Carbohydrates are ubiquitous in all organisms and play a pivotal role due to their ability to promote, drive, and prevent a great quantity of biological events.1-3 For example, carbohydrates exposed on pathogen surface, such as lipopolysaccharide (LPS) of Gram-negative bacteria and the polysaccharide coat (capsular polysaccharides (CPSs)) of encapsulated bacteria, are major virulence factors and essential for the initial steps of adhesion and colonization during infection events. In the same time, infected hosts identify the invading agents through protein-carbohydrate recognition and activate the immune responses, inducing the production of carbohydrate-specific antibodies to defeat the infection. Therefore, this class of molecules represent attractive targets for vaccine design and the induction of antibodies toward CPS is an elegant strategy applied for more than half a century.4, 5 However, most polysaccharide-based vaccines induce T-cellindependent immune responses, with specific immunoglobulin M (IgM) responses but minimal immunoglobulin G (IgG) class switching.6-9 Immunization with pure CPSs fails to induce a booster response because of a lack of sustained T-cell memory, resulting unsuitable for the stimulation of immune responses of children <2 years old, elderly and immunocompromised people. To stimulate B-cell maturation to memory cells, polysaccharides must be coupled to carrier proteins possessing T-cell peptide epitope, affording T-cell-dependent glycoconjugate antigens.6, 10-15 Since the first glycoconjugate vaccine licensed in 1987 against Haemophilus influenzae type b,16 many glycoconjugate constructs have been successfully introduced into routinely vaccination program worldwide or are under advanced clinical trials, playing a fundamental role in preventing infectious diseases caused by pathogens such as H. influenzae, Streptococcus pneumoniae, and Neisseria meningitidis.12, 17 In general, the structure of a glycoconjugate vaccine is based on a carbohydrate B-cell epitope coupled to a T-helper epitope protein which ensure the T-dependent memory response fundamental for the long-lasting protection, even among high-risk persons. The currently licensed proteins are tetanus toxoid (TT), diphtheria toxoid (DT) and its genetically detoxified form (CRM197), Haemophilus protein D (PD), and the outer membrane protein complex of serogroup B meningococcus (OMPC).11, 13 The success of these vaccines has propelled the research on this field forward. In particular, to improve the design and development of new carbohydrate-based vaccines, great attention has been directed to the antigen source,17-19 exploiting novel synthetic pathways and conjugation tools,12 and to more complex structures to take advantage of multivalent expositions of the antigens. In fact, it is well known that carbohydrates interact with their receptor in a very weakly manner and nature exploited the multivalent synergy to have stronger interactions.1, 2 By clustering glycans into multivalent system, the binding affinities obtained from the sum of the single interaction can easily reach the nanomolar (nM) dissociation constant values. It is an astonishing result respect to the range of millimolar (mM) of dissociation constant value generally observed for single and isolated interactions. This phenomenon is known as "cluster glycoside effect"2 and can be observed in living cells, when recognition events mediated by carbohydrates occur. Taking inspiration from what happens in nature, several examples of multiglycans and dendrimers have been reported in the literature.
Glyconanoparticles as versatile platforms for vaccine development: A minireview
Laura Polito
2020
Abstract
Carbohydrates are ubiquitous in all organisms and play a pivotal role due to their ability to promote, drive, and prevent a great quantity of biological events.1-3 For example, carbohydrates exposed on pathogen surface, such as lipopolysaccharide (LPS) of Gram-negative bacteria and the polysaccharide coat (capsular polysaccharides (CPSs)) of encapsulated bacteria, are major virulence factors and essential for the initial steps of adhesion and colonization during infection events. In the same time, infected hosts identify the invading agents through protein-carbohydrate recognition and activate the immune responses, inducing the production of carbohydrate-specific antibodies to defeat the infection. Therefore, this class of molecules represent attractive targets for vaccine design and the induction of antibodies toward CPS is an elegant strategy applied for more than half a century.4, 5 However, most polysaccharide-based vaccines induce T-cellindependent immune responses, with specific immunoglobulin M (IgM) responses but minimal immunoglobulin G (IgG) class switching.6-9 Immunization with pure CPSs fails to induce a booster response because of a lack of sustained T-cell memory, resulting unsuitable for the stimulation of immune responses of children <2 years old, elderly and immunocompromised people. To stimulate B-cell maturation to memory cells, polysaccharides must be coupled to carrier proteins possessing T-cell peptide epitope, affording T-cell-dependent glycoconjugate antigens.6, 10-15 Since the first glycoconjugate vaccine licensed in 1987 against Haemophilus influenzae type b,16 many glycoconjugate constructs have been successfully introduced into routinely vaccination program worldwide or are under advanced clinical trials, playing a fundamental role in preventing infectious diseases caused by pathogens such as H. influenzae, Streptococcus pneumoniae, and Neisseria meningitidis.12, 17 In general, the structure of a glycoconjugate vaccine is based on a carbohydrate B-cell epitope coupled to a T-helper epitope protein which ensure the T-dependent memory response fundamental for the long-lasting protection, even among high-risk persons. The currently licensed proteins are tetanus toxoid (TT), diphtheria toxoid (DT) and its genetically detoxified form (CRM197), Haemophilus protein D (PD), and the outer membrane protein complex of serogroup B meningococcus (OMPC).11, 13 The success of these vaccines has propelled the research on this field forward. In particular, to improve the design and development of new carbohydrate-based vaccines, great attention has been directed to the antigen source,17-19 exploiting novel synthetic pathways and conjugation tools,12 and to more complex structures to take advantage of multivalent expositions of the antigens. In fact, it is well known that carbohydrates interact with their receptor in a very weakly manner and nature exploited the multivalent synergy to have stronger interactions.1, 2 By clustering glycans into multivalent system, the binding affinities obtained from the sum of the single interaction can easily reach the nanomolar (nM) dissociation constant values. It is an astonishing result respect to the range of millimolar (mM) of dissociation constant value generally observed for single and isolated interactions. This phenomenon is known as "cluster glycoside effect"2 and can be observed in living cells, when recognition events mediated by carbohydrates occur. Taking inspiration from what happens in nature, several examples of multiglycans and dendrimers have been reported in the literature.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
