The Design and Analysis of Seroefficacy Studies for Typhoid Conjugate Vaccines.
Antibodies, Bacterial
/ blood
Blood Culture
/ standards
Clinical Trials as Topic
Computer Simulation
Humans
Immunoglobulin G
/ blood
Polysaccharides, Bacterial
/ immunology
Salmonella typhi
Seroepidemiologic Studies
Serologic Tests
/ standards
Typhoid-Paratyphoid Vaccines
/ administration & dosage
Vaccine Potency
Vaccines, Conjugate
/ immunology
antibody
seroefficacy
typhoid
typhoid conjugate vaccine
Journal
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
ISSN: 1537-6591
Titre abrégé: Clin Infect Dis
Pays: United States
ID NLM: 9203213
Informations de publication
Date de publication:
07 03 2019
07 03 2019
Historique:
entrez:
8
3
2019
pubmed:
8
3
2019
medline:
29
5
2020
Statut:
ppublish
Résumé
Demonstrating the 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. We developed a model for Vi-immunoglobin G antibody responses to a Vi-vaccine, incorporating decay over time and natural boosting due to endemic exposures. From this, we simulated clinical trials in which 2 blood samples were taken during follow-up and the relative risk of a serologically defined typhoid infection (seroefficacy) was computed. We aimed to determine (1) whether seroefficacy trial designs could substantially reduce sample sizes, compared with trials using blood culture-confirmed cases; (3) whether the rate of case detection was higher in seroefficacy trials; and (3) the optimal timing of sample collection. The majority (>90%) of blood culture-positive typhoid cases remain unobserved in surveillance studies. In contrast, under-detection 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 the 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. Seroefficacy trials can establish the efficacy of new conjugate vaccines using small trials that enroll hundreds rather than thousands of participants, and without the need for resource-intensive typhoid fever surveillance programs.
Sections du résumé
BACKGROUND
Demonstrating the 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-immunoglobin G antibody responses to a Vi-vaccine, incorporating decay over time and natural boosting due to endemic exposures. From this, we simulated clinical trials in which 2 blood samples were taken during follow-up and the relative risk of a serologically defined typhoid infection (seroefficacy) was computed. We aimed to determine (1) whether seroefficacy trial designs could substantially reduce sample sizes, compared with trials using blood culture-confirmed cases; (3) whether the rate of case detection was higher in seroefficacy trials; and (3) the optimal timing of sample collection.
RESULTS
The majority (>90%) of blood culture-positive typhoid cases remain unobserved in surveillance studies. In contrast, under-detection 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 the 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.
CONCLUSIONS
Seroefficacy trials can establish the efficacy of new conjugate vaccines using small trials that enroll hundreds rather than thousands of participants, and without the need for resource-intensive typhoid fever surveillance programs.
Identifiants
pubmed: 30845326
pii: 5371226
doi: 10.1093/cid/ciy1119
pmc: PMC6405265
doi:
Substances chimiques
Antibodies, Bacterial
0
Immunoglobulin G
0
Polysaccharides, Bacterial
0
Typhoid-Paratyphoid Vaccines
0
Vaccines, Conjugate
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
S183-S190Informations de copyright
© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.
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