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

Author(s)

R.M.F. van der Put, C. Smitsman, A. de Haan, M. Hamzink, H. Timmermans, J. Uittenbogaard, J. Westdijk, M. Stork, O. Ophorst, F. Thouron, C. Guerreiro, Ph.J. Sansonetti, A. Phalipon & L.A. Mulard

Sources

doi.org/10.1021/acscentsci.1c01479

Shigella, the causative agent of shigellosis, is among the leading causes of diarrheal diseases with high morbidity in low-income countries. Relying on chemical synthesis, the design of a multidisciplinary strategy yielded an original glycoconjugate vaccine candidate (SF2a-TT15) targeting Shigella flexneri 2a (SF2a). SF2a-TT15 contains synthetic 15mer oligosaccharides. They correspond to three non-Oacetylated repeats, linked at its reducing end to tetanus toxoid through a thiol-maleimide spacer. The scale-up feasibility under GMP conditions of a high yielding bioconjugation process established a reproducible and controllable glycan/protein ratio.
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Preclinical and clinical batches were conducted following specifications from ICH guidelines and WHO recommendations for polysaccharide conjugate vaccines. The SF2a-TT15 vaccine candidate passed all toxicity-related criteria. It was immunogenic in rabbits and elicited bactericidal antibodies in mice. The induced IgG antibodies recognized a large panel of SF2a circulating strains. These preclinical data pave the way for 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 infectious disease.

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