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. 2021 Nov 23;326(20):2043-2054.
doi: 10.1001/jama.2021.19499.

Association Between mRNA Vaccination and COVID-19 Hospitalization and Disease Severity

Mark W Tenforde  1 , Wesley H Self  2 , Katherine Adams  1 , Manjusha Gaglani  3 , Adit A Ginde  4 , Tresa McNeal  3 , Shekhar Ghamande  3 , David J Douin  5 , H Keipp Talbot  6 , Jonathan D Casey  7 , Nicholas M Mohr  8 , Anne Zepeski  8 , Nathan I Shapiro  9 , Kevin W Gibbs  10 , D Clark Files  10 , David N Hager  11 , Arber Shehu  11 , Matthew E Prekker  12 , Heidi L Erickson  13 , Matthew C Exline  14 , Michelle N Gong  15 , Amira Mohamed  16 , Daniel J Henning  17 , Jay S Steingrub  18 , Ithan D Peltan  19 , Samuel M Brown  19 , Emily T Martin  20 , Arnold S Monto  20 , Akram Khan  21 , Catherine L Hough  21 , Laurence W Busse  22 , Caitlin C Ten Lohuis  23 , Abhijit Duggal  24 , Jennifer G Wilson  25 , Alexandra June Gordon  25 , Nida Qadir  26 , Steven Y Chang  26 , Christopher Mallow  27 , Carolina Rivas  27 , Hilary M Babcock  28 , Jennie H Kwon  28 , Natasha Halasa  29 , James D Chappell  29 , Adam S Lauring  30 , Carlos G Grijalva  31 , Todd W Rice  7 , Ian D Jones  32 , William B Stubblefield  32 , Adrienne Baughman  32 , Kelsey N Womack  33 , Jillian P Rhoads  33 , Christopher J Lindsell  34 , Kimberly W Hart  34 , Yuwei Zhu  34 , Samantha M Olson  1 , Miwako Kobayashi  1 , Jennifer R Verani  1 , Manish M Patel  1 ; Influenza and Other Viruses in the Acutely Ill (IVY) Network
Affiliations

Association Between mRNA Vaccination and COVID-19 Hospitalization and Disease Severity

Mark W Tenforde et al. JAMA. .

Abstract

Importance: A comprehensive understanding of the benefits of COVID-19 vaccination requires consideration of disease attenuation, determined as whether people who develop COVID-19 despite vaccination have lower disease severity than unvaccinated people.

Objective: To evaluate the association between vaccination with mRNA COVID-19 vaccines-mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech)-and COVID-19 hospitalization, and, among patients hospitalized with COVID-19, the association with progression to critical disease.

Design, setting, and participants: A US 21-site case-control analysis of 4513 adults hospitalized between March 11 and August 15, 2021, with 28-day outcome data on death and mechanical ventilation available for patients enrolled through July 14, 2021. Date of final follow-up was August 8, 2021.

Exposures: COVID-19 vaccination.

Main outcomes and measures: Associations were evaluated between prior vaccination and (1) hospitalization for COVID-19, in which case patients were those hospitalized for COVID-19 and control patients were those hospitalized for an alternative diagnosis; and (2) disease progression among patients hospitalized for COVID-19, in which cases and controls were COVID-19 patients with and without progression to death or mechanical ventilation, respectively. Associations were measured with multivariable logistic regression.

Results: Among 4513 patients (median age, 59 years [IQR, 45-69]; 2202 [48.8%] women; 23.0% non-Hispanic Black individuals, 15.9% Hispanic individuals, and 20.1% with an immunocompromising condition), 1983 were case patients with COVID-19 and 2530 were controls without COVID-19. Unvaccinated patients accounted for 84.2% (1669/1983) of COVID-19 hospitalizations. Hospitalization for COVID-19 was significantly associated with decreased likelihood of vaccination (cases, 15.8%; controls, 54.8%; adjusted OR, 0.15; 95% CI, 0.13-0.18), including for sequenced SARS-CoV-2 Alpha (8.7% vs 51.7%; aOR, 0.10; 95% CI, 0.06-0.16) and Delta variants (21.9% vs 61.8%; aOR, 0.14; 95% CI, 0.10-0.21). This association was stronger for immunocompetent patients (11.2% vs 53.5%; aOR, 0.10; 95% CI, 0.09-0.13) than immunocompromised patients (40.1% vs 58.8%; aOR, 0.49; 95% CI, 0.35-0.69) (P < .001) and weaker at more than 120 days since vaccination with BNT162b2 (5.8% vs 11.5%; aOR, 0.36; 95% CI, 0.27-0.49) than with mRNA-1273 (1.9% vs 8.3%; aOR, 0.15; 95% CI, 0.09-0.23) (P < .001). Among 1197 patients hospitalized with COVID-19, death or invasive mechanical ventilation by day 28 was associated with decreased likelihood of vaccination (12.0% vs 24.7%; aOR, 0.33; 95% CI, 0.19-0.58).

Conclusions and relevance: Vaccination with an mRNA COVID-19 vaccine was significantly less likely among patients with COVID-19 hospitalization and disease progression to death or mechanical ventilation. These findings are consistent with risk reduction among vaccine breakthrough infections compared with absence of vaccination.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Self reported receiving grants from the Centers for Disease Control and Prevention (CDC) (principal investigator of the primary funding contract from CDC for this work) during the conduct of the study. Dr Gaglani reported receiving grants from CDC, Vanderbilt University Medical Center, Baylor Scott & White Health (BSWH), and the IVY study during the conduct of the study; grants from CDC–BSWH HAIVEN influenza/COVID-19 vaccine effectiveness study, CDC–BSWH ambulatory US influenza/COVID-19 vaccine effectiveness study, CDC–Abt Associates BSWH RECOVER COVID-19/influenza study, and CDC–Westat BSWH VISION COVID-19/influenza study outside the submitted work; and Pfizer BSWH Independent Grants for Learning & Change for meningococcal vaccination of adolescents and an institutional contract with Janssen (BSWH Observational RSV Study in infants). Dr Ginde reported receiving grants from CDC during the conduct of the study; and grants from the National Institutes of Health (NIH), Department of Defense, and AbbVie outside the submitted work. Dr McNeal reported receiving grants from the CDC HAIVEN study group that become the IVY-3 study group during the conduct of the study. Dr Talbot reported receiving grants from CDC during the conduct of the study. Dr Casey reported receiving grants from NIH K23HL153584 outside the submitted work. Dr Mohr reported receiving grants from CDC during the conduct of the study. Dr Shapiro reported receiving grants from CDC during the conduct of the study. Dr Files reported receiving grants from CDC during the conduct of the study and personal fees from Cytovale and Medpace outside the submitted work. Dr Prekker reported receiving grants from CDC during the conduct of the study. Dr Exline reported receiving a speaking honorarium from Abbott Laboratories outside the submitted work. Dr Gong reported receiving grants from CDC during the conduct of the study; grants from NIH to conduct clinical trials on COVID-19 and non–COVID-19 outside the submitted work; and data and safety monitoring board fees for participating in Regeneron trials outside the submitted work. Dr Henning reported receiving grants from CDC during the conduct of the study. Dr Peltan reported receiving grants from CDC during the conduct of the study; grants from NIH, Intermountain Research and Medical Foundation, and Janssen Pharmaceuticals outside the submitted work; and payment to Intermountain Medical Center for subject enrollment from Regeneron and Asahi Kasei Pharma outside the submitted work. Dr Brown reported receiving grants from CDC during the conduct of the study. Dr Martin reported receiving grants from CDC during the conduct of the study and personal fees from Pfizer outside the submitted work. Dr Khan reported receiving grants from United Therapeutics, Actelion Pharmaceuticals, Eli Lilly, Johnson & Johnson, Regeneron Pharmaceuticals, and Gilead Sciences outside the submitted work. Dr Hough reported receiving grants from CDC during the conduct of the study and grants from NIH outside the submitted work. Dr Wilson reported receiving grants from CDC/Vanderbilt during the conduct of the study. Dr Chang reported receiving personal fees from La Jolla Pharmaceuticals and PureTech Health outside the submitted work. Dr Babcock reported receiving grants from CDC during the conduct of the study. Dr Kwon reported receiving grants from NIH National Institute of Allergy and Infectious Diseases (award 1K23 AI137321-01A1) outside the submitted work. Dr Halasa reported receiving grants from CDC during the conduct of the study; grants from Sanofi outside the submitted work; and hemagglutination inhibition and microneutralization testing, vaccine donation, and grants from Quidel outside the submitted work. Dr Chappell reported receiving grants from CDC during the conduct of the study. Dr Lauring reported receiving consulting fees from Sanofi for an influenza antiviral and fees from Roche as a member of an influenza antiviral trial steering committee outside the submitted work. Dr Grijalva reported receiving a contract from CDC during the conduct of the study; consulting fees from Pfizer, Merck, and Sanofi; a contract from CDC, Campbell Alliance, and the Food and Drug Administration outside the submitted work; and grants from NIH and the Agency for Healthcare Research and Quality outside the submitted work. Dr Rice reported receiving grants from CDC during the conduct of the study and personal fees from Cumberland Pharmaceuticals, Sanofi, and Cytovale outside the submitted work. Dr Lindsell reported receiving grants from CDC to Vanderbilt University during the conduct of the study; grants from NIH to institution, grants from Department of Defense to institution, contracts to Vanderbilt University for research services from bioMérieux, Endpoint Health, and Entegrion. In addition, he had a patent for risk stratification in sepsis and septic shock, issued to Cincinnati Children's Hospital Medical Center. Dr Zhu reported receiving grants from CDC during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participant Flow Through a Study of Association Between COVID-19 mRNA Vaccination and Hospitalizations and Disease Severity
“Syndrome-negative” participants were persons hospitalized without signs or symptoms consistent with acute COVID-19 and who tested negative for SARS-CoV-2 by molecular testing. They were included as a secondary control group because of the theoretical risk of case misclassification in test-negative controls.
Figure 2.
Figure 2.. Association Between Hospitalization for COVID-19 and Prior Vaccination With a 2-Dose mRNA Vaccine
An adjusted odds ratio (aOR) less than 1.0 indicated that COVID-19 hospitalization was associated with being unvaccinated compared with being fully vaccinated. Vaccine effectiveness for prevention of COVID-19 hospitalization can be estimated from the aORs presented here with the following equation: vaccine effectiveness = (1 − aOR) × 100%. BNT162b2 is the vaccine produced by Pfizer-BioNTech and mRNA-1273 is the vaccine produced by Moderna. mRNA indicates messenger RNA. aModels were mixed-effects logistic regression models with vaccination status (fully vaccinated vs unvaccinated) as the primary independent variable, case-control status (hospitalized with COVID-19 vs hospitalized without it) as the dependent variable, enrolling site as a random effect, and the following covariables: admission date (biweekly intervals), age group (18-49, 50-64, and ≥65 years), sex, and self-reported race and ethnicity. Models stratified by age group were adjusted for continuous age in years. bImmunocompromising conditions are defined in the Table. cAlpha estimates restricted to March to June illness-onset dates (Alpha period); Delta estimates restricted to July to August illness-onset dates (Delta period).
Figure 3.
Figure 3.. Association Between Progression to Severe Disease and Prior Vaccination Among Adults Hospitalized With COVID-19
An adjusted odds ratio (aOR) less than 1.0 indicated that progression to death or invasive mechanical ventilation after hospital admission for COVID-19 was associated with being unvaccinated compared with being vaccinated. aModels were adjusted for age group (18-49, 50-64, and ≥65 years), sex, self-reported race and ethnicity, and number of chronic medical comorbidities (0, 1, 2, 3, and ≥4). Models stratified by age group were adjusted for continuous age in years. bImmunocompromising conditions are defined in the Table. cAnalysis restricted to COVID-19 case patients with hypoxemia within 24 hours of admission, defined as receiving supplemental oxygen or having an oxygen saturation less than 92% as measured by pulse oximetry.
Figure 4.
Figure 4.. Competing Risks Regression of Hospital Discharge for Adults Hospitalized With COVID-19
Cumulative incidence of hospital discharge by vaccination status (fully vaccinated with a 2-dose series of mRNA vaccine vs unvaccinated) is shown for patients not immunocompromised (A), those immunocompromised (B), those aged 18 to 64 years (C), and those aged 65 years or older (D). The event of interest was discharge from the hospital before day 28 in the presence of the competing event of death. Patients who remained hospitalized more than 28 days were censored at 28 days. Competing risk models were adjusted for age group (18-49, 50-64, and ≥65 years), sex, self-reported race and ethnicity, and number of medical comorbidities (0, 1, 2, 3, and ≥4). Models by age group were adjusted for continuous age in years. mRNA indicates messenger RNA; and SHR, subdistribution hazard ratio.
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