Abstract
Shigella causes morbidity and mortality worldwide, primarily affecting young children living in low-resource settings. It is also of great concern due to increasing antibiotic resistance, and is a priority organism for the World Health Organization. A Shigella vaccine would decrease the morbidity and mortality associated with shigellosis, improve child health, and decrease the need for antibiotics. Controlled human infection models (CHIMs) are useful tools in vaccine evaluation for early up- or down-selection of vaccine candidates and potentially useful in support of licensure. Over time, the methods employed in these models have become more uniform across sites performing CHIM trials, although some differences in conduct persist. In November 2017, a Shigella CHIM workshop was convened in Washington, District of Columbia. Investigators met to discuss multiple aspects of these studies, including study procedures, clinical and immunological endpoints, and shared experiences. This article serves as a uniform procedure by which to conduct Shigella CHIM studies.
Highlights
The rise of antimicrobial resistance, in addition to the morbidity and mortality caused by Shigella, has led to it becoming a priority pathogen for the World Health Organization (WHO) [13]
The Shigella Controlled human infection models (CHIMs) has been in use to evaluate the efficacy of investigational Shigella vaccines since the studies of Shaughnessy and Olsson in 1946 among prison inmates in Joliet, Illinois [20]
CHIM trials evaluating Shigella vaccine candidates have been conducted at several sites in the United States, mostly with Shigella flexneri 2a [21, 22] and Shigella sonnei [23], and with wild-type and toxin-minus mutants of Shigella dysenteriae type 1 [17, 23,24,25,26,27,28,29]
Summary
Given the somewhat unusual nature of CHIMs, in that a virulent organism is given to healthy volunteers, a close working relationship with regulatory authorities and ethics oversight committees (institutional review boards [IRBs]) is a must. Specific for Shigella CHIM studies, there is a need to highlight the requirement for inpatient admission during the time that a volunteer is infectious or ill. Potential factors to consider include the amount of time a volunteer gives to the study, the risk of illness due to the challenge, and the required confinement. Volunteers for challenge studies are generally healthy volunteers, without significant physical or mental health issues At some sites, those with conditions requiring concomitant medications are excluded. Congo red–positive colonies are tested for agglutination with commercial Shigella serotype-specific antiserum and 10 well-isolated Congo red–positive colonies are picked and used to prepare a bacterial suspension in 3 mL of phosphate-buffered saline (PBS) This suspension is used to inoculate multiple TSA plates to yield confluent growth (~6 plates for 30 volunteers, plus 2–3 extra plates as backup in case of individual plate contamination).
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