Safety and Immunogenicity of a Candidate Bioconjugate Vaccine against Shigella flexneri 2a Administered to Healthy Adults: a Single-Blind, Randomized Phase I Study

Mark S Riddle, Robert W Kaminski, Claudio Di Paolo, Chad K Porter, Ramiro L Gutierrez, Kristen A Clarkson, Hailey E Weerts, Christopher Duplessis, Amy Castellano, Cristina Alaimo, Kristopher Paolino, Robert Gormley, Veronica Gambillara Fonck, Mark S Riddle, Robert W Kaminski, Claudio Di Paolo, Chad K Porter, Ramiro L Gutierrez, Kristen A Clarkson, Hailey E Weerts, Christopher Duplessis, Amy Castellano, Cristina Alaimo, Kristopher Paolino, Robert Gormley, Veronica Gambillara Fonck

Abstract

Several candidate vaccines against Shigella spp. are in development, but the lack of a clear correlate of protection from challenge with the induction of adequate immune responses among the youngest age groups in the developing world has hampered Shigella vaccine development over the past several decades. Bioconjugation technology, exploited here for an Shigella flexneri 2a candidate vaccine, offers a novel and potentially cost-effective way to develop and produce vaccines against a major pathogen of global health importance. Flexyn2a, a novel S. flexneri 2a bioconjugate vaccine made of the polysaccharide component of the S. flexneri 2a O-antigen, conjugated to the exotoxin protein A of Pseudomonas aeruginosa (EPA), was evaluated for safety and immunogenicity among healthy adults in a single-blind, phase I study with a staggered randomization approach. Thirty subjects (12 receiving 10 μg Flexyn2a, 12 receiving Flexyn2a with aluminum adjuvant, and 6 receiving placebo) were administered two injections 4 weeks apart and were followed for 168 days. Flexyn2a was well-tolerated, independently of the adjuvant and number of injections. The Flexyn2a vaccine elicited statistically significant S. flexneri 2a lipopolysaccharide (LPS)-specific humoral responses at all time points postimmunization in all groups that received the vaccine. Elicited serum antibodies were functional, as evidenced by bactericidal activity against S. flexneri 2a. The bioconjugate candidate vaccine Flexyn2a has a satisfactory safety profile and elicited a robust humoral response to S. flexneri 2a LPS with or without inclusion of an adjuvant. Moreover, the bioconjugate also induced functional antibodies, showing the technology's features in producing a promising candidate vaccine. (This study has been registered at ClinicalTrials.gov under registration no. NCT02388009.).

Copyright © 2016 Riddle et al.

Figures

FIG 1
FIG 1
Study flow chart: subject screening, enrollment, and progress through the study.
FIG 2
FIG 2
S. flexneri 2a LPS-specific serum IgG (a) and IgA (b) responses. ELISA endpoint titers over time are shown for day 0 (baseline), day 28 (post-first vaccination), and day 56 (post-second vaccination), with geometric means. §, statistically significantly different from baseline samples; *, statistically significantly different from placebo at the same time point.
FIG 3
FIG 3
Anti-S. flexneri 2a strain 2457T serum bactericidal endpoint titers (with geometric means) of vaccinated subjects over time: day 0 (baseline), day 28 (post-first vaccination), and day 56 (post-second vaccination). §, statistically significant difference from baseline samples; *, statistically significant difference from placebo at the same time point.

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