Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19–Associated Emergency Department or Urgent Care Encounters and Hospitalizations Among Immunocompetent Adults — VISION Network, Nine States, September–November 2022

During June-October 2022, the SARS-CoV-2 Omicron BA.5 sublineage accounted for most of the sequenced viral genomes in the United States, with further Omicron sublineage diversification through November 2022.* Bivalent mRNA vaccines contain an ancestral SARS-CoV-2 strain component plus an updated component of the Omicron BA.4/BA.5 sublineages. On September 1, 2022, a single bivalent booster dose was recommended for adults who had completed a primary vaccination series (with or without subsequent booster doses), with the last dose administered ≥2 months earlier (1). During September 13-November 18, the VISION Network evaluated vaccine effectiveness (VE) of a bivalent mRNA booster dose (after 2, 3, or 4 monovalent doses) compared with 1) no previous vaccination and 2) previous receipt of 2, 3, or 4 monovalent-only mRNA vaccine doses, among immunocompetent adults aged ≥18 years with an emergency department/urgent care (ED/UC) encounter or hospitalization for a COVID-19-like illness.† VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against COVID-19-associated ED/UC encounters was 56% compared with no vaccination, 31% compared with monovalent vaccination only with last dose 2-4 months earlier, and 50% compared with monovalent vaccination only with last dose ≥11 months earlier. VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against COVID-19-associated hospitalizations was 57% compared with no vaccination, 38% compared with monovalent vaccination only with last dose 5-7 months earlier, and 45% compared with monovalent vaccination only with last dose ≥11 months earlier. Bivalent vaccines administered after 2, 3, or 4 monovalent doses were effective in preventing medically attended COVID-19 compared with no vaccination and provided additional protection compared with past monovalent vaccination only, with relative protection increasing with time since receipt of the last monovalent dose. All eligible persons should stay up to date with recommended COVID-19 vaccinations, including receiving a bivalent booster dose. Persons should also consider taking additional precautions to avoid respiratory illness this winter season, such as masking in public indoor spaces, especially in areas where COVID-19 community levels are high.

On December 16, 2022, this report was posted as an MMWR Early Release on the MMWR website (https://www.cdc.gov/mmwr).
During June-October 2022, the SARS-CoV-2 Omicron BA.5 sublineage accounted for most of the sequenced viral genomes in the United States, with further Omicron sublineage diversification through November 2022.* Bivalent mRNA vaccines contain an ancestral SARS-CoV-2 strain component plus an updated component of the Omicron BA.4/BA.5 sublineages. On September 1, 2022, a single bivalent booster dose was recommended for adults who had completed a primary vaccination series (with or without subsequent booster doses), with the last dose administered ≥2 months earlier (1). During September 13-November 18, the VISION Network evaluated vaccine effectiveness (VE) of a bivalent mRNA booster dose (after 2, 3, or 4 monovalent doses) compared with 1) no previous vaccination and 2) previous receipt of 2, 3, or 4 monovalent-only mRNA vaccine doses, among immunocompetent adults aged ≥18 years with an emergency department/urgent care (ED/UC) encounter or hospitalization for a COVID-19-like illness. † VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against COVID-19-associated ED/UC encounters was 56% compared with no vaccination, 31% compared with monovalent vaccination only with last dose 2-4 months earlier, and 50% compared with monovalent vaccination only with last dose ≥11 months earlier. VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against COVID-19-associated hospitalizations was 57% compared with no vaccination, 38% compared with monovalent vaccination only with last dose 5-7 months earlier, and 45% compared with monovalent vaccination only with last dose ≥11 months earlier. Bivalent vaccines administered after 2, 3, or 4 monovalent doses were effective in preventing medically attended COVID-19 compared with no vaccination and provided additional protection compared with past monovalent vaccination only, with relative protection increasing with time since receipt of the last monovalent dose. All eligible persons should stay up to date with recommended COVID-19 vaccinations, including receiving a bivalent booster dose. Persons should also consider taking additional precautions to avoid respiratory illness this winter season, such as masking in public indoor spaces, especially in areas where COVID-19 community levels are high.
Monovalent COVID-19 mRNA vaccines were developed against the spike protein of the ancestral SARS-CoV-2 virus and were found to provide cross-reactive immune protection against Alpha and Delta SARS-CoV-2 variants (2). The SARS-CoV-2 Omicron variant emerged in November 2021 and diversified into sublineages. These Omicron sublineages were associated with decreased protection from vaccination with monovalent vaccine (3). A single booster dose of bivalent mRNA vaccine (Pfizer-BioNTech or Moderna) containing an updated BA.4/BA.5 component was recommended by CDC on September 1, 2022, (1) for adults who had completed a primary series with any Food and Drug Administration-approved or -authorized monovalent vaccine or who had previously received a monovalent booster dose ≥2 months earlier. § The VISION Network ¶ evaluated the effectiveness of a bivalent booster dose among immunocompetent adults during September 13-November 18, 2022, a period during which the Omicron BA.5 sublineage predominated and additional Omicron sublineages emerged. Seven health systems in nine states contributed data for this analysis. VISION methods have been described (3). Briefly, ED/UC encounters and hospitalizations associated with a COVID-19-like illness among adults who received a SARS-CoV-2 molecular test result during the 14 days before through 72 hours after the encounter were included.** Patients were classified as unvaccinated (zero doses received), vaccinated with 2, 3, or 4 doses of a monovalent-only mRNA vaccine, or vaccinated with 2, 3, or 4 monovalent doses plus a bivalent booster dose ≥60 days after receipt of their last monovalent dose. Encounters were excluded if 1) the patient likely had an immunocompromising condition (4); 2) only one mRNA monovalent vaccine dose was received, a second monovalent vaccine dose was received <14 days before the encounter date, or a third or fourth monovalent vaccine dose or a bivalent booster dose was received <7 days before the encounter date; 3) any dose of a non-mRNA vaccine (e.g., Janssen [Johnson & Johnson]) was received; or 4) a vaccine dose was received before being recommended by CDC. † † VE was estimated using a test-negative case-control design, comparing the odds of having received versus having not received a bivalent booster dose among case-patients (those who received a positive SARS-CoV-2 test result) and control patients (those who received a negative SARS-CoV-2 test result).

Discussion
Analysis of data from the multistate VISION Network found that during September-November 2022, when the BA.5 and other Omicron sublineages were the predominant circulating SARS-CoV-2 variants in the United States, bivalent booster doses (after receipt of 2, 3, or 4 monovalent doses) were effective in preventing medically attended COVID-19 compared with no previous vaccination among immunocompetent adults and provided additional protection when compared with previous monovalent mRNA vaccine doses only. VE was similar against COVID-19-associated ED/UC encounters and hospitalizations, which might reflect changing severity of hospitalized cases over time (5). Additional studies are needed to evaluate VE against outcomes such as COVID-19-associated severe respiratory illness or death. The IVY Network, an adult inpatient VE network, recently found higher estimated VE in adults aged ≥65 years compared with estimates for those aged ≥18 years included in this analysis (6). This might reflect differences in population subgroups evaluated. Long-term durability of bivalent booster vaccination protection also could not be assessed because of the short period of observation since bivalent dose receipt. In a recent analysis from VISION, during BA.4/BA.5-predominant circulation, 3-dose monovalent VE against COVID-19-associated hospitalization was observed to wane from 68% at 7-119 days after vaccination to 36% at ≥120 days (5). This might explain why, among patients who had received 2, 3, or 4 monovalent vaccine doses only, a longer   interval since the most recent dose was associated with more relative protection after receipt of the bivalent booster dose. Bivalent COVID-19 booster vaccines were developed to improve protection against circulating Omicron sublineages because of immune escape potentially associated with these subvariants and waning of monovalent vaccine-conferred protection over time (7). Real-world data suggest that bivalent boosters provide a modest degree of protection against symptomatic infection among adults compared with receipt of 2, 3, or 4 doses of monovalent vaccines only (8). Results from this study also demonstrate protection against ED/UC encounters and hospitalization during a period when BA.5 and other Omicron sublineage viruses predominated in the United States. With co-circulation of multiple respiratory viruses, including SARS-CoV-2, influenza, and respiratory syncytial virus, vaccination against respiratory diseases for which vaccines are available is especially important to prevent illnesses resulting in health care encounters and to reduce strain on the health care system (9). Additional studies will be critical to evaluating the durability of added protection, especially with circulation of sublineages of the BA.4/BA.5 Omicron variants such as BQ.1 and BQ.1.1. categories were combined. † † Previous SARS-CoV-2 infection was defined as having a positive SARS-CoV-2 test result (molecular or antigen) documented in the electronic health record ≥15 days before the hospital admission date. This does not capture infections in which testing was not performed or testing was performed but not available in the electronic health record, e.g., at-home testing. § § In-hospital death was identified at each individual site and was defined as a death while hospitalized and ≤28 days after admission.

Summary
What is already known about this topic? Bivalent mRNA COVID-19 booster doses containing an Omicron BA.4/BA.5 sublineage component were recommended on September 1, 2022. The effectiveness of these updated vaccines against COVID-19-associated medical encounters has not been established.
What is added by this report? Bivalent booster doses provided additional protection against COVID-19-associated emergency department/urgent care encounters and hospitalizations in persons who previously received 2, 3, or 4 monovalent vaccine doses. Because of waning of monovalent vaccine-conferred immunity, relative effectiveness of bivalent vaccines was higher with increased time since the previous monovalent dose.
What are the implications for public health practice?
All persons should stay up to date with recommended COVID-19 vaccinations, including receiving a bivalent booster dose if eligible.
The findings in this study are subject to at least six limitations. First, previous SARS-CoV-2 infection was not accounted for in this analysis. A large proportion of the population has now experienced SARS-CoV-2 infection which decreases the risk of future medically attended COVID-19 illness and might affect observed VE due to background immunity (10). Second, although models adjusted for relevant confounders, residual confounding is possible, including by behavioral differences and use of COVID-19 treatments such as nirmatrelvir/ritonavir (Paxlovid). Third, sublineage-specific VE could not be estimated. Fourth, this analysis did not compare product-specific bivalent booster VE estimates. Fifth, relative VE was estimated using the interval since receipt of last monovalent dose; this study was not statistically powered to estimate whether relative VE differed by number of previous monovalent vaccine doses received. Finally, because these data are from nine states, the patients in this analysis might not be representative of the entire population of the United States. Further, this analysis included adults who received bivalent booster doses shortly after authorization who might not be fully representative of the vaccine-eligible population. For example, over one half of bivalent booster recipients had previously received 4 monovalent vaccine doses. Additional VE studies are needed as coverage of bivalent boosters increases.
In this early study of immunocompetent adults, significant protection from a booster dose of bivalent mRNA COVID-19 vaccine (after receipt of 2, 3, or 4 monovalent doses) compared with no vaccination was found, as well as significant relative benefits of a bivalent booster dose when compared with previous receipt of monovalent doses only. These findings support efforts to improve coverage with bivalent vaccines, although optimal timing for receipt of bivalent vaccine booster doses needs to be established. All eligible persons should stay up to date with recommended COVID-19 vaccination, including receiving a bivalent booster dose. In addition, persons should consider taking other precautions to avoid respiratory illness this winter season, including masking in public indoor spaces, especially in areas where COVID-19 community levels are high, to protect themselves and others and reduce strain on the health care system during an ongoing surge in multiple respiratory viruses.