Journal article
Measuring vaccine efficacy against infection and disease in clinical trials: sources and magnitude of bias in COVID-19 vaccine efficacy estimates
- Abstract:
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Background
Phase III trials have estimated COVID-19 vaccine efficacy (VE) against symptomatic and asymptomatic infection. We explore the direction and magnitude of potential biases in these estimates and their implications for vaccine protection against infection and against disease in breakthrough infections.Methods
We developed a mathematical model that accounts for natural and vaccine-induced immunity, changes in serostatus and imperfect sensitivity and specificity of tests for infection and antibodies. We estimated expected biases in VE against symptomatic, asymptomatic and any SARS͏CoV2 infections and against disease following infection for a range of vaccine characteristics and measurement approaches, and the likely overall biases for published trial results that included asymptomatic infections.Results
VE against asymptomatic infection measured by PCR or serology is expected to be low or negative for vaccines that prevent disease but not infection. VE against any infection is overestimated when asymptomatic infections are less likely to be detected than symptomatic infections and the vaccine protects against symptom development. A competing bias towards underestimation arises for estimates based on tests with imperfect specificity, especially when testing is performed frequently. Our model indicates considerable uncertainty in Oxford-AstraZeneca ChAdOx1 and Janssen Ad26.COV2.S VE against any infection, with slightly higher than published, bias-adjusted values of 59.0% (95% uncertainty interval [UI] 38.4 to 77.1) and 70.9% (95% UI 49.8 to 80.7) respectively.Conclusions
Multiple biases are likely to influence COVID-19 VE estimates, potentially explaining the observed difference between ChAdOx1 and Ad26.COV2.S vaccines. These biases should be considered when interpreting both efficacy and effectiveness study results.
- Publication status:
- In press
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 8.4MB, Terms of use)
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(Preview, Supplementary materials, pdf, 2.0MB, Terms of use)
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- Publisher copy:
- 10.1093/cid/ciab914
Authors
- Publisher:
- Oxford University Press
- Journal:
- Clinical Infectious Diseases More from this journal
- Volume:
- 75
- Issue:
- 1
- Pages:
- e764–e773
- Publication date:
- 2021-10-26
- Acceptance date:
- 2021-10-21
- DOI:
- EISSN:
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1537-6591
- ISSN:
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1058-4838
- Language:
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English
- Keywords:
- Pubs id:
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1205778
- Local pid:
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pubs:1205778
- Deposit date:
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2021-10-25
Terms of use
- Copyright holder:
- Williams et al.
- Copyright date:
- 2021
- Rights statement:
- © The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
- Licence:
- CC Attribution (CC BY)
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