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The First-in-Human Synthetic Glycan-Based Conjugate Vaccine Candidate against Shigella

Abstract : Shigella, the causative agent of shigellosis, is among the main causes of diarrheal diseases with still a high morbidity in low-income countries. Relying on chemical synthesis, we implemented a multidisciplinary strategy to design SF2a-TT15, an original glycoconjugate vaccine candidate targeting Shigella flexneri 2a (SF2a). Whereas the SF2a O-antigen features nonstoichiometric O-acetylation, SF2a-TT15 is made of a synthetic 15mer oligosaccharide, corresponding to three non-O-acetylated repeats, linked at its reducing end to tetanus toxoid by means of a thiol-maleimide spacer. We report on the scale-up feasibility under GMP conditions of a high yielding bioconjugation process established to ensure a reproducible and controllable glycan/protein ratio. Preclinical and clinical batches complying with specifications from ICH guidelines, WHO recommendations for polysaccharide conjugate vaccines, and (non)compendial tests were produced. The obtained SF2a-TT15 vaccine candidate passed all toxicity-related criteria, was immunogenic in rabbits, and elicited bactericidal antibodies in mice. Remarkably, the induced IgG antibodies recognized a large panel of SF2a circulating strains. These preclinical data have paved the way forward to the first-in-human study for SF2a-TT15, demonstrating safety and immunogenicity. This contribution discloses the yet unreported feasibility of the GMP synthesis of conjugate vaccines featuring a unique homogeneous synthetic glycan hapten fine-tuned to protect against an infectious disease.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-03699895
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Submitted on : Monday, June 20, 2022 - 3:59:00 PM
Last modification on : Saturday, June 25, 2022 - 3:44:07 AM

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Distributed under a Creative Commons Attribution 4.0 International License

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Robert van der Put, Carolien Smitsman, Alex de Haan, Martin Hamzink, Hans Timmermans, et al.. The First-in-Human Synthetic Glycan-Based Conjugate Vaccine Candidate against Shigella. ACS Central Science, ACS Publications, 2022, 8 (4), pp.449-460. ⟨10.1021/acscentsci.1c01479⟩. ⟨pasteur-03699895⟩

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