Toward a Multivalent Synthetic Oligosaccharide-Based Conjugate Vaccine against Shigella: State-of-the-Art for a Monovalent Prototype and Challenges

Abstract

This review focuses on the molecular glycovaccine concept, a promising option to develop a Shigella glycoconjugate vaccine. Subsequent to original developments involving, as main vaccine component, the detoxified Shigella lipopolysaccharide randomly conjugated at multiple sites to a carrier protein, novelty stems from the use of rationally designed, well-defined chemically synthesized oligosaccharide haptens conceived as functional surrogates of the main surface antigen, linked via single-point attachment onto a carrier. The concept and design of such a fine-tuned Shigella glycovaccine are presented by way of SF2a-TT15, a neoglycoprotein featuring a synthetic 15-mer oligosaccharide, which constitutes an original vaccine prototype targeting Shigella flexneri 2a, one of the predominant circulating strains in endemic settings. The clinical testing of SF2a-TT15 is summarized with the first-in-human phase I trial in young healthy adults showing a good safety profile and tolerability, while inducing bactericidal antibodies towards S. flexneri 2a bacteria. The proof-of-concept of this novel approach being established, an ongoing phase IIa clinical study in the nine-month-old infant target population in endemic area was launched, which is also outlined. Lastly, some challenges to move forward this original approach toward a multivalent cost-effective Shigella synthetic glycan conjugate vaccine are introduced.

A Shigella flexneri 2a synthetic glycan-based vaccine induces a long-lasting immune response in adults

“…Otherwise, added to the original data of phase I clinical trial, the outcome of the present long-term follow-up study strongly supports the further evaluation of SF2a-TT15 for safety and immunogenicity in infants in LMICs and for preliminary efficacy in a CHIM study in North American adult volunteers. Toward this end, both the 2 µg and 10 µg OS doses of SF2a-TT15, adjuvanted or non-adjuvanted, are currently evaluated in young children and 9-month-old infants in Kenya (ClinicalTrials.gov Identifier: NCT04602975), while the 10 µg OS alum-adjuvanted vaccine dose is used in the ongoing CHIM study in North American volunteers (ClinicalTrials.gov Identifier: NCT04078022) 58 .…”

“…Moreover, as for the other most advanced LPS-based Shigella vaccine candidates, a broad serotype coverage Shigella vaccine candidate featuring a suitable combination of rationally designed fine-tuned synthetic OS representative of segments from the O-SPs of selected S. flexneri serotypes and S. sonnei is currently in pre-clinical development 58 .…”

Impact and Control of Sugar Size in Glycoconjugate Vaccines

“…The development of a synthetic Shighella flexneri 2a conjugate vaccine offers another example of the use of carbohydrate synthesis to select the optimal chain length; a conjugate made with a synthetic O-SP pentadecasaccharide, corresponding to 3 RU, was found to be more immunogenic than conjugates with 2 or 1 RU with the same saccharide load density [ 48 ]. This synthetic conjugate is currently in phase 2 clinical trials [ 118 , 119 ] and it constitutes clear evidence for the feasibility of this approach, together with the already commercialized synthetic Hib vaccine (Quimi-Hib, manufactured by CIGB, Cuba), which consists of an octamer end-linked to TT [ 120 ].…”

Chemical Synthesis and Antigenicity Evaluation of Shigella dysenteriae Serotype 10 O-Antigen Tetrasaccharide Containing a (S)-4,6-O-Pyruvyl Ketal

“…Since key epitopes may be altered and labile substitutions may not survive the process of polysaccharide isolation, well-defined synthetic oligosaccharides have been invaluable tools to the growing field of glycoconjugate vaccine development. , Oligosaccharides corresponding to the O-antigens of S. dysenteriae serotypes 1, , 3, 4, , 5, and 8, S.…”

“…dysenteriae serotype 1 O-antigen elicited significantly higher levels of specific IgG than conjugates prepared with the isolated O-antigen in a phase 3 clinical trial. , Mulard et al developed a vaccine candidate against S. flexneri serotype 2a comprising a pentadecasaccharide–tetanus toxoid conjugate that induced a strong antibody response sustained for more than 1 year in adults in a phase 1 clinical trial. ,− An ongoing phase 2a clinical study of this vaccine candidate in a 9-month-old infant target population in Kenya was launched . Based on the synthetic oligosaccharides related to the S.…”