Consensus Report on Shigella Controlled Human Infection Model: Conduct of Studies

Talaat, Kawsar R.; Bourgeois, A. Louis; Frenck, Robert W.; Chen, Wilbur H.; MacLennan, Calman A.; Riddle, Mark S.; Suvarnapunya, Akamol E.; Brubaker, Jessica; Kotloff, Karen L.; Porter, Chad K.

doi:10.1093/cid/ciz892

Cited by 26 publications

(17 citation statements)

References 48 publications

(39 reference statements)

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“…A consensus description of the methods involved in the conduct of a Shigella challenge has recently been published [20] . Essentially, volunteers were healthy male and nonpregnant female adults between 18 and 50 years of age recruited from the Mid-Atlantic area.…”

Section: Methodsmentioning

confidence: 99%

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Human challenge study with a Shigella bioconjugate vaccine: Analyses of clinical efficacy and correlate of protection

et al. 2021

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Background Shigellosis is a major cause of moderate to severe diarrhoea and dysentery in children under 5 years of age in low and middle-income countries. The Flexyn2a vaccine conjugates the O -polysaccharide of Shigella flexneri 2a to Pseudomonas aeruginosa exotoxin A . We describe a Phase 2b proof-of-concept challenge study that evaluated safety, immunogenicity, and efficacy of the Flexyn2a vaccine to protect against shigellosis. Methods In this randomized, double blind, placebo-controlled trial, healthy adults were randomized 1:1 to receive Flexyn2a (10 µg) or placebo intramuscularly, twice, 4 weeks apart, followed by challenge 4 weeks later with 1500 colony forming units (CFUs) of S. flexneri 2a strain 2457T. The primary outcome was vaccine-induced protection. S. flexneri 2a lipopolysaccharide (LPS)-specific immune responses were assessed. Findings Sixty-seven subjects were enrolled, 34 received vaccine and 33 placebo. The vaccine was well tolerated; the majority of adverse events were mild in nature. Thirty vaccinees and 29 placebo recipients received the S. flexneri 2a challenge. Vaccination resulted in a 30.2% reduction in shigellosis compared with placebo (13/30 vs. 18/29; p = 0.11; 95% CI -15 to 62.6). Vaccine efficacy was more robust against severe disease, reaching 51.7% ( p = 0.015, 95% CI 5.3 to 77.9) against moderate/severe diarrhoea or dysentery concurrent with fever or severe enteric symptoms and 72.4% ( p = 0.07) against more severe diarrhoea (≥10 lose stools or ≥1000 g loose stools/24 h). Vaccinated subjects were less likely to need early antibiotic intervention following challenge (protective efficacy 51.7%, p = 0.01; 95% CI 9 to 76.8). In those who developed shigellosis, vaccinated subjects had a lower disease severity score ( p = 0.002) than placebo-recipients. Additionally, LPS-specific serum IgG responses in Flexyn2a recipients were associated with protection against disease ( p = 0.0016) and with a decreased shigellosis disease score ( p = 0.002). Interpretation The Flexyn2a bioconjugate vaccine was immunogenic, well tolerated and protected against severe illness after Shigella challenge and is a promising Shigella vaccine construct. We identified a strong association between anti- S. flexneri 2a serum IgG and a reduction in disease outcomes. (Clinicaltrials.gov, NCT02646371.) Funding Funding for this study was through a grant from the Wellcome Trust.

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Section: Methodsmentioning

confidence: 99%

“…Many of the study procedures for a Shigella human challenge study have since been published [20] , [21] , [22] . During the vaccination phase, volunteers were followed as outpatients for safety and completed a surveillance document for 7 days post each vaccination.…”

Section: Methodsmentioning

confidence: 99%

Human challenge study with a Shigella bioconjugate vaccine: Analyses of clinical efficacy and correlate of protection

et al. 2021

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“…Additional secondary endpoints adjudicated included alternative definitions of shigellosis, as follows: option 1 was severe diarrhea, or moderate diarrhea and fever, or moderate diarrhea with ≥1 moderate constitutional/enteric symptom or dysentery; option 2 was severe diarrhea, or moderate diarrhea and fever, or dysentery and fever, or moderate diarrhea and ≥1 severe constitutional/enteric symptom, or dysentery and ≥1 severe constitutional/enteric symptom. These additional endpoints were applied based on recommendations of a recent convening of experienced Shigella CHIM investigators and vaccine developers that focused on further standardizing clinical endpoint for the Shigella CHIM model ( 9 , 22 ). All clinical endpoints evaluated in this study are outlined in Table 3 .…”

Section: Methodsmentioning

confidence: 99%

Establishment of a Controlled Human Infection Model with a Lyophilized Strain of Shigella sonnei 53G

Frenck

Dickey

Suvarnapunya

et al. 2020

mSphere

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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.

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“…A tool that is useful for early assessment of vaccine efficacy and, at times, utilized to support licensure is the controlled human infection model (CHIM) (16)(17)(18). In response to recent calls for model standardization (19)(20)(21)(22)(23)(24), a lyophilized strain of Shigella sonnei 53G was produced using current good manufacturing practice (cGMP) and evaluated in a dose-escalation manner to determine a dose that safely and reproducibly yielded a Ն60% attack rate for shigellosis (25). Disease outcomes and attack rates with the lyophilized strain of S. sonnei 53G are described elsewhere (25).…”

mentioning

confidence: 99%

Immune Response Characterization after Controlled Infection with Lyophilized Shigella sonnei 53G

Clarkson

Frenck

Dickey

et al. 2020

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Shigella is a major cause of moderate to severe diarrhea largely affecting children (<5 years old) living in low- and middle-income countries. Several vaccine candidates are in development, and controlled human infection models (CHIMs) can be useful tools to provide an early assessment of vaccine efficacy and potentially support licensure. A lyophilized strain of S. sonnei 53G was manufactured and evaluated to establish a dose that safely and reproducibly induced a ≥60% attack rate. Samples were collected pre- and postchallenge to assess intestinal inflammatory responses, antigen-specific serum and mucosal antibody responses, functional antibody responses, and memory B cell responses. Infection with S. sonnei 53G induced a robust intestinal inflammatory response as well as antigen-specific antibodies in serum and mucosal secretions and antigen-specific IgA- and IgG-secreting B cells positive for the α4β7 gut-homing marker. There was no association between clinical disease outcomes and systemic or functional antibody responses postchallenge; however, higher lipopolysaccharide (LPS)-specific serum IgA- and IgA-secreting memory B cell responses were associated with a reduced risk of disease postchallenge. This study provides unique insights into the immune responses pre- and postinfection with S. sonnei 53G in a CHIM, which could help guide the rational design of future vaccines to induce protective immune responses more analogous to those triggered by infection. IMPORTANCE Correlate(s) of immunity have yet to be defined for shigellosis. As previous disease protects against subsequent infection in a serotype-specific manner, investigating immune response profiles pre- and postinfection provides an opportunity to identify immune markers potentially associated with the development of protective immunity and/or with a reduced risk of developing shigellosis postchallenge. This study is the first to report such an extensive characterization of the immune response after challenge with S. sonnei 53G. Results demonstrate an association of progression to shigellosis with robust intestinal inflammatory and mucosal gut-homing responses. An important finding in this study was the association of elevated Shigella LPS-specific serum IgA and memory B cell IgA responses at baseline with reduced risk of disease. The increased baseline IgA responses may contribute to the lack of dose response observed in the study and suggests that IgA responses should be further investigated as potential correlates of immunity.

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Consensus Report on Shigella Controlled Human Infection Model: Conduct of Studies

Cited by 26 publications

References 48 publications

Human challenge study with a Shigella bioconjugate vaccine: Analyses of clinical efficacy and correlate of protection

Human challenge study with a Shigella bioconjugate vaccine: Analyses of clinical efficacy and correlate of protection

Establishment of a Controlled Human Infection Model with a Lyophilized Strain of Shigella sonnei 53G

Immune Response Characterization after Controlled Infection with Lyophilized Shigella sonnei 53G

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