Effectiveness of Bivalent mRNA Vaccines in Preventing Symptomatic SARS-CoV-2 Infection — Increasing Community Access to Testing Program, United States, September–November 2022

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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 <2 months before the SARS-CoV-2 test were excluded from analyses.** In addition, tests from persons who reported a positive result during the preceding 90 days^†† were excluded to avoid analyzing repeated tests for the same illness episode or reinfections within a relatively short time frame. Absolute VE (aVE) was calculated by comparing the odds of receipt of a bivalent booster dose (after 2, 3, or 4 monovalent vaccine doses) to being unvaccinated (zero doses of any COVID-19 vaccine) among case- and control-patients. rVE was calculated by comparing the odds of receiving a bivalent booster dose (after 2, 3, or 4 monovalent doses) versus not receiving a bivalent booster dose (but receiving 2, 3, or 4 monovalent doses). To explore how waning of protection after receipt of the most recent monovalent vaccine dose influenced the measured relative effectiveness of a subsequent bivalent booster dose, rVE of a bivalent booster dose was calculated by interval since receipt of the most recent monovalent vaccine dose among those who had not received a bivalent booster (2–3 months, 4–5 months, 6–7 months, and ≥8 months). Odds ratios (ORs) were calculated using multivariable logistic regression^§§; VE was calculated as (1 − OR) x 100. 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 persons aged ≥18 years reporting COVID-19–compatible symptoms, 360,626 tests were included; of these, 121,687 (34%) persons received positive test results (Table 1). Among these case-patients, 28,874 (24%) reported being unvaccinated, 87,013 (72%) had received 2, 3, or 4 monovalent vaccine doses but no bivalent booster dose, and 5,800 (5%) had received a bivalent booster dose. Among 238,939 control-patients who received negative test results, 72,010 (30%) reported being unvaccinated, 150,455 (63%) had received 2, 3, or 4 monovalent vaccine doses but no bivalent booster dose, and 16,474 (7%) had received a bivalent booster dose. Median interval between receipt of the bivalent booster dose and SARS-CoV-2 testing was 1 month (range = 0–2 months) and did not vary by case status. Self-reported infection >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%).

aVE of a bivalent booster dose received after ≥2 monovalent doses (compared with being unvaccinated) was similar among persons aged 50–64 years (28%) and ≥65 years (22%) but varied somewhat by number of previous monovalent vaccine doses (Table 2). Among adults aged 18–49 years, aVE after ≥2 monovalent doses (43%) was higher than that for older age groups and did not vary among those who received 2 or 3 previous monovalent vaccine doses.

Among persons who received ≥2 monovalent vaccine doses, rVE increased with time since the most recent monovalent vaccine dose in all age groups (Table 3). At 2–3 months and ≥8 months after receipt of the most recent monovalent dose, rVE of a bivalent mRNA COVID-19 vaccine 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.

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

1. Rosenblum HG, Wallace M, Godfrey M, et al. Interim recommendations from the Advisory Committee on Immunization Practices for the use of bivalent booster doses of COVID-19 vaccines—United States, October 2022. MMWR Morb Mortal Wkly Rep 2022;71:1436–41. https://doi.org/10.15585/mmwr.mm7145a2 PMID:36355612
2. Miller MF, Shi M, Motsinger-Reif A, Weinberg CR, Miller JD, Nichols E. Community-based testing sites for SARS-CoV-2—United States, March 2020–November 2021. MMWR Morb Mortal Wkly Rep 2021;70:1706–11. https://doi.org/10.15585/mmwr.mm7049a3 PMID:34882655
3. Fleming-Dutra KE, Britton A, Shang N, et al. Association of prior BNT162b2 COVID-19 vaccination with symptomatic SARS-CoV-2 infection in children and adolescents during Omicron predominance. JAMA 2022;327:2210–9. https://doi.org/10.1001/jama.2022.7493 PMID:35560036
4. Britton A, Embi PJ, Levy ME, et al. Effectiveness of COVID-19 mRNA vaccines against COVID-19–associated hospitalizations among immunocompromised adults during SARS-CoV-2 Omicron predominance—VISION Network, 10 states, December 2021–August 2022. MMWR Morb Mortal Wkly Rep 2022;71:1335–42. https://doi.org/10.15585/mmwr.mm7142a4 PMID:36264840
5. Wang Q, Bowen A, Valdez R, Gherasim C. Antibody responses to Omicron BA.4/BA.5 bivalent mRNA vaccine booster shot. bioRxiv [Preprint posted online October 24, 2022]. https://www.biorxiv.org/content/10.1101/2022.10.22.513349v1 https://doi.org/10.1101/2022.10.22.513349
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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 years without moderate or severe immunocompromise were not eligible for a fourth monovalent (second booster) dose. Because of timing of authorization, not enough persons ≥8 months from the fourth dose (second monovalent booster) were available to include in analyses.
^§ SARS-CoV-2 status after the most recent vaccine dose received.
^¶ Regions defined by HHS and include only states and territories with ICATT sites. U.S. Virgin Islands (Region 2) and Federated States of Micronesia, Guam, Marshall Islands, Northern Mariana Islands, Palau, and American Samoa (Region 9) were not included because they did not have pharmacies participating in ICATT. https://www.hhs.gov/about/agencies/iea/regional-offices/index.html
** 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 0 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
^†† Rapid NAAT was performed on-site on self-collected nasal swabs using ID Now (Abbott Diagnostics Scarborough Inc.) and Accula (Thermo Fisher Scientific).
^§§ Laboratory-based NAAT was performed on self-collected nasal swabs at contracted laboratories using a variety of testing platforms.
^¶¶ Underlying conditions included on the survey 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, chronic lung disease (such as chronic obstructive pulmonary disease, moderate to severe asthma, cystic fibrosis, or pulmonary embolism).

Abbreviations: NA = not applicable; VE = vaccine effectiveness.
* Persons aged <50 years without moderate or severe immunocompromise were not eligible for a fourth monovalent (second booster) dose.

Abbreviations: NA = not applicable; VE = vaccine effectiveness.
* VE estimates with 95% CIs >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 <50 years without moderate or severe immunocompromise were not eligible for a fourth monovalent (second booster) dose. Because of timing of authorization, not enough persons ≥8 months from the fourth dose (second booster) were available to include in analyses.