Classical and novel strategies to develop a Shigella glycoconjugate vaccine: from concept to efficacy in human

Abstract

Shigella are gram-negative bacteria that cause severe diarrhea and dysentery, with a high level of antimicrobial resistance. Disease-induced protection against reinfection in Shigella-endemic areas provides convincing evidence on the feasibility of a vaccine and on the importance of Shigella lipopolysaccharides as targets of the host humoral protective immune response against disease. This article provides an overview of the original and current strategies toward the development of a Shigella glycan-protein conjugate vaccine that would cover the most commonly detected strains. Going beyond pioneering "lattice"-type polysaccharide-protein conjugates, progress, and challenges are addressed with focus on promising alternatives, which have reached phases I and II clinical trial. Glycoengineered bioconjugates and "sun"-type conjugates featuring well-defined synthetic carbohydrate antigens are discussed with insights on the molecular parameters governing the rational design of a cost-effective glycoconjugate vaccine efficacious in preventing diseases caused by Shigella in the most at risk populations, young children living in endemic areas.

Keywords: Bioconjugate; O-acetylation; Shigella; carbohydrate antigen; clinical trial; glycan; glycoconjugate; lipopolysaccharide; oligosaccharide; vaccine.

Figure 1.

Biological RU of the O-Ags from SD1 (ABCD),⁵⁶ SF2a (_AcA¹B¹[E¹]C¹_AcD¹),^13,57 SF6 (_AcA¹B¹C²D²),⁵⁷ and S. sonnei (A³B³).⁵⁸

Scheme 1.

Strategies to detoxified-LPS protein conjugates as potential Shigella vaccines. “Lattice”-type conjugate (left) and “sun”-type conjugate (right). DeLPS: deacylated LPS, pmLPS: LPS polysaccharide moiety, O-AgC: sized O-antigen-core polysaccharide, RU: repeating unit.

Scheme 2.

One-pot PglB-based bioconjugate engineering in E. coli. P: phosphate, Und: undecaprenyl, GT: glycosyl transferase, N: asparagine within the consensus sequence for N-glycosylation.

Figure 2.

Synthetic carbohydrate-based vaccines. Key components and parameters possibly affecting immunogenicity. Abbreviation: OS: oligosaccharide, RU: repeating unit.

Figure 3.

SD1 glycoconjugates demonstrating high immunogenicity in mice with emphasis on chain length (left) and nonreducing terminal residue (right). OSs selected for evaluation in a phase I clinical trial are marked in bold. The ° and ’ labels define residues occurring before and after the basic RU, respectively.

Figure 4.

“Sun”-type SF2a conjugates featuring a synthetic glycan as hapten with emphasis on chain length and on sugar:protein mol/mol ratio. Composition yielding glycoconjugates demonstrating high immunogenicity in mice are highlighted in bold. Abbreviation: TT: Tetanus toxoid.

Scheme 3.

Chemical synthesis of SF2a-TT15, showing starting materials, key synthetic building blocks featuring a convergent strategy emphasizing on the C-D linkage, the [A¹B¹(E¹)C¹D¹]₃-NH₂ hapten, and its ready-for-conjugation counterpart. Abbreviations: Ac: acetyl, All: allyl, Bn: benzyl, Bz: benzoyl, p: fully protected, TT_Mal: maleimide-equipped TT.