Association Between 3 Doses of mRNA COVID-19 Vaccine and Symptomatic Infection Caused by Omicron and Delta Variants | Vaccination | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

Association Between 3 Doses of mRNA COVID-19 Vaccine and Symptomatic Infection Caused by the SARS-CoV-2 Omicron and Delta Variants

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  What is the association between 3 doses of mRNA COVID-19 vaccine and symptomatic SARS-CoV-2 infection with the Omicron and Delta variants?

Findings  In this test-negative case-control analysis that included 70 155 tests from symptomatic adults, the likelihood of vaccination with 3 mRNA vaccine doses (vs unvaccinated) was significantly lower among both Omicron (odds ratio, 0.33) and Delta (odds ratio, 0.065) cases than SARS-CoV-2–negative controls; a similar pattern was observed with 3 vaccine doses vs 2 doses (Omicron odds ratio, 0.34; Delta odds ratio, 0.16).

Meaning  These findings suggest that vaccination with 3 doses of mRNA COVID-19 vaccine, compared with being unvaccinated and with receipt of 2 doses, was associated with protection against both the Omicron and Delta variants, although higher odds ratios for the association with Omicron infection suggest less protection for Omicron than for Delta.

Abstract

Importance  Assessing COVID-19 vaccine performance against the rapidly spreading SARS-CoV-2 Omicron variant is critical to inform public health guidance.

Objective  To estimate the association between receipt of 3 doses of Pfizer-BioNTech BNT162b2 or Moderna mRNA-1273 vaccine and symptomatic SARS-CoV-2 infection, stratified by variant (Omicron and Delta).

Design, Setting, and Participants  A test-negative case-control analysis among adults 18 years or older with COVID-like illness tested December 10, 2021, through January 1, 2022, by a national pharmacy-based testing program (4666 COVID-19 testing sites across 49 US states).

Exposures  Three doses of mRNA COVID-19 vaccine (third dose ≥14 days before test and ≥6 months after second dose) vs unvaccinated and vs 2 doses 6 months or more before test (ie, eligible for a booster dose).

Main Outcomes and Measures  Association between symptomatic SARS-CoV-2 infection (stratified by Omicron or Delta variants defined using S-gene target failure) and vaccination (3 doses vs unvaccinated and 3 doses vs 2 doses). Associations were measured with multivariable multinomial regression. Among cases, a secondary outcome was median cycle threshold values (inversely proportional to the amount of target nucleic acid present) for 3 viral genes, stratified by variant and vaccination status.

Results  Overall, 23 391 cases (13 098 Omicron; 10 293 Delta) and 46 764 controls were included (mean age, 40.3 [SD, 15.6] years; 42 050 [60.1%] women). Prior receipt of 3 mRNA vaccine doses was reported for 18.6% (n = 2441) of Omicron cases, 6.6% (n = 679) of Delta cases, and 39.7% (n = 18 587) of controls; prior receipt of 2 mRNA vaccine doses was reported for 55.3% (n = 7245), 44.4% (n = 4570), and 41.6% (n = 19 456), respectively; and being unvaccinated was reported for 26.0% (n = 3412), 49.0% (n = 5044), and 18.6% (n = 8721), respectively. The adjusted odds ratio for 3 doses vs unvaccinated was 0.33 (95% CI, 0.31-0.35) for Omicron and 0.065 (95% CI, 0.059-0.071) for Delta; for 3 vaccine doses vs 2 doses the adjusted odds ratio was 0.34 (95% CI, 0.32-0.36) for Omicron and 0.16 (95% CI, 0.14-0.17) for Delta. Median cycle threshold values were significantly higher in cases with 3 doses vs 2 doses for both Omicron and Delta (Omicron N gene: 19.35 vs 18.52; Omicron ORF1ab gene: 19.25 vs 18.40; Delta N gene: 19.07 vs 17.52; Delta ORF1ab gene: 18.70 vs 17.28; Delta S gene: 23.62 vs 20.24).

Conclusions and Relevance  Among individuals seeking testing for COVID-like illness in the US in December 2021, receipt of 3 doses of mRNA COVID-19 vaccine (compared with unvaccinated and with receipt of 2 doses) was less likely among cases with symptomatic SARS-CoV-2 infection compared with test-negative controls. These findings suggest that receipt of 3 doses of mRNA vaccine, relative to being unvaccinated and to receipt of 2 doses, was associated with protection against both the Omicron and Delta variants, although the higher odds ratios for Omicron suggest less protection for Omicron than for Delta.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Corresponding Author: Emma K. Accorsi, PhD, COVID-19 Response, US Centers for Disease Control and Prevention, 1600 Clifton Rd Mailstop H24-6, Atlanta, GA 30329 (vgi0@cdc.gov).

Accepted for Publication: January 13, 2022.

Published Online: January 21, 2022. doi:10.1001/jama.2022.0470

Author Contributions: Drs Accorsi and Britton 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 Accorsi and Britton contributed equally as co–first authors; Drs Verani and Schrag contributed equally as co–senior authors.

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

Acquisition, analysis, or interpretation of data: Accorsi, Britton, Fleming-Dutra, Smith, Shang, Derado, Schrag, Verani.

Drafting of the manuscript: Accorsi, Britton, Schrag, Verani.

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

Statistical analysis: Accorsi, Britton, Shang, Derado.

Obtained funding: Miller.

Administrative, technical, or material support: Britton, Smith, Miller, Verani.

Supervision: Miller, Schrag, Verani.

Conflict of Interest Disclosures: None reported.

Funding/Support: Funding for the Increasing Community Access to Testing platform was 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. 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.

References
1.
World Health Organization. Classification of Omicron (B.1.1.529): SARS-CoV-2 variant of concern. Updated November 26, 2021. Accessed December 23, 2021. https://www.who.int/news/item/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concern
2.
World Health Organization. Enhancing response to OMICRON (COVID-19 variant B.1.1.529): Technical brief and priority actions for Member States. January 7, 2022. Accessed January 11, 2022. https://www.who.int/publications/m/item/enhancing-readiness-for-omicron-(b.1.1.529)-technical-brief-and-priority-actions-for-member-states
3.
CDC COVID-19 Response Team.  SARS-CoV-2 B.1.1.529 (Omicron) variant—United States, December 1-8, 2021.   MMWR Morb Mortal Wkly Rep. 2021;70(50):1731-1734. doi:10.15585/mmwr.mm7050e1PubMedGoogle ScholarCrossref
4.
Centers for Disease Control and Prevention. COVID Data Tracker. Accessed January 7, 2021. https://covid.cdc.gov/covid-data-tracker/#variant-proportions
5.
Wang  L , Cheng  G .  Sequence analysis of the emerging SARS-CoV-2 variant Omicron in South Africa.   J Med Virol. 2021;1-6. doi:10.1002/jmv.27516PubMedGoogle Scholar
6.
GISAID. Tracking of variants. Accessed December 23, 2021. https://www.gisaid.org/hcov19-variants/
7.
National Institute for Communicable Diseases. COVID-19 weekly epidemiology brief, South Africa: week 47 2021. November 27, 2021. https://www.nicd.ac.za/wp-content/uploads/2021/12/COVID-19-Weekly-Epidemiology-Brief-week-47-2021.pdf
8.
UK Health Security Agency. SARS-CoV-2 variants of concern and variants under investigation in England. Technical briefing 33. December 23, 2021. Accessed December 23, 2021. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1043807/technical-briefing-33.pdf
9.
European Centre for Disease Prevention and Control. Implications of the further emergence and spread of the SARS-CoV-2 B.1.1.529 variant of concern (Omicron) for the EU/EEA—first update. Updated December 2, 2021. https://www.ecdc.europa.eu/sites/default/files/documents/threat-assessment-covid-19-emergence-sars-cov-2-variant-omicron-december-2021.pdf
10.
Centers for Disease Control and Prevention. Potential Rapid increase of Omicron variant infections in the United States. Updated December 20, 2021. Accessed December 23, 2021. https://www.cdc.gov/coronavirus/2019-ncov/science/forecasting/mathematical-modeling-outbreak.html
11.
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(49):1706-1711. doi:10.15585/mmwr.mm7049a3PubMedGoogle ScholarCrossref
12.
US Department of Health and Human Services. COVID-19 Pandemic Response, Laboratory Data Reporting: CARES Act Section 18115. Updated January 8, 2021. Accessed January 11, 2022. https://www.hhs.gov/sites/default/files/covid-19-laboratory-data-reporting-guidance.pdf
13.
Centers for Disease Control and Prevention. CDC/ATSDR SVI fact sheet. Updated April 28, 2021. Accessed December 23, 2021. https://www.atsdr.cdc.gov/placeandhealth/svi/index.html
14.
Vandenbroucke  JP , Pearce  N .  Test-negative designs: differences and commonalities with other case-control studies with “other patient” controls.   Epidemiology. 2019;30(6):838-844. doi:10.1097/EDE.0000000000001088PubMedGoogle ScholarCrossref
15.
Chua  H , Feng  S , Lewnard  JA ,  et al.  The use of test-negative controls to monitor vaccine effectiveness: a systematic review of methodology.   Epidemiology. 2020;31(1):43-64. doi:10.1097/EDE.0000000000001116PubMedGoogle ScholarCrossref
16.
Sullivan  SG , Tchetgen Tchetgen  EJ , Cowling  BJ .  Theoretical basis of the test-negative study design for assessment of influenza vaccine effectiveness.   Am J Epidemiol. 2016;184(5):345-353. doi:10.1093/aje/kww064PubMedGoogle ScholarCrossref
17.
Jackson  ML , Phillips  CH , Benoit  J ,  et al.  The impact of selection bias on vaccine effectiveness estimates from test-negative studies.   Vaccine. 2018;36(5):751-757. doi:10.1016/j.vaccine.2017.12.022PubMedGoogle ScholarCrossref
18.
Embi  PJ , Levy  ME , Naleway  AL ,  et al.  Effectiveness of 2-dose vaccination with mRNA COVID-19 vaccines against COVID-19–associated hospitalizations among immunocompromised adults—nine states, January-September 2021.   MMWR Morb Mortal Wkly Rep. 2021;70(44):1553-1559. doi:10.15585/mmwr.mm7044e3PubMedGoogle ScholarCrossref
19.
Mbaeyi  S , Oliver  SE , Collins  JP   et al.  The Advisory Committee on Immunization Practices’ interim recommendations for additional primary and booster doses of COVID-19 vaccines—United States, 2021.   MMWR Morb Mortal Wkly Rep. 2021;70:1545-1552. doi:10.15585/mmwr.mm7044e2Google ScholarCrossref
20.
Infectious Diseases Society of America and Association for Molecular Pathology. IDSA and AMP joint statement on the use of SARS-CoV-2 PCR cycle threshold (Ct) values for clinical decision-making. Updated March 12, 2021. https://www.idsociety.org/globalassets/idsa/public-health/covid-19/idsa-amp-statement.pdf
21.
Thermo Fisher Scientific confirms detection of SARS-CoV-2 in samples containing the Omicron variant with its TaqPath COVID-19 tests. Updated November 29, 2021. Accessed December 23, 2021. https://thermofisher.mediaroom.com/2021-11-29-Thermo-Fisher-Scientific-Confirms-Detection-of-SARS-CoV-2-in-Samples-Containing-the-Omicron-Variant-with-its-TaqPath-COVID-19-Tests
22.
Scott  L , Hsiao  NY , Moyo  S ,  et al.  Track Omicron’s spread with molecular data.   Science. 2021;374(6574):1454-1455. doi:10.1126/science.abn4543PubMedGoogle ScholarCrossref
23.
Chemaitelly  H , Tang  P , Hasan  MR ,  et al.  Waning of BNT162b2 vaccine protection against SARS-CoV-2 infection in Qatar.   N Engl J Med. 2021;385(24):e83. doi:10.1056/NEJMoa2114114PubMedGoogle Scholar
24.
Tartof  SY , Slezak  JM , Fischer  H ,  et al.  Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study.   Lancet. 2021;398(10309):1407-1416. doi:10.1016/S0140-6736(21)02183-8PubMedGoogle ScholarCrossref
25.
Tabak  YP , Sun  X , Brennan  TA , Chaguturu  SK .  Incidence and estimated vaccine effectiveness against symptomatic SARS-CoV-2 infection among persons tested in US retail locations, May 1 to August 7, 2021.   JAMA Netw Open. 2021;4(12):e2143346. doi:10.1001/jamanetworkopen.2021.43346PubMedGoogle Scholar
26.
Bruxvoort  KJ , Sy  LS , Qian  L ,  et al.  Effectiveness of mRNA-1273 against delta, mu, and other emerging variants of SARS-CoV-2: test negative case-control study.   BMJ. 2021;375:e068848. doi:10.1136/bmj-2021-068848PubMedGoogle Scholar
27.
Cao  Y , Wang  J , Jian  F ,  et al.  Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies.   Nature. Published online December 23, 2021. doi:10.1038/d41586-021-03796-6Google Scholar
28.
Cele  S , Jackson  L , Khoury  DS ,  et al.  Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization.   Nature. Published online December 23, 2021. doi:10.1038/d41586-021-03824-5Google Scholar
29.
Liu  L , Iketani  S , Guo  Y ,  et al.  Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2.   Nature. Published online December 23, 2021. doi:10.1038/s41586-021-04388-0Google Scholar
30.
Dejnirattisai  W , Shaw  RH , Supasa  P   et al.  Reduced neutralization of SARS-CoV-2 omicron B.1.1.529 variant by post-immunisation serum.   Lancet. 2021;399(10321):234-236. doi:10.1016/S0140-6736(21)02844-0PubMedGoogle ScholarCrossref
31.
Kissler  SM , Fauver  JR , Mack  C ,  et al.  Viral dynamics of SARS-CoV-2 variants in vaccinated and unvaccinated persons.   N Engl J Med. 2021;385(26):2489-2491. doi:10.1056/NEJMc2102507PubMedGoogle ScholarCrossref
32.
Bullard  J , Dust  K , Funk  D ,  et al.  Predicting infectious severe acute respiratory syndrome coronavirus 2 from diagnostic samples.   Clin Infect Dis. 2020;71(10):2663-2666. doi:10.1093/cid/ciaa63Google ScholarCrossref
33.
Al Bayat  S , Mundodan  J , Hasnain  S ,  et al.  Can the cycle threshold (Ct) value of RT-PCR test for SARS CoV2 predict infectivity among close contacts?   J Infect Public Health. 2021;14(9):1201-1205. doi:10.1016/j.jiph.2021.08.013PubMedGoogle ScholarCrossref
34.
Singanayagam  A , Patel  M , Charlett  A ,  et al.  Duration of infectiousness and correlation with RT-PCR cycle threshold values in cases of COVID-19, England, January to May 2020.   Euro Surveill. 2020;25(32):2001483. doi:10.2807/1560-7917.ES.2020.25.32.2001483PubMedGoogle Scholar
35.
Salvatore  PP , Dawson  P , Wadhwa  A ,  et al.  Epidemiological correlates of polymerase chain reaction cycle threshold values in the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).   Clin Infect Dis. 2021;72(11):e761-e767. doi:10.1093/cid/ciaa1469PubMedGoogle ScholarCrossref
36.
Marcus  JE , Frankel  DN , Pawlak  MT ,  et al.  Risk factors associated with COVID-19 transmission among US Air Force trainees in a congregant setting.   JAMA Netw Open. 2021;4(2):e210202-e210202. doi:10.1001/jamanetworkopen.2021.0202PubMedGoogle ScholarCrossref
37.
Regev-Yochay  G , Amit  S , Bergwerk  M ,  et al.  Decreased infectivity following BNT162b2 vaccination: a prospective cohort study in Israel.   Lancet Reg Health Eur. 2021;7:100150-100150. doi:10.1016/j.lanepe.2021.100150PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close