclusively) in areas with higher social vulnerability; therefore, data might not be fully representative of the broader U.S. population. Finally, these results might be susceptible to bias because of differences in testing behaviors between vaccinated and unvaccinated persons. In this study of immunocompetent persons tested at ICATT locations, bivalent booster doses provided significant additional protection against symptomatic SARS-CoV-2 infection during a period when Omicron variant BA.4/BA.5 lineages and their sublineages predominated. All persons should stay up to date with recommended COVID-19 vaccines, including bivalent booster doses, if it has been ≥2 months since their last monovalent vaccine dose ( 1 ). Summary What is already known about this topic? Monovalent mRNA COVID-19 vaccines were less effective against symptomatic infection during the period of SARS-CoV-2 Omicron variant predominance. What is added by this report? In this study of vaccine effectiveness of the U.S.-authorized bivalent mRNA booster formulations, bivalent boosters provided significant additional protection against symptomatic SARS-CoV-2 infection in persons who had previously received 2, 3, or 4 monovalent vaccine doses. Due to waning immunity of monovalent doses, the benefit of the bivalent booster increased with time since receipt of the most recent monovalent vaccine dose. What are the implications for public health practice? All persons should stay up to date with recommended COVID-19 vaccinations, including bivalent booster doses for eligible persons.

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.