This takes its promising step on the feasibility of the synthetic oligosaccharide-based technique for creating a multivalent vaccine. Open in another window Figure 2 Repeatings units from the O-Ags in mind for the introduction of a broad stress insurance vaccine [7,20]. while inducing bactericidal antibodies towards 2a bacterias. The proof-of-concept of the novel approach getting established, a continuing phase IIa scientific research in the nine-month-old baby target inhabitants in endemic region was launched, which is outlined also. Lastly, some issues to move forwards this original strategy toward a multivalent cost-effective artificial glycan conjugate vaccine are presented. vaccine within the last 100 years. Just two of these have reached stage III clinical studies, namely, orally implemented live attenuated strains and parenterally implemented polysaccharide-protein conjugates. Stemming from their previous achievements in the field of b (Hib) vaccination, the concept of polysaccharide-protein conjugate Microtubule inhibitor 1 vaccines was originally introduced by John B. Robbins and colleagues [1]. Briefly, Microtubule inhibitor 1 bacterial polysaccharides that are key targets of the naturally induced immunity are well-known T-cell independent antigens. Their conjugation to a carrier protein enables Microtubule inhibitor 1 the induction of the desired T-cell dependent humoral immunity, including priming of the host memory B cells (for a review see [2]). Of note, several multivalent conjugate vaccines have been successfully implemented against diseases caused by capsulated bacteria, the highest strain coverage being achieved so far with the 13-valent licensed vaccine (for a review see [2]). For O-Ag could provide protection by transudation to the intestinal mucosal surface and bacteria inactivation in the intestine [1,4], the Robbins and Schneersons group at the National Institutes of Health (NIH) extensively investigated the use of detoxified LPSs as the basis for parenteral glycoconjugate vaccines. A diversity of lattice-type conjugatesabbreviated as NIH conjugatesin which the detoxified LPS and the carrier protein are covalently linked at multiple sites, were generated. The proof of concept of their safety, immunogenicity and protective efficacy was established in young adults and children (for a review, see [5]). However, the lack of efficacy of the most advanced NIH vaccine prototype in the main target population of infection, i.e., one-to-two-year-old children, encouraged the search for alternatives to this first generation of conjugate vaccines [5]. Going from concept to phase II clinical trial, the following provides an overview of our achievements in the field of synthetic glycan-based vaccines with focus on SF2a-TT15, a sun-type synthetic glycan-tetanus toxoid (TT) conjugate conceived as a promising 2a Microtubule inhibitor 1 (SF2a) vaccine candidate. Diverging from other options under investigation, the concept of synthetic carbohydrate hapten takes advantage of the versatility of chemical synthesis and its potential when aiming at immunogens fine-tuned to drive the antibody response towards the key protective determinants of the native surface polysaccharide. Providing support to developments ongoing at Institut Pasteur was a report in 1999 by the NIH team on the superior immunogenicity of synthetic oligosaccharide-HSA (Human Serum Albumin) sun-type conjugates compared to a lattice-type counterpart targeting 1 [6]. 2. From Polysaccharide Antigens to SF2a-TT15, a Synthetic Glycan Conjugate Vaccine Prototype 2.1. Concept: Synthetic Glycans as Surrogates for HYAL1 Shigella O-Ags Bacterial O-Ags are defined by linear or branched repeats made of up to eight monosaccharide residues. They feature tremendous disparities in terms of chain length and often owing to the presence of non-stoichiometric labile and/or phase-associated substitutions, which may be essential components of the protective epitopes. By essence, detoxified LPSs are therefore highly heterogenous molecules. Moreover, despite major improvements over the past decades, conjugate manufacturing is not without risk. The chemical manipulations necessary for LPS extraction, detoxification, and subsequent conjugation of the polysaccharide material to a suitable carrier contribute to deliver complex poorly defined glycoconjugates, especially when involving random conjugation at multiple sites on the polysaccharide component. Key epitopes may be altered and labile O-Ag substitutions may not survive the process whilst neo-epitopes may be generated. As a result, partial loss of immunogenicity is not unexpected and quality control is a highly demanding process. In contrast, the use of a well-defined synthetic O-Ag surrogate, preferably a fine-tuned oligosaccharide, equipped with a unique orthogonal reactive moiety provides.