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Association of COVID-19 Vaccination With Symptomatic SARS-CoV-2 Infection by Time Since Vaccination and Delta Variant Predominance

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To identify the key insights or developments described in this article
Key Points

Question  How does the association between prior COVID-19 vaccination and symptomatic SARS-CoV-2 infection change with time since vaccination and the SARS-CoV-2 Delta variant?

Findings  In this test-negative, case-control study that included 1 634 271 tests from symptomatic adults, the odds ratio for prior mRNA vaccination and SARS-CoV-2 test positivity was lower before than during Delta variant predominance. The attenuation in effect size related to time since vaccination was greater than the attenuation related to the Delta variant.

Meaning  The findings are consistent with a steady decline in estimated mRNA vaccine effectiveness over time, separate from variant-specific differences in protection.


Importance  Monitoring COVID-19 vaccine performance over time since vaccination and against emerging variants informs control measures and vaccine policies.

Objective  To estimate the associations between symptomatic SARS-CoV-2 infection and receipt of BNT162b2, mRNA-1273, and Ad26.COV2.S by day since vaccination before and during Delta variant predominance (pre-Delta period: March 13-May 29, 2021; Delta period: July 18-October 17, 2021).

Design, Setting, and Participants  Test-negative, case-control design with data from 6884 US COVID-19 testing sites in the pharmacy-based Increasing Community Access to Testing platform. This study included 1 634 271 laboratory-based SARS-CoV-2 nucleic acid amplification tests (NAATs) from adults 20 years and older and 180 112 NAATs from adolescents 12 to 19 years old with COVID-19–like illness from March 13 to October 17, 2021.

Exposures  COVID-19 vaccination (1 Ad26.COV2.S dose or 2 mRNA doses) 14 or more days prior.

Main Outcomes and Measures  Association between symptomatic infection and prior vaccination measured using the odds ratio (OR) from spline-based multivariable logistic regression.

Results  The analysis included 390 762 test-positive cases (21.5%) and 1 423 621 test-negative controls (78.5%) (59.9% were 20-44 years old; 9.9% were 12-19 years old; 58.9% were female; 71.8% were White). Among adults 20 years and older, the BNT162b2 mean OR for days 14 to 60 after a second dose (initial OR) was lower during the pre-Delta period (0.10 [95% CI, 0.09-0.11]) than during the Delta period (0.16 [95% CI, 0.16-0.17]) and increased with time since vaccination (per-month change in OR, pre-Delta: 0.04 [95% CI, 0.02-0.05]; Delta: 0.03 [95% CI, 0.02-0.03]). The initial mRNA-1273 OR was 0.05 (95% CI, 0.04-0.05) during the pre-Delta period, 0.10 (95% CI, 0.10-0.11) during the Delta period, and increased with time (per-month change in OR, pre-Delta: 0.02 [95% CI, 0.005-0.03]; Delta: 0.03 [95% CI, 0.03-0.04]). The Ad26.COV2.S initial OR was 0.42 (95% CI, 0.37-0.47) during the pre-Delta period and 0.62 (95% CI, 0.58-0.65) during the Delta period and did not significantly increase with time since vaccination. Among adolescents, the BNT162b2 initial OR during the Delta period was 0.06 (95% CI, 0.05-0.06) among 12- to 15-year-olds, increasing by 0.02 (95% CI, 0.01-0.03) per month, and 0.10 (95% CI, 0.09-0.11) among 16- to 19-year-olds, increasing by 0.04 (95% CI, 0.03-0.06) per month.

Conclusions and Relevance  Among adults, the OR for the association between symptomatic SARS-CoV-2 infection and COVID-19 vaccination (as an estimate of vaccine effectiveness) was higher during Delta variant predominance, suggesting lower protection. For mRNA vaccination, the steady increase in OR by month since vaccination was consistent with attenuation of estimated effectiveness over time; attenuation related to time was greater than that related to variant.

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Article Information

Corresponding Author: Amadea Britton, MD, COVID-19 Response, US Centers for Disease Control and Prevention, 1600 Clifton Rd, Mailstop H24-6, Atlanta, GA 30329 (LTO7@cdc.gov).

Accepted for Publication: February 3, 2022.

Published Online: February 14, 2022. doi:10.1001/jama.2022.2068

Author Contributions: Drs Britton and Shang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Britton and Fleming-Dutra contributed equally to this article. Drs Verani and Schrag contributed equally to this article.

Concept and design: Britton, Fleming-Dutra, Shang, Ajani, Schrag, Verani.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Britton, Fleming-Dutra, Shang, Dorji, Schrag, Verani.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Britton, Shang, Dorji, Derado, Accorsi.

Obtained funding: Miller.

Administrative, technical, or material support: Britton, Fleming-Dutra, Smith, Ajani, Miller, Schrag, Verani.

Supervision: Fleming-Dutra, Miller, Schrag, Verani.

Conflict of Interest Disclosures: None reported.

Funding/Support: Funding for the Increasing Community Access to Testing platform is provided by the US Department of Health and Human Services. Funding for this analysis was provided by the Centers for Disease Control and Prevention (CDC).

Role of the Funder/Sponsor: The CDC was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. The CDC controlled publication decisions.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC.

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