The First-in-Human Synthetic Glycan-Based Conjugate Vaccine Candidate against <i>Shigella</i>

Put, Robert M. F. van der; Smitsman, Carolien; Haan, Alex de; Hamzink, M.; Timmermans, Hans; Uittenbogaard, Joost P.; Westdijk, Janny; Stork, Michiel; Ophorst, Olga; Thouron, Françoise; Guerreiro, Catherine; Sansonetti, Philippe J.; Phalipon, Armelle; Mulard, Laurence A.

doi:10.1021/acscentsci.1c01479

Cited by 31 publications

(28 citation statements)

References 71 publications

(173 reference statements)

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“…Previous studies have found that O -acetylation had an impact on the immunogenicity of isolated meningococcal and Salmonella typhi vaccines, whereas in contrast for others such as the semisynthetic Shigella vaccines, no effect of acetylation was observed. 89 − 93 We found that both acetylated ( 1 through 4 ) and the nonacetylated antigen 53 elicited IgG responses with functional activity against E. coli , suggesting that for this particular antigen, acetyl groups may have a limited effect on immunogenicity. Overall, the binding studies with the mAbs suggest that an O25B glycoconjugate vaccine elicits IgGs characterized by heterogeneous epitope recognition patterns.…”

Section: Discussionmentioning

confidence: 83%

Semisynthetic Glycoconjugate Vaccine Candidates against Escherichia coli O25B Induce Functional IgG Antibodies in Mice

Naini¹,

Bartetzko²,

Sanapala³

et al. 2022

JACS Au

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Extraintestinal pathogenic Escherichia coli (ExPEC) is a major health concern due to emerging antibiotic resistance. Along with O1A, O2, and O6A, E. coli O25B is a major serotype within the ExPEC group, which expresses a unique O -antigen. Clinical studies with a glycoconjugate vaccine of the above-mentioned O -types revealed O25B as the least immunogenic component, inducing relatively weak IgG titers. To evaluate the immunological properties of semisynthetic glycoconjugate vaccine candidates against E. coli O25B, we here report the chemical synthesis of an initial set of five O25B glycan antigens differing in length, from one to three repeat units, and frameshifts of the repeat unit. The oligosaccharide antigens were conjugated to the carrier protein CRM 197 . The resulting semisynthetic glycoconjugates induced functional IgG antibodies in mice with opsonophagocytic activity against E. coli O25B. Three of the oligosaccharide–CRM 197 conjugates elicited functional IgGs in the same order of magnitude as a conventional CRM 197 glycoconjugate prepared with native O25B O -antigen and therefore represent promising vaccine candidates for further investigation. Binding studies with two monoclonal antibodies (mAbs) revealed nanomolar anti-O25B IgG responses with nanomolar K D values and with varying binding epitopes. The immunogenicity and mAb binding data now allow for the rational design of additional synthetic antigens for future preclinical studies, with expected further improvements in the functional antibody responses. Moreover, acetylation of a rhamnose residue was shown to be likely dispensable for immunogenicity, as a deacylated antigen was able to elicit strong functional IgG responses. Our findings strongly support the feasibility of a semisynthetic glycoconjugate vaccine against E. coli O25B.

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Section: Discussionmentioning

confidence: 83%

Semisynthetic Glycoconjugate Vaccine Candidates against Escherichia coli O25B Induce Functional IgG Antibodies in Mice

Naini¹,

Bartetzko²,

Sanapala³

et al. 2022

JACS Au

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“…The original synthesis of SF2a-TT15 was scaled up successfully. A GMP batch was produced [ 11 ]. SF2a-TT15 GMP was immunogenic in rabbits and passed all toxicity criteria [ 11 ].…”

Section: From Polysaccharide Antigens To Sf2a-tt15 a Shigel...mentioning

confidence: 99%

“…A GMP batch was produced [ 11 ]. SF2a-TT15 GMP was immunogenic in rabbits and passed all toxicity criteria [ 11 ]. Moreover, SF2a-TT15-induced sera in mice recognized a large panel of SF2a strains circulating worldwide [ 11 ].…”

Section: From Polysaccharide Antigens To Sf2a-tt15 a Shigel...mentioning

confidence: 99%

“…SF2a-TT15 GMP was immunogenic in rabbits and passed all toxicity criteria [ 11 ]. Moreover, SF2a-TT15-induced sera in mice recognized a large panel of SF2a strains circulating worldwide [ 11 ]. Based on these data, this original vaccine prototype was move forward into a first-in-human evaluation.…”

Section: From Polysaccharide Antigens To Sf2a-tt15 a Shigel...mentioning

confidence: 99%

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

Phalipon

Mulard

2022

Vaccines

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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.

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“…Fully synthetic antigens reached the clinic by the synthetic Haemophilus influenzae type b (Hib) vaccine in Cuba, 18 and more recently a vaccine to fight shigellosis has progressed to phase II clinical trials. 19,20 The use of synthetic glycans with modern structural glycobiology approaches, such as glycan arrays, X-ray crystallography, surface plasmon resonance, and saturation transfer difference NMR, can nowadays be used for rational rather than trial-and-error-based glycoconjugate vaccine design. 21,22 This review aims at discussing the advancement of glycoconjugate vaccines based on synthetic carbohydrates to improve existing vaccines and identify novel candidates to combat AMR.…”

Section: Introductionmentioning

confidence: 99%

Synthetic Glycans to Improve Current Glycoconjugate Vaccines and Fight Antimicrobial Resistance

Bino

Østerlid

et al. 2022

Chem. Rev.

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Antimicrobial resistance (AMR) is emerging as the next potential pandemic. Different microorganisms, including the bacteria Acinetobacter baumannii, Clostridioides diff icile, Escherichia coli, Enterococcus faecium, Klebsiella pneumoniae, Neisseria gonorrhoeae, Pseudomonas aeruginosa, non-typhoidal Salmonella, and Staphylococcus aureus, and the fungus Candida auris, have been identified by the WHO and CDC as urgent or serious AMR threats. Others, such as group A and B Streptococci, are classified as concerning threats. Glycoconjugate vaccines have been demonstrated to be an efficacious and cost-effective measure to combat infections against Haemophilus inf luenzae, Neisseria meningitis, Streptococcus pneumoniae, and, more recently, Salmonella typhi. Recent times have seen enormous progress in methodologies for the assembly of complex glycans and glycoconjugates, with developments in synthetic, chemoenzymatic, and glycoengineering methodologies. This review analyzes the advancement of glycoconjugate vaccines based on synthetic carbohydrates to improve existing vaccines and identify novel candidates to combat AMR. Through this literature survey we built an overview of structure−immunogenicity relationships from available data and identify gaps and areas for further research to better exploit the peculiar role of carbohydrates as vaccine targets and create the next generation of synthetic carbohydrate-based vaccines.

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

Cited by 31 publications

References 71 publications

Semisynthetic Glycoconjugate Vaccine Candidates against Escherichia coli O25B Induce Functional IgG Antibodies in Mice

Semisynthetic Glycoconjugate Vaccine Candidates against Escherichia coli O25B Induce Functional IgG Antibodies in Mice

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

Synthetic Glycans to Improve Current Glycoconjugate Vaccines and Fight Antimicrobial Resistance

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