Vaccine effectiveness against SARS-CoV-2 infection or COVID-19 hospitalization with the Alpha, Delta, or Omicron SARS-CoV-2 variant: A nationwide Danish cohort study
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Abstract
Background: The continued occurrence of more contagious Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants and waning immunity over time require ongoing reevaluation of the vaccine effectiveness (VE). This study aimed to estimate the effectiveness in 2 age groups (12 to 59 and 60 years or above) of 2 or 3 vaccine doses (BNT162b2 mRNA or mRNA-1273) by time since vaccination against SARS-CoV-2 infection and Coronavirus Disease 2019 (COVID-19) hospitalization in an Alpha-, Delta-, or Omicron-dominated period. Methods and findings: A Danish nationwide cohort study design was used to estimate VE against SARS-CoV-2 infection and COVID-19 hospitalization with the Alpha, Delta, or Omicron variant. Information was obtained from nationwide registries and linked using a unique personal identification number. The study included all previously uninfected residents in Denmark aged 12 years or above (18 years or above for the analysis of 3 doses) in the Alpha (February 20 to June 15, 2021), Delta (July 4 to November 20, 2021), and Omicron (December 21, 2021 to January 31, 2022) dominated periods. VE estimates including 95% confidence intervals (CIs) were calculated (1-hazard ratio∙100) using Cox proportional hazard regression models with underlying calendar time and adjustments for age, sex, comorbidity, and geographical region. Vaccination status was included as a time-varying exposure. In the oldest age group, VE against infection after 2 doses was 90.7% (95% CI: 88.2; 92.7) for the Alpha variant, 82.3% (95% CI: 75.5; 87.2) for the Delta variant, and 39.9% (95% CI: 26.3; 50.9) for the Omicron variant 14 to 30 days since vaccination. The VE waned over time and was 73.2% (Alpha, 95% CI: 57.1; 83.3), 50.0% (Delta, 95% CI: 46.7; 53.0), and 4.4% (Omicron, 95% CI: −0.1; 8.7) >120 days since vaccination. Higher estimates were observed after the third dose with VE estimates against infection of 86.1% (Delta, 95% CI: 83.3; 88.4) and 57.7% (Omicron, 95% CI: 55.9; 59.5) 14 to 30 days since vaccination. Among both age groups, VE against COVID-19 hospitalization 14 to 30 days since vaccination with 2 or 3 doses was 98.1% or above for the Alpha and Delta variants. Among both age groups, VE against COVID-19 hospitalization 14 to 30 days since vaccination with 2 or 3 doses was 95.5% or above for the Omicron variant. The main limitation of this study is the nonrandomized study design including potential differences between the unvaccinated (reference group) and vaccinated individuals. Conclusions: Two vaccine doses provided high protection against SARS-CoV-2 infection and COVID-19 hospitalization with the Alpha and Delta variants with protection, notably against infection, waning over time. Two vaccine doses provided only limited and short-lived protection against SARS-CoV-2 infection with Omicron. However, the protection against COVID-19 hospitalization following Omicron SARS-CoV-2 infection was higher. The third vaccine dose substantially increased the level and duration of protection against infection with the Omicron variant and provided a high level of sustained protection against COVID-19 hospitalization among the +60-year-olds.
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Numerous studies conducted during the Omicron BA.1 period have reported an increase in VE against infection caused by this variant following a booster dose.
“Still, numerous studies conducted during the Omicron BA.1 period have reported an increase in VE against infection caused by this variant following a booster dose [19,26,32-35].”
From Vaccine effectiveness and duration of protection of COVID-19 mRNA vaccines against Delta and Omicron BA.1 symptomatic and severe COVID-19 outcomes in adults aged 50 years and over in France (2023) · cites this paper as [34]
The Results section reports higher vaccine effectiveness against Omicron infection after three doses than after two, and the Discussion describes similar findings from other studies. But the Strengths and limitations section says BA.1 and BA.2 both circulated during the study period and the authors could not estimate effectiveness separately for BA.1. This source therefore supports the booster finding for Omicron, not specifically for BA.1. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn Gram et al, following the booster dose, protection against COVID-19 hospitalization with Delta variant increased to 97.2% (95% CI: 94.6-98.5%) 14-30 days since vaccination.
“Following the booster dose, protection increased to 97.2% (95% CI: 94.6 98.5%) 14-30 days and 91.7% (95% CI: 78.7 96.7%) 6190 days since vaccination [34].”
From Vaccine effectiveness and duration of protection of COVID-19 mRNA vaccines against Delta and Omicron BA.1 symptomatic and severe COVID-19 outcomes in adults aged 50 years and over in France (2023) · cites this paper as [34]
The Results section on hospitalization after three mRNA doses reports exactly 97.2% (95% CI: 94.6–98.5) at 14–30 days for the Delta variant. That estimate applies to individuals aged 60 years or above, a qualification the citing sentence omits; the estimate for ages 18–59 was 93.2%. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn Gram et al, protection induced by any mRNA vaccine against COVID-19 hospitalization with Delta variant after 2 doses, among individuals aged 60 years or above, was estimated at 87.5% (95% CI: 85.6-89.2%) >120 days since vaccination.
“In the Canadian study by Gram et al, protection induced by any mRNA vaccine against COVID-19 hospitalization with Delta variant after 2 doses, among individuals aged 60 years or above, was estimated at 87.5% (95% CI: 85.6 89.2%) >120 days since vaccination.”
From Vaccine effectiveness and duration of protection of COVID-19 mRNA vaccines against Delta and Omicron BA.1 symptomatic and severe COVID-19 outcomes in adults aged 50 years and over in France (2023) · cites this paper as [34]
The Results section on hospitalization after two mRNA doses reports exactly 87.5% effectiveness against Delta hospitalization (95% CI: 85.6–89.2) more than 120 days after vaccination among people aged 60 or above. However, the citing sentence calls Gram et al. a Canadian study, whereas the source identifies itself as a nationwide Danish cohort study. (LLM, conf=0.91)
Experimental — accuracy not yet measuredOur results were comparable to those from studies in other countries.
“Nevertheless our results were comparable to those from studies in other countries [19,20,34].”
In Gram et al, following the booster dose, protection against COVID-19 hospitalization with Delta variant was 91.7% (95% CI: 78.7-96.7%) 61-90 days since vaccination.
“Following the booster dose, protection increased to 97.2% (95% CI: 94.6 98.5%) 14-30 days and 91.7% (95% CI: 78.7 96.7%) 6190 days since vaccination [34].”
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- Authors
- 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., Rasmussen, M., Fonager, J., Sieber, R. N., Stegger, M., Ethelberg, S., Valentiner-Branth, P., & Hansen, C. H.
- Affiliations
- Statens Serum Institut (DK)
- Corresponding author
- Gram, Mie Agermose
- ORCID
- Venue
- PLOS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2022-09-01
- Volume
- 19
- Issue
- 9
- Pages
- e1003992
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- PMC
- PMC9436060
- OpenAlex
- W4294043822
- Cited by
- 146
- References
- 24
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 38 · 2023: 65 · 2022: 18
- FWCI
- 16.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- medRxiv (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Medical Research Council (MR/R010161/1)
- Statens Serum Institut
- 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
- vaccine effectiveness, SARS-CoV-2, COVID-19 pandemic, BNT162b2 mRNA vaccine, mRNA-1273 vaccine, Omicron variant, Delta variant, Alpha variant, waning immunity, COVID-19 hospitalization, breakthrough infection, age differences, booster vaccination, Danish population, 2021-2022 pandemic
- MeSH terms
- COVID-19, SARS-CoV-2, Vaccine Efficacy, BNT162 Vaccine, Denmark, Hospitalization, Humans, Viral Vaccines, Cohort Studies
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