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The Complex World of Polysaccharides 

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Yao, H.T.; Huang, S.Y.; Chiang, M.T. (2008). A comparative study on hypoglycemic and 

hypocholesterolemic effects of high and low molecular weight chitosan in 

streptozotocin-induced diabetic rats. Food and Chemical Toxicology, 46:1525-1534. 

Zhang, J.; Zhang, J.; Liu, J.; Li, L.; Xia, W. (2008). Dietary chitosan improves 

hypercholesterolemia in rats fed high-fat diets. Nutrition Research, 28:383-390. 

Zhbankov, R.G.; Firsov, S.P.; Grinshpan, D.D.; Baran, J.M.K.; Marchewkac, Ratajczak, H. 

(2003). Vibrational spectra and noncovalent interactions of carbohydrates molecules. 

Journal of Molecular Structure, 645:9-16. 

Zheng, D.; Lu, T. (1997). Electrochemical reactions of cyanocobalamin in acidic media. 

Journal of Electroanalytical Chemistry, 429:61-65. 

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Chapter 24 

 

 

 

 

© 2012 Snippe et al., licensee InTech. This is an open access chapter distributed under the terms of the 

Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits 

unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 

The Future of Synthetic Carbohydrate Vaccines: 

Immunological Studies on Streptococcus 

pneumoniae Type 14 

Dodi Safari, Ger Rijkers and Harm Snippe 

Additional information is available at the end of the chapter 

http://dx.doi.org/10.5772/48326 

1. Introduction 

Studies on synthetic carbohydrates to be used as potential vaccine candidates for 

polysaccharide encapsulated bacteria were started in the mid-1970s. They were the logical 

follow-up to studies being performed at that time on the immunogenicity of antigens 

composed of carrier proteins and synthetic hapten groups. Hapten-carrier complexes were 

first introduced in immunology by Karl Landsteiner in the early 1900s [1]. He discovered 

that (i) small organic molecules with a simple structure, such as phenyl arsonates and 

nitrophenyls, do not provoke antibodies by themselves, but (ii) if those molecules are 

attached covalently, by simple chemical reactions, to a protein carrier, then antibodies 

against those small organic molecules are evoked. Since their introduction, these hapten-

carrier complexes have become excellent tools to elucidate the role of different antigen-

reactive cells in the immune response [2]. The key players in this immunological process are 

thymus-derived T cells and bone marrow-derived B cells. The former group of lymphoid 

cells is responsible for various phenomena of cell-mediated immunity, e.g. delayed 

hypersensitivity, allograft-, and graft-versus-host reactions, and reacts with specific 

determinants on the carrier protein (T cell epitopes). The latter group of lymphoid cells (B 

cells) give rise to the precursors of antibody-secreting cells, and reacts with both the carrier 

protein and the synthetic haptenic determinants. This results in antibody formation to both 

the carrier and the hapten. 

The reason to apply the above concepts and techniques to carbohydrate antigens was to 

address an immunological problem: polysaccharide molecules are classified as so-called 

thymus-independent (TI) antigens, because they do not require T cells to induce an immune 

response of B cells. As a result, the antibodies formed are mainly of the IgM class and have a 

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The Complex World of Polysaccharides 

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low avidity. Moreover, no immunological memory is generated and the antigens are poorly 

immunogenic in infants. Latter characteristic has major implications for development of 

vaccines against polysaccharide encapsulated bacteria. It was hypothesized that by linking 

small carbohydrates (oligosaccharides) to a carrier protein, the immunogenic behavior 

would change to that of a thymus-dependent (TD) antigen. Therefore, the studies of both 

Goebel [3, 4] and Campbell and Pappenheimer [5], who first isolated the antigenic 

determinant of Streptococcus pneumoniae type 3, were combined and extended. The hapten-

inhibition studies by Mage and Kabat [6] demonstrated that the antibody-combining site of 

type 3 pneumococcal polysaccharide consists of two to three cellobiuronic acid units. In the 

dextran-anti-dextran system extensively studied by Kabat and colleagues [7] the upper size 

limit of the antibody-combining site appeared to be a hexa- or heptasaccharide and the lower 

limit was estimated to be somewhat larger than a monosaccharide. Snippe and colleagues [8] 

proved in 1983 that small synthetic oligosaccharides (tetra- and hexasaccharides) of S. 

pneumoniae type 3 could be transformed into TD antigens by conjugating them to a protein 

carrier. This opened the way to explore the synthesis and immunogenicity of numerous 

oligosaccharide-carrier protein conjugates of different pneumococcal serotypes. Those 

studies culminated in 2004 in the large-scale synthesis and introduction of a synthetic 

oligosaccharide vaccine for Haemophilus influenzae type b for use in humans in Cuba [9]. The 

recent exploration of gold nanoclusters coated with synthetic oligosaccharides and peptides 

as a vaccine are a promising platform towards the development of fully synthetic 

carbohydrate-based vaccines [10]. 

2. Streptococcus pneumoniae 

Streptococcus pneumoniae (S. pneumoniae or pneumococcus) is a leading cause of bacterial 

pneumonia, meningitis, and sepsis in children worldwide. It is estimated that 1.6 million 

people die from these infections each year, of whom one million are children [11, 12]. S. 

pneumoniae are lancet-shaped, gram-positive, and alpha-hemolytic bacteria that colonize the 

mucosal surfaces of the upper respiratory tract [13]. Three major surface layers can be 

distinguished from the inside to the outside: the plasma membrane, the cell wall, and the 

capsule (Fig. 1) [14]. The cell wall consists of a triple-layered peptidoglycan backbone that 

anchors the capsular polysaccharide, the cell wall polysaccharide, and also various proteins 

such as pneumococcal surface protein A (pspA) and hyluronate lyase (Hyl) (Fig. 1). The 

capsule is the thickest layer, completely concealing the inner structures of exponentially 

growing S. pneumoniae bacteria.  

3. Capsular polysaccharide 

Capsular polysaccharides are well known as the major virulence factors of S. pneumoniae. 

Today more than 92 serotypes have been identified based on the different chemical structures 

of these polysaccharides [16, 17]. This diversity determines the ability of the serotypes to 

survive in the bloodstream and very likely the ability to cause invasive disease, especially in 

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