Early Estimates of Bivalent mRNA Booster Dose Vaccine Effectiveness in Preventing Symptomatic SARS-CoV-2 Infection Attributable to Omicron BA.5– and XBB/XBB.1.5–Related Sublineages Among Immunocompetent Adults — Increasing Community Access to Testing Program, United States, December 2022–January 2023

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The SARS-CoV-2 Omicron sublineage XBB was first detected in the United States in August 2022.* XBB together with a sublineage, XBB.1.5, accounted for >50% of sequenced lineages in the Northeast by December 31, 2022, and 52% of sequenced lineages nationwide as of January 21, 2023. COVID-19 vaccine effectiveness (VE) can vary by SARS-CoV-2 variant; reduced VE has been observed against some variants, although this is dependent on the health outcome of interest. The goal of the U.S. COVID-19 vaccination program is to prevent severe disease, including hospitalization and death (1); however, VE against symptomatic infection can provide useful insight into vaccine protection against emerging variants in advance of VE estimates against more severe disease. Data from the Increasing Community Access to Testing (ICATT) national pharmacy program for SARS-CoV-2 testing were analyzed to estimate VE of updated (bivalent) mRNA COVID-19 vaccines against symptomatic infection caused by BA.5-related and XBB/XBB.1.5-related sublineages among immunocompetent adults during December 1, 2022–January 13, 2023. Reduction or failure of spike gene (S-gene) amplification (SGTF) in real-time reverse transcription–polymerase chain reaction (RT-PCR) was used as a proxy indicator of infection with likely BA.5-related sublineages and S-gene target presence (SGTP) of infection with likely XBB/XBB.1.5-related sublineages (2). Among 29,175 nucleic acid amplification tests (NAATs) with SGTF or SGTP results available from adults who had previously received 2–4 monovalent COVID-19 vaccine doses, the relative VE of a bivalent booster dose given 2–3 months earlier compared with no bivalent booster in persons aged 18–49 years was 52% against symptomatic BA.5 infection and 48% against symptomatic XBB/XBB.1.5 infection. As new SARS-CoV-2 variants emerge, continued vaccine effectiveness monitoring is important. Bivalent vaccines appear to provide additional protection against symptomatic BA.5-related sublineage and XBB/XBB.1.5-related sublineage infections in persons who had previously received 2, 3, or 4 monovalent vaccine doses. All persons should stay up to date with recommended COVID-19 vaccines, including receiving a bivalent booster dose when they are eligible.

ICATT is designed to increase access to SARS-CoV-2 testing in areas with high social vulnerability^† through testing at selected pharmacy- and community-based testing sites nationwide.^§ ICATT VE methods have been described previously (3,4). Briefly, at test registration, adults report information on vaccination history,^¶ current COVID-19–like illness symptoms, previous positive SARS-CoV-2 test results, and underlying medical conditions. Adults receiving testing at participating sites during December 1, 2022–January 13, 2023, who reported one or more COVID-19–like illness symptoms were included. For this analysis, eligible tests were those performed at a commercial laboratory that used the real-time RT-PCR TaqPath COVID-19 Combo Kit (ThermoFischer Scientific); quantitative results were reported as cycle threshold (Ct) values for each of three SARS-CoV-2 gene targets (S, N, and ORF1ab). Specimens with missing Ct values for N or ORF1ab were excluded. SARS-CoV-2–positive specimens with either null or reduced amplification of the spike S-gene (Ct for S-gene >4 cycles from the average of N and ORF1ab Ct values) were considered to have SGTF (5); SARS-CoV-2–positive specimens without SGTF were considered to exhibit SGTP. SGTF or SGTP can serve as a proxy marker of SARS-CoV-2 lineages and sublineages with or without a deletion of amino acids 69–70 in the N-terminal domain of the spike protein, respectively (5). Currently circulating SARS-CoV-2 variants were classified by SGTF (BQ.1.1, BQ.1, BF.7, and other BA.4 and BA.5 sublineages) and SGTP (XBB.1.5, XBB, BN.1, and other BA.2 sublineages). During the week ending December 3, 2022, approximately 13% of specimens sequenced nationwide were BA.2 sublineages, including 2.4% XBB.1.5 (95% CI = 0.6%–6.2%) and 5.0% XBB (95% CI = 3.7%–6.6%); by the end of the analytic period, these proportions had risen to approximately 41%, including 37.2% XBB.1.5 (95% prediction interval [PI] = 26.8%–49.0%) and 4.0% XBB (95% PI = 3.3%–4.7%).**

Case-patients were persons who received a positive laboratory-based NAAT result classified as SGTF (BA.5-related) or SGTP (XBB/XBB.1.5-related); control-patients were those who received a negative NAAT result. Tests among persons fulfilling any of following criteria were excluded from analyses: 1) presence of an immunocompromising condition^††; 2) unvaccinated or receipt of only 1 COVID-19 vaccine dose; 3) receipt of a non-mRNA COVID-19 vaccine; 4) receipt of >4 monovalent mRNA doses if aged ≥50 years or >3 monovalent doses if aged 18–49 years; or 5) receipt of only 2 mRNA doses, with the second dose received <4 months before the SARS-CoV-2 test. Persons reporting an mRNA booster dose on or after September 1, 2022, were assumed to have received a bivalent dose because monovalent mRNA doses were not authorized for use as booster doses at that time.^§§ In addition, tests from persons who reported a positive SARS-CoV-2 test result during the preceding 90 days^¶¶ were excluded to avoid analyzing multiple tests for the same illness episode or reinfections within a relatively short time frame. Relative VE of a bivalent booster dose was calculated by comparing odds of receipt of a bivalent booster dose with those of no bivalent booster dose among persons who had received 2–4 monovalent vaccine doses. Odds ratios (ORs) were estimated using multivariable logistic regression***; VE was calculated separately based on SGTF/SGTP status as (1 − OR) x 100.

As of January 16, 2023, genomic sequencing data were available for a random subset of ICATT specimens with SGTP and collection dates through January 2, showing an increase in XBB.1.5 prevalence over time. During December 1, 2022–January 2, 2023, XBB.1.5 comprised 33% (495) of specimens exhibiting SGTP. During the interval December 11–January 2, XBB.1.5 accounted for 38% of sequenced ICATT specimens with SGTP (377), and during the interval December 18–January 2, XBB.1.5 accounted for 43% of sequenced ICATT specimens with SGTP (252)(2). As XBB.1.5 has continued to increase nationwide, true proportions of XBB.1.5 in the analytic dataset, which included tests through January 13, were likely higher, but sequencing results were not yet available for specimens collected during the whole period. Sensitivity analyses were conducted using two intervals, December 11, 2022–January 13, 2023, and December 18, 2022–January 13, 2023, to assess the effect of different proportions of the XBB.1.5 sublineage among SGTP cases during early December. Analyses were conducted using R software (version 4.1.2; R Foundation). This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.^†††

Among 29,175 NAAT results among persons with COVID-19–like illness symptoms eligible for this analysis, 13,648 (47%) were positive for SARS-CoV-2, including 10,596 (78%) with SGTF (BA.5-related) and 3,052 (22%) with SGTP (XBB/XBB.1.5-related) (Table 1). More control-patients who received negative SARS-CoV-2 test results reported having received a bivalent COVID-19 mRNA booster (34%) than did case-patients with positive SARS-CoV-2 test results (SGTF = 22%; SGTP = 21%). Among those who had received only monovalent vaccine doses, 45% reported a positive SARS-CoV-2 test result >90 days before the current test, compared with 34% among those who received a bivalent dose. Among those who had received only monovalent vaccine doses, the median interval since the last dose was 13 months (IQR = 11–17) for case-patients and 13 months (IQR = 11–18) for control-patients.

Across age groups, VE was generally similar against BA.5-related infections and XBB/XBB.1.5-related infections. VE against symptomatic BA.5-related infection was 52% among persons aged 18–49 years, 43% among persons aged 50–64, and 37% among those aged ≥65 years (Table 2). VE against symptomatic XBB/XBB.1.5-related infection was 49% among persons aged 18–49, 40% among persons aged 50–64 years, and 43% among those aged ≥65 years. Evidence of waning VE by 2–3 months after receiving a bivalent dose based on point estimates was minimal, although estimates were imprecise. Sensitivity analyses did not show a meaningful change in VE by different analytic period start dates (Table 3).

Acknowledgments

Stephanie Schrag, CDC; teams at Aegis Sciences Lab and Walgreens Co.

Corresponding author: Ruth Link-Gelles, media@cdc.gov.

¹National Center for Immunization and Respiratory Diseases, CDC; ²Eagle Health Analytics, San Antonio, Texas; ³Center for Preparedness and Response, CDC. ⁴Epidemic Intelligence Service, CDC.

References

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Abbreviations: HHS = U.S. Department of Health and Human Services; ICATT = Increasing Community Access to Testing program; NH = non-Hispanic; SGTF = S-gene target failure; SGTP = S-gene target presence; SVI = Social Vulnerability Index.
* Regions are defined by HHS and include only states and territories with ICATT sites. U.S. Virgin Islands (Region 2) and American Samoa, Federated States of Micronesia, Guam, Marshall Islands, Northern Mariana Islands, and Palau (Region 9) were not included because they did not have pharmacies participating in ICATT. States included in each region are available at https://www.hhs.gov/about/agencies/iea/regional-offices/index.html. For purposes of this analysis and because of the regional pattern of XBB-lineage infections, HHS Region 2 was split into “Region 2 – New York and New Jersey only” and “Region 2 – Puerto Rico only.”
^† SVI is a tool that uses U.S. Census Bureau data on 16 social factors to rank social vulnerability by U.S. Census Bureau tract. The scale is from zero to 1; higher SVIs represent more vulnerable communities. Tests with missing SVI data (<1% of total) were excluded from all analyses. https://www.atsdr.cdc.gov/placeandhealth/svi/data_documentation_download.html
^§ Underlying conditions included on the test registration questionnaire were heart conditions, high blood pressure, overweight or obesity, diabetes, current or former smoker, kidney failure or end stage renal disease, cirrhosis of the liver, and chronic lung disease (e.g., chronic obstructive pulmonary disease, moderate to severe asthma, cystic fibrosis, or pulmonary embolism).
^¶ Test registrants who reported receiving COVID-19 vaccines were asked to report the total number of doses and manufacturers of vaccines received and for the most recent dose, month, and year of receipt; 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 years without moderate or severe immunocompromise were not eligible for a fourth monovalent (second booster) dose.

Abbreviations: Ref = referent group; SGTF = S-gene target failure; SGTP = S-gene target presence; VE = vaccine effectiveness.
* VE = (1 – adjusted odds ratio) x 100. Odds ratios were calculated using multivariable logistic regression, adjusting for single year of age, gender, race, ethnicity, Social Vulnerability Index of the testing location (<0.5 versus ≥0.5), underlying conditions (presence versus absence), U.S. Department of Health and Human Services region, local incidence (cases per 100,000 by individual county and state in the 7 days before test date), and testing calendar date.
^† For doses received in the same month or the month preceding 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 years without moderate or severe immunocompromise were not eligible for a fourth monovalent (second booster) dose, so the Ref for this age stratum includes only those who received 2–3 monovalent doses.

Abbreviations: Ref = referent group; SGTF = S-gene target failure; SGTP = S-gene target presence; VE = vaccine effectiveness.
* VE = (1 – adjusted odds ratio) x 100. Odds ratios were calculated using multivariable logistic regression, adjusting for single year of age, gender, race, ethnicity, Social Vulnerability Index of the testing location (<0.5 versus ≥0.5), underlying conditions (presence versus absence), U.S. Department of Health and Human Services region, local incidence (cases per 100,000 by individual county and state in the 7 days before test date), and testing calendar date.
^† 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; only doses received ≥2 weeks before testing were included.
^§ Total tests include those that returned positive results for SARS-CoV-2 and had SGTF but are not included in this table. Row totals do not sum to 100%.
^¶ Persons aged <50 years without moderate or severe immunocompromise were not eligible for a fourth monovalent (second booster) dose, so the Ref for this age strata includes only those who received 2–3 monovalent doses.