Vaccine effectiveness against SARS-CoV-2 infection, hospitalization, and death when combining a first dose ChAdOx1 vaccine with a subsequent mRNA vaccine in Denmark: A nationwide population-based cohort study

  1. Mie Agermose Gram
  2. Jens Nielsen
  3. Astrid Blicher Schelde
  4. Katrine Finderup Nielsen
  5. Ida Rask Moustsen-Helms
  6. Anne Katrine Bjørkholt Sørensen
  7. Palle Valentiner-Branth
  8. Hanne-Dorthe Emborg

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Abstract

The recommendations in several countries to stop using the ChAdOx1 vaccine has led to vaccine programs combining different Coronavirus Disease 2019 (COVID-19) vaccine types, which necessitates knowledge on vaccine effectiveness (VE) of heterologous vaccine schedules. The aim of this Danish nationwide population-based cohort study was therefore to estimate the VE against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and COVID-19–related hospitalization and death following the first dose of the ChAdOx1 vaccine and the combination of the ChAdOx1/mRNA vaccines.

Methods and findings

All individuals alive in or immigrating to Denmark from 9 February 2021 to 23 June 2021 were identified in the Danish Civil Registration System. Information on exposure, outcomes, and covariates was obtained from Danish national registries. Poisson and Cox regression models were used to calculate crude and adjusted VE, respectively, along with 95% confidence intervals (CIs) against SARS-CoV-2 infection and COVID-19–related hospitalization or death comparing vaccinated versus unvaccinated individuals. The VE estimates were adjusted for calendar time as underlying time and for sex, age, comorbidity, country of origin, and hospital admission. The analyses included 5,542,079 individuals (97.6% of the total Danish population). A total of 144,360 individuals were vaccinated with the ChAdOx1 vaccine as the first dose, and of these, 136,551 individuals received an mRNA vaccine as the second dose. A total of 1,691,464 person-years and 83,034 SARS-CoV-2 infections were included. The individuals vaccinated with the first dose of the ChAdOx1 vaccine dose had a median age of 45 years. The study population was characterized by an equal distribution of males and females; 6.7% and 9.2% originated from high-income and other countries, respectively. The VE against SARS-CoV-2 infection when combining the ChAdOx1 and an mRNA vaccine was 88% (95% CI: 83; 92) 14 days after the second dose and onwards. There were no COVID-19–related hospitalizations or deaths among the individuals vaccinated with the combined vaccine schedule during the study period. Study limitations including unmeasured confounders such as risk behavior and increasing overall vaccine coverage in the general population creating herd immunity are important to take into consideration when interpreting the results.

Conclusions

In this study, we observed a large reduction in the risk of SARS-CoV-2 infection when combining the ChAdOx1 and an mRNA vaccine, compared with unvaccinated individuals.

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  1. Version published to 10.1371/journal.pmed.1003874
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    SciScore for 10.1101/2021.07.26.21261130: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variableInformation on date of birth and sex (male/female) was retrieved from the Danish Civil Registration System (11).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Strengths and limitations: The strengths of this study are the high-quality registers and the possibility to use the unique personal identifier to link data on all residents in Denmark. The national testing strategy during the study period, including unlimited access to free-of-charge RT-PCR tests nationwide, led to a high proportion of the population being tested, which enabled us to capture data on both asymptomatic and symptomatic infections. Another strength was the access to national data on all laboratory confirmed RT-PCR SARS-CoV-2 infections. Also, a high sensitivity (97.1%) and specificity (99.98%) was observed for the RT-PCR test (21) ensuring a low risk of misclassification. An effort was made to ensure that all individuals had equal opportunities to receive the COVID-19 vaccines. This was done through an online booking system, special campaigns, offering vaccination in some workplaces, translating the material to other languages than Danish and English and arranging transport for those who were not able to reach the vaccination clinics on their own. This study has also several limitations. Since we were not able to discriminate between asymptomatic and symptomatic infections, it was not possible to assess the severity of a COVID-19 infection after vaccination based on symptoms. We used a positive SARS-CoV-2 test prior to hospitalization and death (i.e. COVID-19 related hospitalization and death) as proxy for the severity of COVID-19, although this definition might...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

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  3. Version published to 10.1101/2021.07.26.21261130v1 on medRxiv