Discovery of Semi- and Fully-Synthetic Carbohydrate Vaccines Against Bacterial Infections Using a Medicinal Chemistry Approach

Abstract

The glycocalyx, a thick layer of carbohydrates, surrounds the cell wall of most bacterial and parasitic pathogens. Recognition of these unique glycans by the human immune system results in destruction of the invaders. To elicit a protective immune response, polysaccharides either isolated from the bacterial cell surface or conjugated with a carrier protein, for T-cell help, are administered. Conjugate vaccines based on isolated carbohydrates currently protect millions of people against Streptococcus pneumoniae , Haemophilus influenzae type b, and Neisseria meningitides infections. Active pharmaceutical ingredients (APIs) are increasingly discovered by medicinal chemistry and synthetic in origin, rather than isolated from natural sources. Converting vaccines from biologicals to pharmaceuticals requires a fundamental understanding of how the human immune system recognizes carbohydrates and could now be realized. To illustrate the chemistry-based approach to vaccine discovery, I summarize efforts focusing on synthetic glycan-based medicinal chemistry to understand the mammalian antiglycan immune response and define glycan epitopes for novel synthetic glycoconjugate vaccines against Streptococcus pneumoniae , Clostridium difficile , Klebsiella pneumoniae , and other bacteria. The chemical tools described here help us gain fundamental insights into how the human system recognizes carbohydrates and drive the discovery of carbohydrate vaccines.

The role of vaccines in combating antimicrobial resistance (AMR) bacteria

“…Vaccines for C. difficile that are currently being developed target toxin A and toxin B, which are the primary virulence factors ( Seeberger, 2021 ). Pfizer’s TcdA and TcdB toxoid vaccine and Valneva’s VLA84 already in their phase III trials, are both very immunogenic and have proved to be effective ( de Bruyn et al, 2021 , Stevens et al, 2021 ).…”

Semi- and fully synthetic carbohydrate vaccines against pathogenic bacteria: recent developments

“…Semisynthetic carbohydrate-based vaccines are comprised of mono- or multivalent glycans conjugated to a carrier protein, and an adjuvant is co-administered as a separate molecule ( Figure 2A ) [ 3 , 18 ]. One of the most commonly used carrier proteins is CRM 197.…”

“…In fully synthetic carbohydrate-based vaccines, the carbohydrate moiety conjugated to the synthetic carrier, such as a glycolipid, synthetic peptide, or a nanoparticle, is combined with different adjuvants all to form one (macro)molecule ( Figure 2B ). Interestingly, even in the absence of a carrier protein, fully synthetic solutions based on glycolipids carrying liposomes, zwitterionic polysaccharides, or carbohydrate-based nanoparticles induce T cell-dependent response through different mechanisms successfully [ 3 , 18 , 19 ]. Although co-localization of the elements in the same molecule triggers a more potent antibody response than in the case of semisynthetic vaccines, none of the fully synthetic vaccine formulations is currently marketed [ 20 ].…”

“…We focus on preclinical and clinical studies of vaccines targeting Streptococcus pneumoniae , Streptococcus Groups A and B, Neisseria meningitis , Shigella flexneri , Salmonella enterica , Vibrio cholerae , and Burkholderia pseudomallei and mallei . We refer the interested reader to a recent comprehensive review that provides an in-depth examination of synthetic-carbohydrate technology and its use against bacterial infections [ 3 ].…”

Synthetic Pseudaminic-Acid-Based Antibacterial Vaccine Confers Effective Protection against Acinetobacter baumannii Infection

“… 12 , 13 Bacterial surface carbohydrates have been proven effective as potential antigens for development of vaccines against infectious diseases. 14 − 16 Glycoconjugate vaccines have been successfully developed and effectively used against Haemophilus influenzae type B, 17 selected serotypes of Streptococcus pneumoniae , 18 , 19 Neisseria meningitidis serogroups A, C, W, and Y, 20 Salmonella typhi , 21 and Campylobacter jejuni . 22 The structure of carbohydrate-based antibacterial vaccines is commonly composed of carbohydrate antigens, linkers, and carrier proteins.…”