Journal article
The design and analysis of seroefficacy studies for typhoid conjugate vaccines
- Abstract:
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Background Demonstrating efficacy of new Vi-conjugate typhoid vaccines is challenging due to the cost of field trials requiring tens of thousands of participants. New trial designs that use serologically-defined typhoid infections (seroefficacy trials) rather than blood culture positivity as a study endpoint may be useful to assess efficacy using small trials.
Methods We developed a model for Vi-IgG antibody response to a Vi-vaccine, decay over time, and natural boosting due to endemic exposures. From this we simulated clinical trials in which two blood samples were taken during follow-up, and the relative risk of serologically-defined typhoid infection (seroefficacy) was computed. We aimed to determine if seroefficacy trial designs could substantially reduce sample sizes compared with trials using blood-culture-confirmed cases; if case detection was higher in seroefficacy trials; and the optimal timing of sample collection.
Results The majority (>90%) of blood-culture-positive typhoid cases remain unobserved in surveillance studies. In contrast, underdetection in simulated seroefficacy trials of equivalent vaccines was as little as 26%, and estimates of the relative risk of typhoid infection were unbiased. For simulated trials of non-equivalent vaccines, relative risks were slightly inflated by at least 5% depending on sample collection times. Seroefficacy trials required as few as 460 participants per arm, compared with 10,000 per arm for trials using blood-culture-confirmed cases.
Conclusion Seroefficacy trials can establish the efficacy of new conjugate vaccines using small trials enrolling hundreds rather than thousands of participants, and without the need for resource-intensive typhoid fever surveillance programmes.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 294.1KB, Terms of use)
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- Publisher copy:
- 10.1093/cid/ciy1119
Authors
- Publisher:
- Oxford University Press
- Journal:
- Clinical Infectious Diseases More from this journal
- Volume:
- 68
- Issue:
- S2
- Pages:
- S183–S190
- Publication date:
- 2019-03-07
- Acceptance date:
- 2018-12-21
- DOI:
- EISSN:
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1537-6591
- ISSN:
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1058-4838
- Keywords:
- Pubs id:
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pubs:958210
- UUID:
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uuid:b3779381-3d04-46bf-a605-09bf624c417a
- Local pid:
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pubs:958210
- Source identifiers:
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958210
- Deposit date:
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2019-01-09
- ARK identifier:
Terms of use
- Copyright holder:
- Liu et al
- Copyright date:
- 2019
- Notes:
- © The Author(s) 2019. 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 (http://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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