COVID-19 Incidence and Mortality Among Unvaccinated and Vaccinated Persons Aged ≥12 Years by Receipt of Bivalent Booster Doses and Time Since Vaccination — 24 U.S. Jurisdictions, October 3, 2021–December 24, 2022

On September 1, 2022, CDC recommended an updated (bivalent) COVID-19 vaccine booster to help restore waning protection conferred by previous vaccination and broaden protection against emerging variants for persons aged ≥12 years (subsequently extended to persons aged ≥6 months).* To assess the impact of original (monovalent) COVID-19 vaccines and bivalent boosters, case and mortality rate ratios (RRs) were estimated comparing unvaccinated and vaccinated persons aged ≥12 years by overall receipt of and by time since booster vaccination (monovalent or bivalent) during Delta variant and Omicron sublineage (BA.1, BA.2, early BA.4/BA.5, and late BA.4/BA.5) predominance.† During the late BA.4/BA.5 period, unvaccinated persons had higher COVID-19 mortality and infection rates than persons receiving bivalent doses (mortality RR = 14.1 and infection RR = 2.8) and to a lesser extent persons vaccinated with only monovalent doses (mortality RR = 5.4 and infection RR = 2.5). Among older adults, mortality rates among unvaccinated persons were significantly higher than among those who had received a bivalent booster (65-79 years, RR = 23.7 and ≥80 years; 10.3) or a monovalent booster (65-79 years, 8.3 and ≥80 years; 4.2). In a second analysis stratified by time since booster vaccination, there was a progressive decline from the Delta period (RR = 50.7) to the early BA.4/BA.5 period (7.4) in relative COVID-19 mortality rates among unvaccinated persons compared with persons receiving who had received a monovalent booster within 2 weeks-2 months. During the early BA.4/BA.5 period, declines in relative mortality rates were observed at 6-8 (RR = 4.6), 9-11 (4.5), and ≥12 (2.5) months after receiving a monovalent booster. In contrast, bivalent boosters received during the preceding 2 weeks-2 months improved protection against death (RR = 15.2) during the late BA.4/BA.5 period. In both analyses, when compared with unvaccinated persons, persons who had received bivalent boosters were provided additional protection against death over monovalent doses or monovalent boosters. Restored protection was highest in older adults. All persons should stay up to date with COVID-19 vaccination, including receipt of a bivalent booster by eligible persons, to reduce the risk for severe COVID-19.

On September 1, 2022, CDC recommended an updated (bivalent) COVID-19 vaccine booster to help restore waning protection conferred by previous vaccination and broaden protection against emerging variants for persons aged ≥12 years (subsequently extended to persons aged ≥6 months).* To assess the impact of original (monovalent) COVID-19 vaccines and bivalent boosters, case and mortality rate ratios (RRs) were estimated comparing unvaccinated and vaccinated persons aged ≥12 years by overall receipt of and by time since booster vaccination (monovalent or bivalent) during Delta variant and Omicron sublineage (BA.1, BA.2, early BA.4/BA.5, and late BA.4/BA.5) predominance. † During the late BA.4/BA.5 period, unvaccinated persons had higher COVID-19 mortality and infection rates than persons receiving bivalent doses (mortality RR = 14.1 and infection RR = 2.8) and to a lesser extent persons vaccinated with only monovalent doses (mortality RR = 5.4 and infection RR = 2.5). Among older adults, mortality rates among unvaccinated persons were significantly higher than among those who had received a bivalent booster (65-79 years, RR = 23.7 and ≥80 years; 10 relative COVID-19 mortality rates among unvaccinated persons compared with persons receiving who had received a monovalent booster within 2 weeks-2 months. During the early BA.4/BA.5 period, declines in relative mortality rates were observed at 6-8 (RR = 4.6), 9-11 (4.5), and ≥12 (2.5) months after receiving a monovalent booster. In contrast, bivalent boosters received during the preceding 2 weeks-2 months improved protection against death (RR = 15.2) during the late BA.4/BA.5 period. In both analyses, when compared with unvaccinated persons, persons who had received bivalent boosters were provided additional protection against death over monovalent doses or monovalent boosters. Restored protection was highest in older adults. All persons should stay up to date with COVID-19 vaccination, including receipt of a bivalent booster by eligible persons, to reduce the risk for severe COVID-19.
Previous reports on COVID-19 vaccine impact indicated that protection against infection and, to a lesser degree, severe illness, declined with waning of vaccine-induced immunity and emergence of the SARS-CoV-2 Delta and Omicron variants § (1)(2)(3)(4) Weekly counts of COVID-19 cases (October 3, 2021-December 24, 2022) and associated deaths (October 3, 2021-December 3, 2022) by primary series vaccination and § https://covid.cdc.gov/covid-data-tracker/#covidnet-hospitalizations-vaccination booster status, including bivalent boosters (the week starting September 18, 2022), were reported from 24 jurisdictions ¶ that routinely link case surveillance data to immunization registries (vaccinations) and vital registration databases (deaths). Accounting for case and death reporting lags (2 weeks and 5 weeks, respectively) permitted more complete reporting, data linkage, and mortality ascertainment. Standardized definitions were used for COVID-19 cases** and COVID-19-associated deaths † † by vaccination status § § with specimen collection dates used as reference dates; vaccinated persons who did not complete a primary COVID-19 vaccination series were excluded. Analysis periods were determined based on U.S. variant proportion estimates. Rate denominators were calculated from vaccine administration data, with numbers of unvaccinated persons estimated by subtracting numbers of persons vaccinated with at least a primary series and persons with an incomplete primary series from 2019 U.S. intercensal population estimates. ¶ ¶ A continuity correction assumed that ≥5% of each age group and jurisdiction would always be unvaccinated (i.e., ≤95% vaccination coverage).*** Average ¶ The 24 jurisdictions included in this analysis represent 52% of the U. COVID-19 diagnosis who died and whose report local health authorities reviewed to make that determination (e.g., using vital records, public health investigation, or other data sources). Per national guidance, this group should include persons whose death certificate lists COVID-19 or SARS-CoV-2 as an underlying cause or a significant condition contributing to death (https:// preparedness.cste.org/wp-content/uploads/2022/12/CSTE-Revised-Classification-of-COVID-19-associated-Deaths.Final_.11.22.22.pdf). Rates of COVID-19 deaths by vaccination status are reported based on when specimens were tested for COVID-19, not the date the patient died. § § COVID-19 cases among unvaccinated persons and persons vaccinated with a primary series with or without a monovalent or bivalent booster dose were defined as previously described (https://www.cdc.gov/coronavirus/2019ncov/php/hd-breakthrough.html). COVID-19 patients who had received a primary series or a monovalent booster were combined in the "vaccinated with monovalent vaccines only" category. Cases were excluded among persons who received ≥1 FDA-authorized vaccine dose but did not complete a primary series ≥14 days before the positive specimen collection date. ¶ ¶ https://www.census.gov/programs-surveys/popest/data/tables.2019.html *** A continuity correction was applied to denominators by capping the percentage of population coverage at 95%. To do this, it was assumed that ≥5% of each age group would always be unvaccinated in each jurisdiction. Adding this correction ensures that there is always a reasonable denominator for the unvaccinated population and prevents incidence and death rates from growing unrealistically large because of potential overestimates of vaccination coverage.
weekly incidence and mortality were calculated during each period and stratified by age group (12-17, 18-49, 50-64, 65-79 and ≥80 years) and vaccination status; overall rates were age-standardized using the 2000 U.S. Census Bureau standard population. † † † Two sets of analyses of incidence and mortality rates overall (24 jurisdictions) and by time since last monovalent or bivalent booster vaccination (23 jurisdictions) were conducted. Overall and strata-specific RRs were calculated by dividing rates among unvaccinated persons by rates among vaccinated persons; after detrending the underlying linear changes in rates, 95% CIs were calculated from the remaining variation in observed weekly rates § § § (8,9). SAS (version 9.4; SAS Institute) and R (version 4.1.2; R Foundation) were used to conduct all analyses. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy. ¶ ¶ ¶ Among persons aged ≥12 years, a total of 21,296,326 COVID-19 cases and 115,078 associated deaths were reported during October 3, 2021-December 24, 2022, and October 3, 2021-December 3, 2022, respectively, from 24 U.S. jurisdictions (Table). Average weekly age-standardized incidence and mortality (cases and deaths per 100,000 population aged ≥12 years) increased substantially during the Omicron BA.1 period and to a lesser extent during the early BA.4/BA.5 period ( Figure 1). During all periods, average weekly age-standardized incidence and mortality were consistently higher among unvaccinated persons (ranges = 216.1-1,256.0 and 1.6-15.8, respectively) than among monovalent-only vaccine recipients (ranges = 86.4-487.7 and 0.3-1.4, respectively); average weekly incidence and mortality during the late BA.4/BA.5 period were lowest among bivalent booster recipients (78.5 and 0.1, respectively).
Overall, age-standardized case RRs (unvaccinated persons compared with monovalent-only vaccine recipients) declined from 4.0 during the Delta period to 2.6 during the Omicron BA. 1    In stratified comparisons of unvaccinated persons and vaccinated persons who had received a monovalent booster dose 2 weeks-2 months earlier, progressive declines in case RRs were more pronounced between the Delta (7.0) and BA.1  Abbreviation: RR = rate ratio.
* Cases per 100,000 persons aged ≥12 years. COVID-19 cases among unvaccinated persons and persons vaccinated with a primary series with or without a monovalent or bivalent booster dose were defined as previously described (https://www.cdc.gov/coronavirus/2019-ncov/php/hd-breakthrough.html). Cases with primary series or a monovalent booster were combined in the "vaccinated only with monovalent vaccines" category. Cases were excluded among persons who received ≥1 Food and Drug Administration-authorized vaccine dose but did not complete a primary series ≥14 days before the positive specimen collection date. † Deaths per 100,000 persons aged ≥12 years. A COVID-19-associated death occurred in a person with a documented COVID-19 diagnosis who died, and whose report local health authorities reviewed to make that determination (e.g., using vital records, public health investigation, or other data sources). Per national guidance, this group includes persons whose death certificate lists COVID-19 or SARS-CoV-2 as an underlying cause of death or a significant condition contributing to death. COVID-19 mortality by vaccination status is reported based on COVID-19 test date, not the date the patient died.   Positive specimen collection date Positive specimen collection date COVID-19 cases COVID-19-associated deaths * Cases per 100,000 persons aged ≥12 years. COVID-19 cases among unvaccinated persons and persons vaccinated with a primary series with or without a monovalent or bivalent booster dose were defined as previously described (https://www.cdc.gov/coronavirus/2019-ncov/php/hd-breakthrough.html). Cases with primary series or a monovalent booster were combined in the "vaccinated only with monovalent vaccines" category. Cases were excluded among persons who received ≥1 Food and Drug Administration-authorized vaccine dose but did not complete a primary series ≥14 days before the positive specimen collection date. † Deaths per 100,000 persons aged ≥12 years. A COVID-19-associated death occurred in a person with a documented COVID-19 diagnosis who died, and whose report local health authorities reviewed to make that determination (e.g., using vital records, public health investigation, or other data sources). Per national guidance, this group should include persons whose death certificate lists COVID-19 or SARS-CoV-2 as an underlying cause or a significant condition contributing to death. Rates of COVID-19 deaths by vaccination status are reported based on when the patient was tested for COVID-19, not the date the patient died. § Bivalent boosters were recommended during September 1-December 24, 2022. Based on case definitions, a case after vaccination occurred in a person ≥14 days postvaccination. ¶ These 24 jurisdictions represent 52% of the overall U.S. population and were included in this analysis: Alabama, Arizona, Arkansas, Colorado, District of Columbia, Georgia, Idaho, Indiana, Kansas, Kentucky, Louisiana, Massachusetts, Michigan, Minnesota, Nebraska, New Jersey, New Mexico, New York, North Carolina, Tennessee, Texas, Utah, Washington, and West Virginia; New York did not provide mortality data. ** Date range for age-standardized weekly COVID-19 incidence is October 3, 2021-December 24, 2022; date range for COVID-19-associated mortality rates is October 3, 2021-December 3, 2022.

Discussion
This multijurisdictional report of COVID-19 case and mortality rates included two sets of analyses with different comparisons by vaccination status. In the first, overall rates among unvaccinated persons were compared to rates in persons with only monovalent doses or bivalent boosters. Receipt of bivalent booster added protection against infection and death for circulating Omicron BA.4/BA.5 sublineages. When stratifying by time since vaccination for the second analysis, comparisons during the late BA.4/BA.5 period of monovalent and bivalent boosters found that bivalent boosters restored protection against mortality and provided similar protection against infection at 2 weeks through 2 months. Although long-term protection could not yet be assessed, evidence of waning protection against infection 3 months after bivalent booster dose receipt was observed. This study supports previous findings of protection afforded by bivalent vaccines against infection and medically attended illness during BA.4/BA.5 predominance (5-7) and provides additional evidence of enhanced protection against COVID-19-associated mortality. To date, however, bivalent booster coverage has been low (17.5% among persons aged ≥12 years). § § § § § § § § https://covid.cdc.gov/covid-data-tracker/#vaccinations_vacc-total-adminrate-total During the early BA.4/BA.5 period, waning protection against COVID-19-associated death was observed ≥6 months after receipt of monovalent boosters, although decreases were not always statistically significant. Findings were similar to those reported in a 2021 study on waning immunity from primary COVID-19 vaccination during the Delta period (4). Patterns of waning protection against COVID-19-associated death after receiving a monovalent booster were less apparent during the late BA.4/BA.5 period; this might be related to smaller sample sizes and potential boosts to immunity over time resulting from recent infections or receipt of boosters that were not matched to existing vaccination records. Wellcontrolled VE studies conducted during the BA.4/BA.5 period have shown waning protection of monovalent doses against hospitalization starting at 4 months, with incremental benefits of bivalent boosters with increasing time since the last monovalent dose ¶ ¶ ¶ ¶ (6,7).
The findings in this report are subject to at least six limitations. First, authorizations for monovalent and bivalent boosters were not concurrent; the median time after vaccination was longer for persons who received monovalent boosters than for those who received bivalent boosters, which limits direct comparability. Second, distinguishing monovalent boosters from additional primary doses administered to immunocompromised persons was not possible, which could result in reduced RRs because of lower VE in this population. Third, this ecologic study could not adjust for important confounders that might contribute to rate differences, such as possible ¶ ¶ ¶ ¶ https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-09-01/04-covid-link-gelles-508.pdf variations in infection-derived immunity, co-morbidities, and testing or prevention behaviors by age and vaccination status (1). Increased at-home test use has affected trends in case incidence more than trends in mortality over time (1); however, increases have been noted in COVID-19-associated deaths without laboratory-confirmation,***** which were not included in data reported by vaccination status, possibly reducing recent RRs. Fourth, national variant prevalence estimates were used, but variant prevalence differs by region. Fifth, misclassification of bivalent or monovalent boosters could influence RRs (10). Cases in bivalent booster recipients might have been preferentially identified because accounting for bivalent doses reported as first and second doses was possible, whereas distinguishing unlinked monovalent boosters from first or second doses was not possible. Finally, these data represent approximately one half of the U.S. population, and therefore, might not be generalizable. This report presents evidence of the enhanced protection provided by bivalent COVID-19 boosters compared to monovalent vaccines against infection and death during the BA.4/BA.5 period and are consistent with other VE studies. Continued monitoring of the impact of emerging variants on VE against severe COVID-19 outcomes is needed. For the best protection against severe COVID-19, all persons should stay up to date with recommended COVID-19 vaccination, including receipt of a bivalent booster by eligible persons.