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Structure of a protective epitope reveals the importance of acetylation of Neisseria meningitidis serogroup A capsular polysaccharide.

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Henriques, Pedro 
Dello Iacono, Lucia 
Romano, Maria Rosaria 


Meningococcal meningitis remains a substantial cause of mortality and morbidity worldwide. Until recently, countries in the African meningitis belt were susceptible to devastating outbreaks, largely attributed to serogroup A Neisseria meningitidis (MenA). Vaccination with glycoconjugates of MenA capsular polysaccharide led to an almost complete elimination of MenA clinical cases. To understand the molecular basis of vaccine-induced protection, we generated a panel of oligosaccharide fragments of different lengths and tested them with polyclonal and monoclonal antibodies by inhibition enzyme-linked immunosorbent assay, surface plasmon resonance, and competitive human serum bactericidal assay, which is a surrogate for protection. The epitope was shown to optimize between three and six repeating units and to be O-acetylated. The molecular interactions between a protective monoclonal antibody and a MenA capsular polysaccharide fragment were further elucidated at the atomic level by saturation transfer difference NMR spectroscopy and X-ray crystallography. The epitope consists of a trisaccharide anchored to the antibody via the O- and N-acetyl moieties through either H-bonding or CH-π interactions. In silico docking showed that 3-O-acetylation of the upstream residue is essential for antibody binding, while O-acetate could be equally accommodated at three and four positions of the other two residues. These results shed light on the mechanism of action of current MenA vaccines and provide a foundation for the rational design of improved therapies.



Neisseria meningitidis, carbohydrates, structural glycobiology, vaccines, Acetylation, Adolescent, Antibodies, Bacterial, Child, Clinical Trials, Phase II as Topic, Crystallography, X-Ray, Epitopes, Female, Humans, Immunogenicity, Vaccine, Immunoglobulin Fab Fragments, Male, Meningitis, Meningococcal, Meningococcal Vaccines, Molecular Docking Simulation, Multicenter Studies as Topic, Neisseria meningitidis, Polysaccharides, Bacterial, Randomized Controlled Trials as Topic, Serogroup, Serum Bactericidal Antibody Assay, Vaccines, Conjugate

Journal Title

Proc Natl Acad Sci U S A

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Proceedings of the National Academy of Sciences