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Clin Infect Dis. 2019 Dec 9;69(Supplement_8):S591-S595. doi: 10.1093/cid/ciz891.

Consensus Report on Shigella Controlled Human Infection Model: Clinical Endpoints.

Author information

1
Bill & Melinda Gates Foundation, London, United Kingdom.
2
F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda.
3
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland.
4
Center for Immunization Research, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
5
Bill & Melinda Gates Foundation, Seattle, Washington.
6
Enteric Vaccine Initiative, PATH, Washington, District of Columbia.
7
Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Ohio.
8
Division of Infectious Disease and Tropical Pediatrics, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore.
9
Enteric Disease Department, Naval Medical Research Center, Silver Spring, Maryland.

Abstract

The Shigella controlled human infection model (CHIM) is valuable for assessing candidate Shigella vaccine efficacy and potentially accelerating regulatory approval. The Shigella CHIM is currently being conducted at 3 sites in the United States using Shigella flexneri 2a strain 2457T and Shigella sonnei strain 53G. Shigellosis can present variably as watery diarrhea alone or with dysentery, and can be accompanied by manifestations including fever, abdominal cramps, tenesmus, and malaise. For comparability, it is important to harmonize the primary clinical endpoint. An expert working group was convened on 2 February 2018 to review clinical data from Shigella CHIM studies performed to date and to develop a consensus primary endpoint. The consensus endpoint enabled "shigellosis" to present as severe diarrhea or moderate diarrhea or dysentery. The latter 2 criteria are met when concurrent with fever of 38.0°C and/or vomiting, and/or a constitutional/enteric symptom graded at least as "moderate" severity. The use of a blinded independent committee to adjudicate the primary endpoint by subject was also regarded as important. As safety of volunteers in challenge studies is of paramount importance and treatment timing can affect primary outcomes, a standard for early antibiotic administration was established as follows: (1) when the primary endpoint is met; (2) if a fever of ≥39.0°C develops; or (3) if the study physician deems it appropriate. Otherwise, antibiotics are given at 120 hours postinfectious challenge. The working group agreed on objective and subjective symptoms to be solicited, and standardized methods for assessing subject-reported severity of symptoms.

KEYWORDS:

Shigella ; controlled human infection model; endpoints; human infection studies

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