Observational Study

. 2022 Mar 9:376:e069761.

doi: 10.1136/bmj-2021-069761.

Clinical severity of, and effectiveness of mRNA vaccines against, covid-19 from omicron, delta, and alpha SARS-CoV-2 variants in the United States: prospective observational study

Adam S Lauring¹, Mark W Tenforde², James D Chappell³, Manjusha Gaglani⁴, Adit A Ginde⁵, Tresa McNeal⁴, Shekhar Ghamande⁴, David J Douin⁶, H Keipp Talbot^{7

8}, Jonathan D Casey⁸, Nicholas M Mohr⁹, Anne Zepeski⁹, Nathan I Shapiro¹⁰, Kevin W Gibbs¹¹, D Clark Files¹¹, David N Hager¹², Arber Shehu¹², Matthew E Prekker^{13

14}, Heidi L Erickson¹⁴, Matthew C Exline¹⁵, Michelle N Gong¹⁶, Amira Mohamed¹⁶, Nicholas J Johnson^{17

18}, Vasisht Srinivasan¹⁸, Jay S Steingrub¹⁹, Ithan D Peltan²⁰, Samuel M Brown²⁰, Emily T Martin²¹, Arnold S Monto²¹, Akram Khan²², Catherine L Hough²², Laurence W Busse²³, Caitlin C Ten Lohuis²⁴, Abhijit Duggal²⁵, Jennifer G Wilson²⁶, Alexandra June Gordon²⁶, Nida Qadir²⁷, Steven Y Chang²⁷, Christopher Mallow²⁸, Carolina Rivas²⁸, Hilary M Babcock²⁹, Jennie H Kwon²⁹, Natasha Halasa³, Carlos G Grijalva⁷, Todd W Rice⁸, William B Stubblefield³⁰, Adrienne Baughman³⁰, Kelsey N Womack³¹, Jillian P Rhoads³¹, Christopher J Lindsell³², Kimberly W Hart³², Yuwei Zhu³², Katherine Adams², Stephanie J Schrag², Samantha M Olson², Miwako Kobayashi², Jennifer R Verani², Manish M Patel², Wesley H Self^{33

31}; Influenza and Other Viruses in the Acutely Ill (IVY) Network

Affiliations

¹ Departments of Internal Medicine and Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA.
² CDC COVID-19 Response Team, Atlanta, GA, USA.
³ Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴ Baylor Scott and White Health, Texas A&M University College of Medicine, Temple, TX, USA.
⁵ Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
⁶ Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO, USA.
⁷ Department of Health Policy, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹ Department of Emergency Medicine, University of Iowa, Iowa City, IA, USA.
¹⁰ Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹¹ Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹² Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Department of Emergency Medicine, Hennepin County Medical Center, Minneapolis, MN, USA.
¹⁴ Department of Medicine, Hennepin County Medical Center, Minneapolis, MN, USA.
¹⁵ Department of Medicine, The Ohio State University, Columbus, OH, USA.
¹⁶ Department of Medicine, Montefiore Health System, Albert Einstein College of Medicine, Bronx, New York, NY, USA.
¹⁷ Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA, USA.
¹⁸ Department of Emergency Medicine, University of Washington, Seattle, WA, USA.
¹⁹ Department of Medicine, Baystate Medical Center, Springfield, MA, USA.
²⁰ Department of Medicine, Intermountain Medical Center, Murray, Utah and University of Utah, Salt Lake City, UT, USA.
²¹ School of Public Health, University of Michigan, Ann Arbor, MI, USA.
²² Department of Medicine, Oregon Health and Sciences University, Portland, OR, USA.
²³ Department of Medicine, Emory University, Atlanta, GA, USA.
²⁴ Emory Critical Care Center, Emory Healthcare, Atlanta, GA, USA.
²⁵ Department of Medicine, Cleveland Clinic, Cleveland, OH, USA.
²⁶ Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA, USA.
²⁷ Department of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
²⁸ Department of Medicine, University of Miami, Miami, FL, USA.
²⁹ Department of Medicine, Washington University, St Louis, MI, USA.
³⁰ Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
³¹ Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA.
³² Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
³³ Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA wesley.self@vumc.org.

PMID: 35264324
PMCID: PMC8905308
DOI: 10.1136/bmj-2021-069761

Observational Study

Clinical severity of, and effectiveness of mRNA vaccines against, covid-19 from omicron, delta, and alpha SARS-CoV-2 variants in the United States: prospective observational study

Adam S Lauring et al. BMJ. 2022.

. 2022 Mar 9:376:e069761.

doi: 10.1136/bmj-2021-069761.

Authors

Affiliations

¹ Departments of Internal Medicine and Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA.
² CDC COVID-19 Response Team, Atlanta, GA, USA.
³ Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴ Baylor Scott and White Health, Texas A&M University College of Medicine, Temple, TX, USA.
⁵ Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
⁶ Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO, USA.
⁷ Department of Health Policy, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹ Department of Emergency Medicine, University of Iowa, Iowa City, IA, USA.
¹⁰ Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹¹ Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹² Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Department of Emergency Medicine, Hennepin County Medical Center, Minneapolis, MN, USA.
¹⁴ Department of Medicine, Hennepin County Medical Center, Minneapolis, MN, USA.
¹⁵ Department of Medicine, The Ohio State University, Columbus, OH, USA.
¹⁶ Department of Medicine, Montefiore Health System, Albert Einstein College of Medicine, Bronx, New York, NY, USA.
¹⁷ Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA, USA.
¹⁸ Department of Emergency Medicine, University of Washington, Seattle, WA, USA.
¹⁹ Department of Medicine, Baystate Medical Center, Springfield, MA, USA.
²⁰ Department of Medicine, Intermountain Medical Center, Murray, Utah and University of Utah, Salt Lake City, UT, USA.
²¹ School of Public Health, University of Michigan, Ann Arbor, MI, USA.
²² Department of Medicine, Oregon Health and Sciences University, Portland, OR, USA.
²³ Department of Medicine, Emory University, Atlanta, GA, USA.
²⁴ Emory Critical Care Center, Emory Healthcare, Atlanta, GA, USA.
²⁵ Department of Medicine, Cleveland Clinic, Cleveland, OH, USA.
²⁶ Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA, USA.
²⁷ Department of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
²⁸ Department of Medicine, University of Miami, Miami, FL, USA.
²⁹ Department of Medicine, Washington University, St Louis, MI, USA.
³⁰ Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
³¹ Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA.
³² Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
³³ Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA wesley.self@vumc.org.

PMID: 35264324
PMCID: PMC8905308
DOI: 10.1136/bmj-2021-069761

Abstract

Objectives: To characterize the clinical severity of covid-19 associated with the alpha, delta, and omicron SARS-CoV-2 variants among adults admitted to hospital and to compare the effectiveness of mRNA vaccines to prevent hospital admissions related to each variant.

Design: Case-control study.

Setting: 21 hospitals across the United States.

Participants: 11 690 adults (≥18 years) admitted to hospital: 5728 with covid-19 (cases) and 5962 without covid-19 (controls). Patients were classified into SARS-CoV-2 variant groups based on viral whole genome sequencing, and, if sequencing did not reveal a lineage, by the predominant circulating variant at the time of hospital admission: alpha (11 March to 3 July 2021), delta (4 July to 25 December 2021), and omicron (26 December 2021 to 14 January 2022).

Main outcome measures: Vaccine effectiveness calculated using a test negative design for mRNA vaccines to prevent covid-19 related hospital admissions by each variant (alpha, delta, omicron). Among patients admitted to hospital with covid-19, disease severity on the World Health Organization's clinical progression scale was compared among variants using proportional odds regression.

Results: Effectiveness of the mRNA vaccines to prevent covid-19 associated hospital admissions was 85% (95% confidence interval 82% to 88%) for two vaccine doses against the alpha variant, 85% (83% to 87%) for two doses against the delta variant, 94% (92% to 95%) for three doses against the delta variant, 65% (51% to 75%) for two doses against the omicron variant; and 86% (77% to 91%) for three doses against the omicron variant. In-hospital mortality was 7.6% (81/1060) for alpha, 12.2% (461/3788) for delta, and 7.1% (40/565) for omicron. Among unvaccinated patients with covid-19 admitted to hospital, severity on the WHO clinical progression scale was higher for the delta versus alpha variant (adjusted proportional odds ratio 1.28, 95% confidence interval 1.11 to 1.46), and lower for the omicron versus delta variant (0.61, 0.49 to 0.77). Compared with unvaccinated patients, severity was lower for vaccinated patients for each variant, including alpha (adjusted proportional odds ratio 0.33, 0.23 to 0.49), delta (0.44, 0.37 to 0.51), and omicron (0.61, 0.44 to 0.85).

Conclusions: mRNA vaccines were found to be highly effective in preventing covid-19 associated hospital admissions related to the alpha, delta, and omicron variants, but three vaccine doses were required to achieve protection against omicron similar to the protection that two doses provided against the delta and alpha variants. Among adults admitted to hospital with covid-19, the omicron variant was associated with less severe disease than the delta variant but still resulted in substantial morbidity and mortality. Vaccinated patients admitted to hospital with covid-19 had significantly lower disease severity than unvaccinated patients for all the variants.

PubMed Disclaimer

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare the following. This study was funded by the US Centers for Disease Control and Prevention (CDC). ASL reports consultant fees from Sanofi and fees from Roche for membership on a trial steering committee. JDC reports grant support from CDC and National Institutes of Health (NIH). MG reports grant support from CDC. AAG reports grant support from CDC, NIH, Department of Defense (DoD), and an investigator initiated grant support from AbbVie and Faron Pharmaceuticals. HKT reports a grant from CDC. JDC reports a grant from the NIH (K23HL153584). DCF reports consultant fees from Cytovale and membership on a Medpace data safety monitoring board (DSMB). DNH reports a contract from CDC (via subcontract with Vanderbilt University Medical Center) and salary support from Incyte, EMPACT Precision Medicine, and the Marcus Foundation. MCE reports talks on nutrition in covid-19 pneumonia at the Nutritional Science and Practice Conference sponsored by Abbott Laboratories. MNG reports grant support from CDC, funding from the National Heart, Lung, and Blood Institute, and fees for participating on a DSMB for Regeneron. IDP reports grants from CDC, NIH, Intermountain Research and Medical Foundation, and Janssen Pharmaceuticals, institutional fees from Asahi Kasei Pharma and from Regeneron. SMB reports grants from CDC, Sedana, Janssen, NIH, and DoD; fees from Hamilton for chairing a DSMB; institutional fees from Faron; book royalties from Oxford University and Brigham Young University; and personal fees from New York University for service on a DSMB. ETM reports a grant from Merck for unrelated work. AK reports grants from Gilead, Ely Lily, United Therapeutics, Johnson and Johnson (Actelion), Liquidia Pharmaceuticals, and 4D Medical. SYC was a speaker for La Jolla Pharmaceuticals and a consultant for PureTech Health. JHK reports grant support from NIH/National Institute of Allergy and Infectious Diseases (1K23 AI137321-01A1). NH reports grants from CDC, Sanofi, and Quidel. CGG reports consultant fees from Pfizer, Merck, and Sanofi-Pasteur and grants from Campbell Alliance/Syneos Health, CDC, NIH, Food and Drug Administration, Agency for Healthcare Research and Quality, and Sanofi. TR reports grant support from CDC. CJL reports grants from CDC, NIH, DoD, and the Marcus Foundation; organizational contract fees from bioMerieux, Endpoint, and Entegrion; and a patent issued to Cincinnati Children’s Hospital Medical Center for risk stratification in sepsis and septic shock. WHS reports grant funding from CDC for this work, grants and consultant fees from Merck outside this work, and consultant fees from Aerpio Pharmaceuticals outside this work.

Figures

**Fig 1**
Genome sequenced SARS-CoV-2 variants by week among participants with covid-19 admitted to hospital between 11 March 2021 and 14 January 2022 in 21 hospitals in the United States. Dashed lines represent start of delta variant period (4 July 2021) and start of omicron variant period (26 December 2021). The figure includes all enrolled cases with a sequencing result, without restriction to cases included in vaccine effectiveness analyses. SARS-CoV-2 variant lineages were identified for 3017 cases: alpha (n=299), beta (n=8), delta (n=2209), gamma (n=52), omicron (n=286), and lineage not designated as variant of concern (VOC, n=163)

**Fig 2**
Vaccine effectiveness (VE) of mRNA vaccines to prevent hospital admissions with covid-19 by variant group, including alpha, delta, and omicron. *Groups with ≥150 cases and controls were reported. Groups with <150 cases or <150 controls were not reported owing to low precision of VE estimates with these sample sizes. †Obtained using structured medical chart review, and defined as one or more of the following: active solid organ cancer (active cancer defined as treatment for the cancer or newly diagnosed cancer in past six months), active hematologic cancer, HIV infection without AIDS, AIDS, congenital immunodeficiency syndrome, previous splenectomy, previous solid organ transplant, immunosuppressive drugs, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, scleroderma, or inflammatory bowel disease, including Crohn’s disease or ulcerative colitis. ‡Obtained using structured medical chart review, and defined as conditions within one or more of the following categories: cardiovascular disease, neurologic disease, pulmonary disease, gastrointestinal disease, endocrine disease, renal disease, hematologic disease, malignancy, immunosuppression not captured in other categories, autoimmune condition, or other condition (sarcoidosis, amyloidosis, or unintentional weight loss ≥10 pounds (4.5 kg) in past 90 days)

**Fig 3**
Severity of covid-19 during index hospital admission among adults with covid-19, by SARS-CoV-2 variant for unvaccinated and vaccinated patients. Disease severity was classified based on the highest severity level reached on the World Health Organization clinical progression scale, which ranged from hospital admission without supplemental oxygen (lowest level) to death (highest level). Among unvaccinated patients, severity was higher for the delta than alpha variant (adjusted proportional odds ratio 1.28, 95% confidence interval 1.11 to 1.46) and lower for the omicron than delta variant (0.61, 0.49 to 0.77). For each variant, severity was lower for vaccinated patients (two or three doses of an mRNA vaccine) than unvaccinated patients, including for alpha (adjusted proportional odds ratio 0.33, 0.23 to 0.49), delta (0.44, 0.37 to 0.51), and omicron (0.61, 0.44 to 0.85)

**Fig 4**
Effectiveness of two or three doses of mRNA vaccines among adults admitted to hospital with covid-19 to prevent disease progression to invasive mechanical ventilation (IMV) or death, by SARS-CoV-2 variant. VE=vaccine effectiveness

See this image and copyright information in PMC

Update of

Clinical Severity and mRNA Vaccine Effectiveness for Omicron, Delta, and Alpha SARS-CoV-2 Variants in the United States: A Prospective Observational Study.
Lauring AS, Tenforde MW, Chappell JD, Gaglani M, Ginde AA, McNeal T, Ghamande S, Douin DJ, Talbot HK, Casey JD, Mohr NM, Zepeski A, Shapiro NI, Gibbs KW, Files DC, Hager DN, Shehu A, Prekker ME, Erickson HL, Exline MC, Gong MN, Mohamed A, Johnson NJ, Srinivasan V, Steingrub JS, Peltan ID, Brown SM, Martin ET, Monto AS, Khan A, Hough CL, Busse LW, Ten Lohuis CC, Duggal A, Wilson JG, Gordon AJ, Qadir N, Chang SY, Mallow C, Rivas C, Babcock HM, Kwon JH, Halasa N, Grijalva CG, Rice TW, Stubblefield WB, Baughman A, Womack KN, Rhoads JP, Lindsell CJ, Hart KW, Zhu Y, Adams K, Schrag SJ, Olson SM, Kobayashi M, Verani JR, Patel MM, Self WH; Influenza and Other Viruses in the Acutely Ill (IVY) Network. Lauring AS, et al. medRxiv [Preprint]. 2022 Feb 7:2022.02.06.22270558. doi: 10.1101/2022.02.06.22270558. medRxiv. 2022. Update in: BMJ. 2022 Mar 9;376:e069761. doi: 10.1136/bmj-2021-069761. PMID: 35169811 Free PMC article. Updated. Preprint.

References

1. Lauring AS, Hodcroft EB. Genetic Variants of SARS-CoV-2-What Do They Mean? JAMA 2021;325:529-31. 10.1001/jama.2020.27124. - DOI - PubMed
1. Tracking SARS-CoV-2 variants. https://www.who.int/health-topics/typhoid/tracking-SARS-CoV-2-variants (accessed 26 Oct 2021).
1. GISAID - hCov19 Variants. https://www.gisaid.org/hcov19-variants/ (accessed 26 Oct 2021).
1. Sheikh A, McMenamin J, Taylor B, Robertson C, Public Health Scotland and the EAVE II Collaborators . SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness. Lancet 2021;397:2461-2. 10.1016/S0140-6736(21)01358-1. - DOI - PMC - PubMed
1. Twohig KA, Nyberg T, Zaidi A, et al. COVID-19 Genomics UK (COG-UK) consortium . Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study. Lancet Infect Dis 2022;22:35-42. 10.1016/S1473-3099(21)00475-8. - DOI - PMC - PubMed

Publication types

Actions
Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Supplementary concepts

Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
Medical
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Clinical severity of, and effectiveness of mRNA vaccines against, covid-19 from omicron, delta, and alpha SARS-CoV-2 variants in the United States: prospective observational study

Affiliations

Clinical severity of, and effectiveness of mRNA vaccines against, covid-19 from omicron, delta, and alpha SARS-CoV-2 variants in the United States: prospective observational study

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Update of

References

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous