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  3. Comparative effectiveness of bivalent BA.4-5 and BA.1 mRNA booster vaccines among adults aged ≥50 years in Nordic countries: nationwide cohort study
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Research

Comparative effectiveness of bivalent BA.4-5 and BA.1 mRNA booster vaccines among adults aged ≥50 years in Nordic countries: nationwide cohort study

BMJ 2023; 382 doi: https://doi.org/10.1136/bmj-2022-075286 (Published 25 July 2023) Cite this as: BMJ 2023;382:e075286

Linked Opinion

Why older adults can continue to benefit from covid-19 boosters
  1. Niklas Worm Andersson, doctoral student1,
  2. Emilia Myrup Thiesson, statistician1,
  3. Ulrike Baum, statistical researcher2,
  4. Nicklas Pihlström, statistician3,
  5. Jostein Starrfelt, senior adviser4,
  6. Kristýna Faksová, junior epidemiologist1,
  7. Eero Poukka, doctoral student2 5,
  8. Hinta Meijerink, senior adviser6,
  9. Rickard Ljung, professor7 8,
  10. Anders Hviid, head of department and professor1 9
  1. 1Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
  2. 2Infectious Disease Control and Vaccinations Unit, Department of Health Security, Finnish Institute for Health and Welfare, Helsinki, Finland
  3. 3Division of Licensing, Swedish Medical Products Agency, Uppsala, Sweden
  4. 4Department of Infection Control and Preparedness, Norwegian Institute of Public Health, Oslo, Norway
  5. 5Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland
  6. 6Department of Infection Control and Vaccines, Norwegian Institute of Public Health, Oslo, Norway
  7. 7Division of Use and Information, Swedish Medical Products Agency, Uppsala, Sweden
  8. 8Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  9. 9Pharmacovigilance Research Center, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  1. Correspondence to: N W Andersson nian{at}ssi.dk (or @nw_andersson on Twitter)
  • Accepted 17 May 2023

Abstract

Objective To estimate the effectiveness of the bivalent mRNA booster vaccines containing the original SARS-CoV-2 and omicron BA.4-5 or BA.1 subvariants as the fourth dose against severe covid-19.

Design Nationwide cohort analyses, using target trial emulation.

Setting Denmark, Finland, Norway, and Sweden, from 1 July 2022 to 10 April 2023.

Participants People aged ≥50 years who had received at least three doses of covid-19 vaccine (that is, a primary course and a first booster).

Main outcome measures The Kaplan-Meier estimator was used to compare the risk of hospital admission and death related to covid-19 in people who received a bivalent Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) BA.4-5 or BA.1 mRNA booster vaccine as a fourth dose (second booster) with three dose (first booster) vaccinated people and between four dose vaccinated people.

Results A total of 1 634 199 people receiving bivalent BA.4-5 fourth dose booster and 1 042 124 receiving bivalent BA.1 fourth dose booster across the four Nordic countries were included. Receipt of a bivalent BA.4-5 booster as a fourth dose was associated with a comparative vaccine effectiveness against admission to hospital with covid-19 of 67.8% (95% confidence interval 63.1% to 72.5%) and a risk difference of –91.9 (95% confidence interval –152.4 to –31.4) per 100 000 people at three months of follow-up compared with having received three doses of vaccine (289 v 893 events). The corresponding comparative vaccine effectiveness and risk difference for bivalent BA.1 boosters (332 v 977 events) were 65.8% (59.1% to 72.4%) and –112.9 (–179.6 to –46.2) per 100 000, respectively. Comparative vaccine effectiveness and risk difference against covid-19 related death were 69.8% (52.8% to 86.8%) and –34.1 (–40.1 to –28.2) per 100 000 for bivalent BA.4-5 booster (93 v 325 events) and 70.0% (50.3% to 89.7%) and –38.7 (–65.4 to –12.0) per 100 000 for BA.1 booster (86 v 286) as a fourth dose. Comparing bivalent BA.4-5 and BA.1 boosters as a fourth dose directly resulted in a three month comparative vaccine effectiveness and corresponding risk difference of –14.9% (–62.3% to 32.4%) and 10.0 (–14.4 to 34.4) per 100 000 people for admission to hospital with covid-19 (802 v 932 unweighted events) and –40.7% (–123.4% to 42.1%) and 8.1 (–3.3 to 19.4) per 100 000 for covid-19 related death (229 v 243 unweighted events). The comparative vaccine effectiveness did not differ across sex and age (</≥70 years) and seemed to be sustained up to six months from the day of vaccination with modest waning.

Conclusion Vaccination with bivalent BA.4-5 or BA.1 mRNA booster vaccines as a fourth dose was associated with reduced rates of covid-19 related hospital admission and death among adults aged ≥50 years. The protection afforded by the bivalent BA.4-5 and BA.1 boosters did not differ significantly when directly compared, and any potential difference would most likely be very small in absolute numbers.

Footnotes

  • Contributors: NWA, EMT, and AH conceptualised the study. NWA drafted the manuscript. EMT, UB, JS, and NP did the statistical analyses. All authors interpreted the results and critically reviewed the manuscript. AH supervised the study. NWA and AH are the guarantors. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: This research was supported by the European Medicines Agency. The funders had no role in considering the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. This document expresses the opinion of the authors of the paper and may not be understood or quoted as being made on behalf of, or reflecting the position of, the European Medicines Agency or one of its committees or working parties.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from the European Medicines Agency; EP has received a grant from the Finnish Medical Foundation; RL has received grants from Sanofi Aventis paid to his institution and personal fees from Pfizer (all outside the submitted work); no other relationships or activities that could appear to have influenced the submitted work.

  • The lead authors (the manuscript’s guarantors) affirm that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

  • Dissemination to participants and related patient and public communities: Studied participants were anonymised in the data sources used; therefore, direct dissemination to study participants is not possible. The study results will be disseminated to the public and health professionals by a press release written using layman’s terms.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

Data availability statement

Owing to data privacy regulations in each country, the raw data cannot be shared.

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