Association Between 3 Doses of mRNA COVID-19 Vaccine and Symptomatic Infection Caused by the SARS-CoV-2 Omicron and Delta Variants
Open accessAbstract
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.
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Real-world vaccine effectiveness studies during Delta and Omicron circulation showed less vaccine-induced protection against Omicron than against Delta.
“Real-word VE studies published during the periods of circulation of these two variants showed differences in vaccine-induced protection against Delta and Omicron variants-related infections, with less protection against Omicron than Delta [18-22].”
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Cites
Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies
Cao, Y., Wang, J., Jian, F., Xiao, T., Song, W., Yisimayi, A., Huang, W., Li, Q., Wang, P., An, R., et al. (2022) · Nature · doi:10.1038/s41586-021-04385-3 · Cited by 2,006 · see citing works
Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2
Liu, L., Iketani, S., Guo, Y., Chan, J. F.-W., Wang, M., Liu, L., Luo, Y., Chu, H., Huang, Y., Nair, M. S., et al. (2022) · Nature · doi:10.1038/s41586-021-04388-0 · Cited by 1,290 · see citing works
Tartof, S. Y., Slezak, J. M., Fischer, H., Hong, V., Ackerson, B. K., Ranasinghe, O. N., Frankland, T. B., Ogun, O. A., Zamparo, J. M., Gray, S., et al. (2021) · The Lancet · doi:10.1016/s0140-6736(21)02183-8 · Cited by 1,167 · see citing works
Decreased infectivity following BNT162b2 vaccination: A prospective cohort study in Israel
Regev-Yochay, G., Amit, S., Bergwerk, M., Lipsitch, M., Leshem, E., Kahn, R., Lustig, Y., Cohen, C., Doolman, R., Ziv, A., et al. (2021) · The Lancet Regional Health - Europe · doi:10.1016/j.lanepe.2021.100150 · Cited by 111 · see citing works
Flagged first, then by citations
Research works printed but not linked: 21
- 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. mm7050e1 · DOI
- 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. 27516 · DOI
- 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. mm7049a3 · DOI
- 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.0000000000001088 · DOI
- 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. 0000000000001116 · DOI
- 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/kww064 · DOI
- 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.2017.12.022 · DOI
- 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.mm7044e3 · DOI
- 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.mm7044e2 · DOI
- 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. abn4543 · DOI
- 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/NEJMoa2114114 · DOI · Paper page
- 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. 43346 · DOI
- 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-2021-068848 · DOI · Paper page
- 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- 03824-5 · DOI
- 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)02844-0 · DOI
- 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/NEJMc2102507 · DOI · Paper page
- 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/ciaa63 · DOI
- 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.2021.08.013 · DOI
- 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. 2020.25.32.2001483 · DOI · Paper page
- 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/ciaa1469 · DOI
- 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.2021.0202 · DOI
Cited by
Sorted by citations
Effectiveness of mRNA-1273 against SARS-CoV-2 omicron and delta variants
Tseng, H. F., Ackerson, B. K., Luo, Y., Sy, L. S., Talarico, C. A., Tian, Y., Bruxvoort, K. J., Tubert, J. E., Florea, A., Ku, J. H., et al. (2022) · doi:10.1101/2022.01.07.22268919 · Cited by 541 · see citing works
Buchan, S. A., Chung, H., Brown, K. A., Austin, P. C., Fell, D. B., Gubbay, J. B., Nasreen, S., Schwartz, K. L., Sundaram, M. E., Tadrous, M., et al. (2022) · JAMA Network Open · doi:10.1001/jamanetworkopen.2022.32760 · Cited by 356 · see citing works
Gram, M. A., Emborg, H.-D., Schelde, A. B., Friis, N. U., Nielsen, K. F., Moustsen-Helms, I. R., Legarth, R., Lam, J. U. H., Chaine, M., Malik, A. Z., et al. (2022) · PLOS Medicine · doi:10.1371/journal.pmed.1003992 · Cited by 146 · see citing works
Au, W. Y., & Cheung, P. P.-H. (2022) · BMJ · doi:10.1136/bmj-2022-069989 · Cited by 143 · see citing works
Lin, D.-Y., Gu, Y., Xu, Y., Wheeler, B., Young, H., Sunny, S. K., Moore, Z., & Zeng, D. (2022) · JAMA · doi:10.1001/jama.2022.17876 · Cited by 129 · see citing works
Buchan, S. A., Chung, H., Brown, K. A., Austin, P. C., Fell, D. B., Gubbay, J. B., Nasreen, S., Schwartz, K. L., Sundaram, M. E., Tadrous, M., et al. (2022) · doi:10.1101/2021.12.30.21268565 · Cited by 356 · see citing works
Chu, L., Montefiori, D., Huang, W., Nestorova, B., Chang, Y., Carfi, A., Edwards, D. K., Oestreicher, J., Legault, H., Girard, B., et al. (2021) · doi:10.1101/2021.09.29.21264089 · Cited by 105 · see citing works
Self-citationMonge, S., Rojas-Benedicto, A., Olmedo, C., Mazagatos, C., José Sierra, M., Limia, A., Martín-Merino, E., Larrauri, A., Hernán, M. A., Moreno, D., et al. (2022) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(22)00292-4 · Cited by 81 · see citing works
Wang, W., Lusvarghi, S., Subramanian, R., Epsi, N. J., Wang, R., Goguet, E., Fries, A. C., Echegaray, F., Vassell, R., Coggins, S., et al. (2022) · doi:10.1101/2022.07.05.498883 · Cited by 68 · see citing works
Imprinted antibody responses against SARS-CoV-2 Omicron sublineages
Park, Y.-J., Pinto, D., Walls, A. C., Liu, Z., De Marco, A., Benigni, F., Zatta, F., Silacci-Fregni, C., Bassi, J., Sprouse, K. R., et al. (2022) · doi:10.1101/2022.05.08.491108 · Cited by 251 · see citing works
The Vaccine Efficacy Against the SARS-CoV-2 Omicron: A Systemic Review and Meta-Analysis
Zou, Y., Huang, D., Jiang, Q., Guo, Y., & Chen, C. (2022) · Frontiers in Public Health · doi:10.3389/fpubh.2022.940956 · Cited by 52 · see citing works
Külper-Schiek, W., Piechotta, V., Pilic, A., Batke, M., Dreveton, L.-S., Geurts, B., Koch, J., Köppe, S., Treskova, M., Vygen-Bonnet, S., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.940562 · Cited by 44 · see citing works
Tartof, S. Y., Slezak, J. M., Puzniak, L., Hong, V., Frankland, T. B., Xie, F., Ackerson, B. K., Valluri, S. R., Jodar, L., & McLaughlin, J. M. (2023) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(22)00354-x · Cited by 36 · see citing works
Song, S., Madewell, Z. J., Liu, M., Longini, I. M., & Yang, Y. (2023) · Frontiers in Public Health · doi:10.3389/fpubh.2023.1195908 · Cited by 34 · see citing works
Pratama, N. R., Wafa, I. A., Budi, D. S., Sutanto, H., Asmarawati, T. P., Barlian Effendi, G., & Wungu, C. D. K. (2022) · Vaccines · doi:10.3390/vaccines10122180 · Cited by 30 · see citing works
Rahman, M. O., Kamigaki, T., Thandar, M. M., Haruyama, R., Yan, F., Shibamura-Fujiogi, M., Khin Maung Soe, J., Islam, M. R., Yoneoka, D., Miyahara, R., et al. (2023) · BMJ Open · doi:10.1136/bmjopen-2023-076892 · Cited by 29 · see citing works
Tamandjou Tchuem, C. R., Auvigne, V., Vaux, S., Montagnat, C., Paireau, J., Monnier Besnard, S., Gabet, A., Benhajkassen, N., Le Strat, Y., Parent Du Chatelet, I., et al. (2023) · Vaccine · doi:10.1016/j.vaccine.2023.02.062 · Cited by 27 · see citing works
“Real-word VE studies published during the periods of circulation of these two variants showed differences in vaccine-induced protection against Delta and Omicron variants-related infections, with less protection against Omicron than Delta [18–22].”
Meggiolaro, A., Sane Schepisi, M., Farina, S., Castagna, C., Mammone, A., Siddu, A., Stefanelli, P., Boccia, S., & Rezza, G. (2022) · Expert Review of Vaccines · doi:10.1080/14760584.2022.2130773 · Cited by 17 · see citing works
Arashiro, T., Miwa, M., Nakagawa, H., Takamatsu, J., Oba, K., Fujimi, S., Kikuchi, H., Iwasawa, T., Kanbe, F., Oyama, K., et al. (2024) · Vaccine · doi:10.1016/j.vaccine.2023.12.033 · Cited by 11 · see citing works
- Authors
- Accorsi, E. K., Britton, A., Fleming-Dutra, K. E., Smith, Z. R., Shang, N., Derado, G., Miller, J., Schrag, S. J., & Verani, J. R.
- Affiliations
- Centers for Disease Control and Prevention (US)
- Corresponding author
- Accorsi, Emma K.
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2022-02-15
- Volume
- 327
- Issue
- 7
- Pages
- 639
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC8848203
- OpenAlex
- W4206040938
- Cited by
- 628
- References
- 4
- Citations by year
- 2026: 10 · 2025: 29 · 2024: 78 · 2023: 178 · 2022: 332 · 2021: 1
- FWCI
- 75.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Physical Sciences › Mathematics › Modeling and Simulation › COVID-19 epidemiological studies
- Social Sciences › Health › Vaccine Coverage and Hesitancy
- Keywords
- COVID-19 vaccines, third vaccine dose, booster vaccination, mRNA-1273, BNT162b2, Omicron variant, Delta variant, symptomatic infection, vaccine effectiveness, S-gene target failure, cycle threshold, test-negative case-control, COVID-19 prevention
- MeSH terms
- COVID-19, SARS-CoV-2, COVID-19 Vaccines, Vaccine Efficacy, BNT162 Vaccine, 2019-nCoV Vaccine mRNA-1273, Adolescent, Adult, Aged, Dose-Response Relationship, Immunologic, Humans, Immunization, Secondary, Middle Aged, Regression Analysis, Retrospective Studies, Risk Factors, Odds Ratio, Case-Control Studies, Young Adult
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