TY - JOUR
T1 - Human challenge study with a Shigella bioconjugate vaccine
T2 - Analyses of clinical efficacy and correlate of protection
AU - Talaat, Kawsar R.
AU - Alaimo, Cristina
AU - Martin, Patricia
AU - Bourgeois, A. Louis
AU - Dreyer, Anita M.
AU - Kaminski, Robert W.
AU - Porter, Chad K.
AU - Chakraborty, Subhra
AU - Clarkson, Kristen A.
AU - Brubaker, Jessica
AU - Elwood, Daniel
AU - Frölich, Rahel
AU - DeNearing, Barbara
AU - Weerts, Hailey
AU - Feijoo, Brittany L.
AU - Halpern, Jane
AU - Sack, David
AU - Riddle, Mark S.
AU - Fonck, Veronica Gambillara
N1 - Funding Information:
CA, PM, AMD, RF and VGF were employees of LimmaTech Biologics at the time of the study. KRT, CA, PM, ALB, AMD, RWK, SC, KAC, JB, RF, BD, HW, BF, JH, DS, VGF received grant support from the Wellcome Trust. The authors declare no other competing interests.
Funding Information:
KRT: Helped with study design, oversaw conduct of study and care of volunteers, assisted with data analysis and interpretation, drafted and edited manuscript. CA: Helped with study design, data analysis, interpretation, did significant writing and editing of manuscript. PM: Helped with data interpretation, editing of paper, ALB: Helped with study design, helped prepare challenge strain, oversaw laboratory assays and analysis, contributed to manuscript and editing. AMD: Helped with statistical and laboratory design and analysis, contributed to manuscript and editing. RWK: Helped with study design, provided challenge strain, conducted laboratory assays and analysis, contributed to manuscript and editing. CKP: Helped with study design, developed statistical plan, contributed to data analysis and statistical analysis, did significant writing and editing of manuscript. SC: Oversaw laboratory assays and analysis, contributed to manuscript and editing. KAC: Conducted laboratory assays and analysis, contributed to manuscript and editing. JB: Helped prepare challenge strain, conducted laboratory assays and analysis, provided data for manuscript, approved manuscript. DE: Coordinated study, gave feedback on paper. RF: Helped with study coordination and clinical operational documentation. BD: Coordinated study, gave feedback on paper. HW: Performed laboratory assays for the study. BF: Performed clinical assessments and clinical care of volunteers, gave feedback on the paper. JH: Performed clinical assessments and clinical care of volunteers, gave feedback on the paper. DS: Oversaw microbiology and immunology lab. Assisted with regulatory aspects. Served as advisor for study. MSR: Independent medical monitor for study. Helped with study design, data interpretation. Gave feedback on paper. VGF: Oversaw trial from Sponsor perspective. Helped design study, analyse data and gave feedback on paper. We thank Wellcome Trust for having provided funding for this study and we thank the study volunteers without whom this trial would not have been possible. The study teams, both clinical and laboratory, worked incredibly hard during this study, and we are indebted to them. We are also grateful to the members of the adjudication committee and to the Emmes Corporation for data management and study monitoring. The data that support the findings of this study will be available on Clinicaltrials.gov (NCT02646371) and from the corresponding author upon reasonable request.
Publisher Copyright:
© 2021 The Authors
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
KW - Bioconjugate vaccine
KW - Controlled human challenge study
KW - Shigella
KW - Shigella flexneri 2a
KW - Vaccine
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U2 - 10.1016/j.ebiom.2021.103310
DO - 10.1016/j.ebiom.2021.103310
M3 - Article
C2 - 33862589
AN - SCOPUS:85104052439
SN - 2352-3964
VL - 66
JO - EBioMedicine
JF - EBioMedicine
M1 - 103310
ER -