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

On September 1, 2022, CDC's Advisory Committee on Immunization Practices (ACIP) recommended a single bivalent mRNA COVID-19 booster dose for persons aged ≥12 years who had completed at least a monovalent primary series. Early vaccine effectiveness (VE) estimates among adults aged ≥18 years showed receipt of a bivalent booster dose provided additional protection against COVID-19-associated emergency department and urgent care visits and hospitalizations compared with that in persons who had received only monovalent vaccine doses (1); however, insufficient time had elapsed since bivalent vaccine authorization to assess the durability of this protection. The VISION Network* assessed VE against COVID-19-associated hospitalizations by time since bivalent vaccine receipt during September 13, 2022-April 21, 2023, among adults aged ≥18 years with and without immunocompromising conditions. During the first 7-59 days after vaccination, compared with no vaccination, VE for receipt of a bivalent vaccine dose among adults aged ≥18 years was 62% (95% CI = 57%-67%) among adults without immunocompromising conditions and 28% (95% CI = 10%-42%) among adults with immunocompromising conditions. Among adults without immunocompromising conditions, VE declined to 24% (95% CI = 12%-33%) among those aged ≥18 years by 120-179 days after vaccination. VE was generally lower for adults with immunocompromising conditions. A bivalent booster dose provided the highest protection, and protection was sustained through at least 179 days against critical outcomes, including intensive care unit (ICU) admission or in-hospital death. These data support updated recommendations allowing additional optional bivalent COVID-19 vaccine doses for certain high-risk populations. All eligible persons should stay up to date with recommended COVID-19 vaccines.

On September 1, 2022, CDC's Advisory Committee on Immunization Practices (ACIP) recommended a single bivalent mRNA COVID-19 booster dose for persons aged ≥12 years who had completed at least a monovalent primary series. Early vaccine effectiveness (VE) estimates among adults aged ≥18 years showed receipt of a bivalent booster dose provided additional protection against COVID-19-associated emergency department and urgent care visits and hospitalizations compared with that in persons who had received only monovalent vaccine doses (1); however, insufficient time had elapsed since bivalent vaccine authorization to assess the durability of this protection. The VISION Network* assessed VE against COVID-19-associated hospitalizations by time since bivalent vaccine receipt during September 13, 2022-April 21, 2023, among adults aged ≥18 years with and without immunocompromising conditions. During the first 7-59 days after vaccination, compared with no vaccination, VE for receipt of a bivalent vaccine dose among adults aged ≥18 years was 62% (95% CI = 57%-67%) among adults without immunocompromising conditions and 28% (95% CI = 10%-42%) among adults with immunocompromising conditions. Among adults without immunocompromising conditions, VE declined to 24% (95% CI = 12%-33%) among those aged ≥18 years by 120-179 days after vaccination. VE was generally lower for adults with immunocompromising conditions. A bivalent booster dose provided the highest protection, and protection was sustained through at least 179 days against critical outcomes, including intensive care unit (ICU) admission or in-hospital death. These data support updated recommendations allowing additional optional bivalent COVID-19 vaccine doses for certain high-risk populations. All eligible persons should stay up to date with recommended COVID-19 vaccines.
The VISION Network evaluated VE of bivalent vaccines against COVID-19-associated hospitalization by length of time since receipt of the most recent dose during September 13, 2022-April 21, 2023, across five sites in seven states. VE methods used by the VISION Network have been previously described (2). For this analysis, adults aged ≥18 years with and without immunocompromising conditions who were hospitalized with COVID-19-like illness † were included if the patient received molecular testing (e.g., real-time reverse transcription-polymerase chain reaction) for SARS-CoV-2 during the 14 days preceding or up to 72 hours after hospital admission. Patients were categorized as immunocompromised or not based on International Classification of Diseases, Tenth Revision (ICD-10) discharge codes. § Patients were classified on the index date ¶ as unvaccinated (no COVID-19 vaccine doses received), vaccinated with monovalent doses only, or vaccinated with one mRNA bivalent booster dose (regardless of number of previous monovalent doses received). Patients who received only monovalent doses were included if they received any combination of 1-4 doses (or 1-5 doses if immunocompromised) monovalent mRNA (Moderna or Pfizer-BioNTech), Janssen (Johnson & Johnson), or Novavax vaccine doses; recipients of a single monovalent mRNA dose or a single Novavax dose were excluded. In addition, patients were excluded if any vaccine dose was received <7 days before the index date, if a bivalent dose was received ≥180 days before the index date, or if >1 bivalent dose was received.** Patients aged <50 years without documented immunocompromising conditions were excluded if they had received >3 monovalent doses. Patients were considered to have critical illness if they were admitted to an ICU, died, or both. † † Absolute VE was estimated using a test-negative case-control design comparing the odds of vaccination (either bivalent booster or monovalent doses only versus being unvaccinated) § Immunocompromising conditions were obtained from ICD-10 discharge codes. The specific codes used were Hematological Malignancy:   (Table 1). Median age of case-and control patients was 76 years and 71 years, respectively. Among case-and control patients, 25.9% and 23.2% were unvaccinated, respectively; a bivalent vaccine dose had been received by 16.3% of case-patients and 20.6% of control patients. VE against COVID-19-associated hospitalization was similar across age groups, but waned over time, from 62% during the first 7-59 days after the bivalent dose to 24% by 120-179 days among adults aged ≥18 years ( Table 2). Among those who received monovalent doses only, VE was 21% a median 376 days after the last dose. VE against critical illness was 69% during the 7-59 days after receipt of a bivalent dose and was more sustained (50% at 120-179 days after bivalent vaccination) than VE against hospitalization.
Among 18,934 hospitalized patients with immunocompromising conditions who met inclusion criteria, 1,834 (9.7%) were case-patients and 17,100 (90.3%) were control patients (  and 25.1% of control patients had received a bivalent dose. Among patients aged ≥18 years with immunocompromising conditions, VE against COVID-19-associated hospitalization was 28% during the first 7-59 days after receipt of the bivalent dose and declined to 13% by 120-179 days. VE for those who received monovalent doses only was 3% (median 355 days after the last dose). Estimates of relative and absolute VE were similar (Supplementary Table, https://stacks.cdc.gov/ view/cdc/128421).

Discussion
In this multistate analysis of 85,075 hospitalizations of persons with COVID-19-like illness, bivalent doses were 62% effective among adults without immunocompromising conditions, and 28% effective in those with immunocompromising conditions in preventing COVID-19-associated hospitalization during the first 7-59 days after vaccination. Waning was evident in adults without immunocompromising conditions from 60-179 days (2-6 months) after vaccination. VE was more sustained against critical illness (50% at     120-179 days after vaccination) in adults without immunocompromising conditions, which suggests that bivalent vaccines provide durable protection against the most severe outcomes from COVID-19. In this analysis, receipt of a bivalent dose boosted protection against COVID-19-associated hospitalization that had waned since receipt of previous monovalent doses; however, protection afforded by a bivalent dose against COVID-19-associated hospitalization in adults without immunocompromising conditions waned in a similar pattern to that seen after receipt of a monovalent dose during Omicron predominance, with high initial VE and a decrease over time since the last dose. Among adults without immunocompromising conditions, bivalent VE was similar against COVID-19-associated hospitalization and critical illness within the first 2 months after vaccination but appeared to be more durable against critical illness, consistent with previous CDC research showing durable protection by monovalent mRNA vaccines against critical illness, defined as invasive mechanical ventilation or death (3). Although VE point estimates were lower among persons with immunocompromising conditions compared with those without such conditions, waning was not evident in this group, possibly because of heterogeneity in immune response among those with immunocompromising conditions or because of limited  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 MV doses, ≥7 days earlier versus unvaccinated, 2) vaccinated with an mRNA BV dose, 7-59 days earlier versus unvaccinated, 3) vaccinated with an mRNA BV dose, 60-119 days earlier versus unvaccinated, and 4) vaccinated with an mRNA BV dose, 120-179 days earlier versus unvaccinated. ¶ Vaccination was defined as having received the last MV or BV dose within the specified range of days before the 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 admission date, or the admission date if testing only occurred after the admission. ** Includes persons who received a single dose of Janssen (Johnson & Johnson) vaccine. Persons who received a single dose of Pfizer-BioNTech, Moderna, or Novavax vaccine were excluded from the analysis. † † Variant predominance was defined as the period when a variant accounted for ≥50% of all sequenced specimens in the U.S. Department of Health and Human Services region where the site is located. XBB-related sublineages predominated at Intermountain Healthcare beginning January 28, 2023; at HealthPartners, KPNC, and Regenstrief Institute beginning February 4, 2023; and at KPCHR beginning February 11, 2023. § § Other race includes American Indian or Alaska Native, Asian, Native Hawaiian or other Pacific Islander, other races not listed, and multiple races. Because of small numbers, these categories were combined. ¶ ¶ Because persons might have received vaccine from more than one manufacturer, columns might sum to >100%. *** In-hospital death was identified at each individual site and was defined as a death while hospitalized or ≤28 days after admission. statistical power to detect differences by time. Previous analyses have shown differences in VE by type of immunocompromising condition (4); however, this analysis did not have sufficient statistical power to differentiate VE by condition type.

Most recent dose product manufacturer
As of May 10, 2023, only one in five (20.5%) U.S. adults had received a bivalent booster dose.*** Among U.S. adults who previously received a monovalent vaccine but had yet to *** https://covid.cdc.gov/covid-data-tracker/#vaccinations_vacc-people-boosterpercent-pop5 receive a bivalent mRNA booster, most received their last vaccine dose >1 year ago. † † † Results of this analysis indicate that these adults might have relatively little remaining protection against COVID-19-associated hospitalization compared with unvaccinated persons, although might have more remaining protection against critical illness.  On April 19, 2023, CDC amended recommendations to permit adults aged ≥65 years and those with immunocompromising conditions to receive ≥1 additional bivalent dose. In this analysis, waning VE patterns were the same in younger and older adults; however, rates of COVID-19-associated hospitalization and death remain substantially higher among older adults, which suggests that an additional dose might confer additional benefit. In addition, although this analysis did not demonstrate clear evidence of waning VE in immunocompromised adults, overall VE among immunocompromised adults was lower than among those without immunocompromising conditions. Like older adults, persons with immunocompromising conditions remain at higher risk for COVID-19 hospitalization and death and might benefit from additional bivalent doses, although this will require future evaluation.

TABLE 2. COVID-19 vaccine effectiveness* against laboratory-confirmed COVID-19-associated hospitalizations and critical illness † among adults aged ≥18 years, by age group and immunocompromise status -seven states, § September 2022-April 2023
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. According to a national seroprevalence survey, a large proportion of the population has now experienced SARS-CoV-2 infection; infection-induced immunity decreases the risk for future medically attended COVID-19 illness and might affect observed VE. § § § The findings of this analysis should therefore be interpreted in the context of this underlying immunity as the incremental benefit provided by COVID-19 vaccination. Second, although all case-patients included in the analysis had COVID-19-like illness and a positive SARS-CoV-2 test result at the time of the included hospitalization, some might have had relatively mild COVID-19 disease and been hospitalized because of reasons unrelated to COVID-19, which could lower measured VE. Third, although models adjusted for relevant confounders, such as age and     * Hospitalizations with a discharge code consistent with COVID-19-like illness were included. COVID-19-like illness diagnoses included acute respiratory illness, respiratory signs or symptoms or febrile signs or symptoms using diagnosis codes from the International Classification of Diseases, Tenth Revision. Clinician-ordered molecular assays (e.g., real-time reverse transcription-polymerase chain reaction) for SARS-CoV-2 occurring ≤14 days before to <72 hours after the date of admission were included. † California (September 13, 2022-April 21, 2023), Indiana (September 13, 2022-April 12, 2023), Minnesota and Wisconsin (September 13, 2022-April 21, 2023), Oregon and Washington (September 13, 2022-April 14, 2023), and Utah (September 13, 2022-April 21, 2023). § An absolute SMD >0.20 indicates a nonnegligible difference in variable distributions between hospitalizations for vaccinated versus unvaccinated patients or for patients with a positive SARS-CoV-2 test result versus patients with a negative SARS-CoV-2 test result. For mRNA COVID-19 vaccination status, a single SMD was calculated by averaging the absolute SMDs obtained from pairwise comparisons of each vaccinated category versus unvaccinated. Specifically, it was calculated as the average of the absolute value of the SMDs for 1) vaccinated with only MV doses, ≥7 days earlier versus unvaccinated, 2) vaccinated with an mRNA BV dose, 7-59 days earlier versus unvaccinated, 3) vaccinated with an mRNA BV dose, 60-119 days earlier versus unvaccinated, and 4) vaccinated with an mRNA BV dose, 120-179 days earlier versus unvaccinated. ¶ Vaccination was defined as having received the last MV or BV dose within the specified range of days before the 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 admission date or the admission date if testing only occurred after the admission. ** Includes persons who received a single dose of Janssen (Johnson & Johnson) vaccine. Persons who received a single dose of Pfizer-BioNTech, Moderna, or Novavax vaccine were excluded from the analysis. † † Variant predominance was defined as the period when a variant accounted for ≥50% of all sequenced specimens in the U.S. Department of Health and Human Services region where the site is located. XBB-related sublineages predominated at Intermountain Healthcare beginning January 28, 2023; at HealthPartners, KPNC, and Regenstrief Institute beginning February 4, 2023; and at KPCHR beginning February 11, 2023. § § Other race includes American Indian or Alaska Native, Asian, Native Hawaiian or other Pacific Islander, other races not listed, and multiple races. Because of small numbers, these categories were combined. ¶ ¶ Because persons might have received vaccine from more than one manufacturer, columns might sum to >100%. *** In-hospital death was identified at each individual site and was defined as a death while hospitalized or ≤28 days after admission. calendar time, residual confounding is possible, including by behavioral differences, history of previous SARS-CoV-2 infection, and use of COVID-19 treatments such as nirmatrelvirritonavir (Paxlovid). Fourth, differences in sublineage-specific VE could not be compared because of limited statistical power. Fifth, this analysis did not compare product-specific bivalent booster VE estimates. Finally, because these data are from seven states, the patients in this analysis might not be representative of the entire U.S. population.
In this study of durability of bivalent VE, bivalent doses helped provide protection against COVID-19-associated hospitalization and critical disease. Although waning of protection was evident in some groups, VE was more sustained for critical illness, indicating the vaccines are continuing to help protect adults from the most severe COVID-19 outcomes. All adults should stay up to date with recommended COVID-19 vaccines.