Establishment of a Controlled Human Infection Model with a Lyophilized Strain of <named-content content-type="genus-species">Shigella sonnei</named-content> 53G

ABSTRACT Controlled human infection models (CHIMs) are useful for vaccine development. To improve on existing models, we developed a CHIM using a lyophilized preparation of Shigella sonnei strain 53G produced using current good manufacturing practice (cGMP). Healthy adults were enrolled in an open-l...

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Autores principales:	Robert W. Frenck, Michelle Dickey, Akamol E. Suvarnapunya, Lakshmi Chandrasekaran, Robert W. Kaminski, Kristen A. Clarkson, Monica McNeal, Amanda Lynen, Susan Parker, Amy Hoeper, Sachin Mani, Alan Fix, Nicole Maier, Malabi M. Venkatesan, Chad K. Porter
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	controlled human infection models shigellosis Shigella diarrhea enteric disease human challenge Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/93466a6d389e45019b54871b82a4c79c
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spelling	oai:doaj.org-article:93466a6d389e45019b54871b82a4c79c2021-11-15T15:30:58ZEstablishment of a Controlled Human Infection Model with a Lyophilized Strain of <named-content content-type="genus-species">Shigella sonnei</named-content> 53G10.1128/mSphere.00416-202379-5042https://doaj.org/article/93466a6d389e45019b54871b82a4c79c2020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00416-20https://doaj.org/toc/2379-5042ABSTRACT Controlled human infection models (CHIMs) are useful for vaccine development. To improve on existing models, we developed a CHIM using a lyophilized preparation of Shigella sonnei strain 53G produced using current good manufacturing practice (cGMP). Healthy adults were enrolled in an open-label dose-ranging study. Following administration of a dose of rehydrated S. sonnei strain 53G, subjects were monitored for development of disease. The first cohort received 500 CFU of 53G, and dosing of subsequent cohorts was based on results from the previous cohort. Subjects were administered ciprofloxacin on day 5 and discharged home on day 8. Subjects returned as outpatients for clinical checks and sample collection. Attack rates increased as the dose of S. sonnei was increased. Among those receiving the highest dose (1,760 CFU), 70% developed moderate to severe diarrhea, 50% had dysentery, and 40% had fever. Antilipopolysaccharide responses were observed across all cohorts. An S. sonnei CHIM using a lyophilized lot of strain 53G was established. A dose in the range of 1,500 to 2,000 CFU of 53G was selected as the dose for future challenge studies using this product. This model will enable direct comparison of study results between institutions and ensure better consistency over time in the challenge inoculum. IMPORTANCE Controlled human infection models (CHIMs) are invaluable tools utilized to understand the human response to infection, potentially leading to protective immune mechanisms and allowing efficacy testing of enteric countermeasures, including vaccines, antibiotics, and other products. The development of an improved Shigella CHIM for both Shigella sonnei and Shigella flexneri is consistent with international efforts, supported by international donors and the World Health Organization, focused on standardizing Shigella CHIMs and using them to accelerate Shigella vaccine development. The use of lyophilized Shigella challenge strains rather than plate-grown inoculum preparations is considered an important step forward in the standardization process. Furthermore, the results of studies such as this justify the development of lyophilized preparations for additional epidemiologically important S. flexneri serotypes, including S. flexneri 3a and S. flexneri 6.Robert W. FrenckMichelle DickeyAkamol E. SuvarnapunyaLakshmi ChandrasekaranRobert W. KaminskiKristen A. ClarksonMonica McNealAmanda LynenSusan ParkerAmy HoeperSachin ManiAlan FixNicole MaierMalabi M. VenkatesanChad K. PorterAmerican Society for Microbiologyarticlecontrolled human infection modelsshigellosisShigelladiarrheaenteric diseasehuman challengeMicrobiologyQR1-502ENmSphere, Vol 5, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	controlled human infection models shigellosis Shigella diarrhea enteric disease human challenge Microbiology QR1-502
spellingShingle	controlled human infection models shigellosis Shigella diarrhea enteric disease human challenge Microbiology QR1-502 Robert W. Frenck Michelle Dickey Akamol E. Suvarnapunya Lakshmi Chandrasekaran Robert W. Kaminski Kristen A. Clarkson Monica McNeal Amanda Lynen Susan Parker Amy Hoeper Sachin Mani Alan Fix Nicole Maier Malabi M. Venkatesan Chad K. Porter Establishment of a Controlled Human Infection Model with a Lyophilized Strain of <named-content content-type="genus-species">Shigella sonnei</named-content> 53G
description	ABSTRACT Controlled human infection models (CHIMs) are useful for vaccine development. To improve on existing models, we developed a CHIM using a lyophilized preparation of Shigella sonnei strain 53G produced using current good manufacturing practice (cGMP). Healthy adults were enrolled in an open-label dose-ranging study. Following administration of a dose of rehydrated S. sonnei strain 53G, subjects were monitored for development of disease. The first cohort received 500 CFU of 53G, and dosing of subsequent cohorts was based on results from the previous cohort. Subjects were administered ciprofloxacin on day 5 and discharged home on day 8. Subjects returned as outpatients for clinical checks and sample collection. Attack rates increased as the dose of S. sonnei was increased. Among those receiving the highest dose (1,760 CFU), 70% developed moderate to severe diarrhea, 50% had dysentery, and 40% had fever. Antilipopolysaccharide responses were observed across all cohorts. An S. sonnei CHIM using a lyophilized lot of strain 53G was established. A dose in the range of 1,500 to 2,000 CFU of 53G was selected as the dose for future challenge studies using this product. This model will enable direct comparison of study results between institutions and ensure better consistency over time in the challenge inoculum. IMPORTANCE Controlled human infection models (CHIMs) are invaluable tools utilized to understand the human response to infection, potentially leading to protective immune mechanisms and allowing efficacy testing of enteric countermeasures, including vaccines, antibiotics, and other products. The development of an improved Shigella CHIM for both Shigella sonnei and Shigella flexneri is consistent with international efforts, supported by international donors and the World Health Organization, focused on standardizing Shigella CHIMs and using them to accelerate Shigella vaccine development. The use of lyophilized Shigella challenge strains rather than plate-grown inoculum preparations is considered an important step forward in the standardization process. Furthermore, the results of studies such as this justify the development of lyophilized preparations for additional epidemiologically important S. flexneri serotypes, including S. flexneri 3a and S. flexneri 6.
format	article
author	Robert W. Frenck Michelle Dickey Akamol E. Suvarnapunya Lakshmi Chandrasekaran Robert W. Kaminski Kristen A. Clarkson Monica McNeal Amanda Lynen Susan Parker Amy Hoeper Sachin Mani Alan Fix Nicole Maier Malabi M. Venkatesan Chad K. Porter
author_facet	Robert W. Frenck Michelle Dickey Akamol E. Suvarnapunya Lakshmi Chandrasekaran Robert W. Kaminski Kristen A. Clarkson Monica McNeal Amanda Lynen Susan Parker Amy Hoeper Sachin Mani Alan Fix Nicole Maier Malabi M. Venkatesan Chad K. Porter
author_sort	Robert W. Frenck
title	Establishment of a Controlled Human Infection Model with a Lyophilized Strain of <named-content content-type="genus-species">Shigella sonnei</named-content> 53G
title_short	Establishment of a Controlled Human Infection Model with a Lyophilized Strain of <named-content content-type="genus-species">Shigella sonnei</named-content> 53G
title_full	Establishment of a Controlled Human Infection Model with a Lyophilized Strain of <named-content content-type="genus-species">Shigella sonnei</named-content> 53G
title_fullStr	Establishment of a Controlled Human Infection Model with a Lyophilized Strain of <named-content content-type="genus-species">Shigella sonnei</named-content> 53G
title_full_unstemmed	Establishment of a Controlled Human Infection Model with a Lyophilized Strain of <named-content content-type="genus-species">Shigella sonnei</named-content> 53G
title_sort	establishment of a controlled human infection model with a lyophilized strain of <named-content content-type="genus-species">shigella sonnei</named-content> 53g
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/93466a6d389e45019b54871b82a4c79c
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Establishment of a Controlled Human Infection Model with a Lyophilized Strain of <named-content content-type="genus-species">Shigella sonnei</named-content> 53G

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