From Immunologically Archaic to Neoteric Glycovaccines

Abstract

Polysaccharides (PS) are present in the outermost surface of bacteria and readily come in contact with immune cells. They interact with specific antibodies, which in turn confer protection from infections. Vaccines with PS from pneumococci, meningococci, Haemophilus influenzae type b, and Salmonella typhi may be protective, although with the important constraint of failing to generate permanent immunological memory. This limitation has in part been circumvented by conjugating glycovaccines to proteins that stimulate T helper cells and facilitate the establishment of immunological memory. Currently, protection evoked by conjugated PS vaccines lasts for a few years. The same approach failed with PS from staphylococci, Streptococcus agalactiae, and Klebsiella. All those germs cause severe infections in humans and often develop resistance to antibiotic therapy. Thereby, prevention is of increasing importance to better control outbreaks. As only 23 of more than 90 pneumococcal serotypes and 4 of 13 clinically relevant Neisseria meningitidis serogroups are covered by available vaccines there is still tremendous clinical need for PS vaccines. This review focuses on glycovaccines and the immunological mechanisms for their success or failure. We discuss recent advances that may facilitate generation of high affinity anti-PS antibodies and confer specific immunity and long-lasting protection.

Keywords: T cell help; conjugate; immunosenescence; polysaccharide; serotype; vaccine.

Figure 1

Repeating polysaccharide units of bacterial capsules. (a) The polyribosylribitol phosphate (PRP) repeating unit of Haemophilus influenzae type b (Hib) consists of two riboses (one reduced to ribitol) linked to a phosphate; (b) The capsular Vi antigen of S. typhi is built from a single sugar: N-acetyl galactosaminouronate. The monomeric Vi repeating units are α-1-4 linked.

Figure 2

Polysaccharide coupled α-GalCer induces long-lived memory B cells and high-affinity, class-switched antibodies with the help of iNKT cells. A naïve B cell endocytoses the polysaccharide vaccine (α-GalCer-PS) via its B cell receptor (BCR). The vaccine is processed during its trafficking through the endolysosome and α-galactosylceramide (α-GalCer), an antigen stimulating all iNKT cells, is released from the complex. The free antigen is loaded onto CD1d molecules that also recycles within same endocytic compartment. The CD1d-α-GalCer complexes traffic to the plasma membrane and stimulate iNKT cells. Activated iNKT cells develop into follicular helper iNKT (iNKTfh) cells that participate in a germinal center reaction together with PS-specific B cells and contribute to generation of hypermutated, class-switched antibodies and establishment of immunological memory.

Figure 3

Synthetic polysaccharide vaccine building blocks. A minimal polysaccharide (PS) vaccine needs to provide the B and T cell epitope together with an adjuvant that determines the nature of the immune response. Peptides are used as example where classic T cells would help B cells.