Abstract
The development and use of antibacterial glycoconjugate vaccines have significantly reduced the occurrence of potentially fatal childhood and adult diseases such as bacteremia, bacterial meningitis, and pneumonia. In these vaccines, the covalent linkage of bacterial glycans to carrier proteins augments the immunogenicity of saccharide antigens by triggering T cell-dependent B cell responses, leading to high-affinity antibodies and durable protection. Licensed glycoconjugate vaccines either contain long-chain bacterial polysaccharides, medium-sized oligosaccharides, or short synthetic glycans. Here, we discuss factors that affect the glycan chain length in vaccines and review the available literature discussing the impact of glycan chain length on vaccine efficacy. Furthermore, we evaluate the available clinical data on licensed glycoconjugate vaccine preparations with varying chain lengths against two bacterial pathogens, Haemophilus influenzae type b and Neisseria meningitidis group C, regarding a possible correlation of glycan chain length with their efficacy. We find that long-chain glycans cross-linked to carrier proteins and medium-sized oligosaccharides end-linked to carriers both achieve high immunogenicity and efficacy. However, end-linked glycoconjugates that contain long untethered stretches of native glycan chains may induce hyporesponsiveness by T cell-independent activation of B cells, while cross-linked medium-sized oligosaccharides may suffer from suboptimal saccharide epitope accessibility.
Highlights
Bacterial polysaccharide (PS) molecules are versatile compounds that include lipopolysaccharides with their O antigens, capsular PSs, and exopolysaccharides
Adaptive immunity to the bacterial PSs remains inefficient since saccharide structures are poorly bound by the antigen-presenting cells’ major histocompatibility complex (MHC), which leads to minimal T-helper cell-dependent antibody responses[4]
A thorough review of the literature suggested that cross-linked glycoconjugates may require long-chain PSs for optimal immunogenicity, whereas end-linked constructs may benefit from medium-sized OSs
Summary
Bacterial polysaccharide (PS) molecules are versatile compounds that include lipopolysaccharides with their O antigens, capsular PSs, and exopolysaccharides. Adaptive immunity to the bacterial PSs remains inefficient since saccharide structures are poorly bound by the antigen-presenting cells’ major histocompatibility complex (MHC), which leads to minimal T-helper cell-dependent antibody responses[4]. By the 1970s and 1980s, bacterial capsular PS vaccines became part of routine vaccinations, and licensed vaccines for adults based on purified PSs had been established for disease caused by Neisseria meningitidis, Haemophilus influenzae type b (Hib), Salmonella enterica serovar Typhi, and Streptococcus pneumoniae, among others[6,7] Immunogenicity of those plain (i.e., unconjugated) PS vaccines is dependent on the capacity of long-chain PSs to cross-link surface immunoglobulin receptors on B cells[8,9,10], leading to an antibody response with typical T cellindependent characteristics. A variety of alternative carrier proteins are actively explored, such as modified versions of exotoxin A from Pseudomonas
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