Modelling Meningococcal Polysaccharides: Conformation and Flexibility

Session: 
S5.2 Bacterial glycan assembly
Code: 
FL5.2.3
Location (hall): 
Mannose
Start/end time: 
Tuesday, July 2, 2019 - 15:25 to 15:30
Neil
Ravenscroft

Neil Ravenscroft1, Michelle Kuttel1

1University Of Cape Town, Rondebosch, South Africa

Infections by Neisseria meningitidis (Nm) cause life-threatening illnesses such as meningitis, bacteraemia and pneumonia and vaccination is the most cost-effective way to control meningococcal disease. The capsular polysaccharide (CPS) is the main virulence factor and immunity to infection is conferred by antibodies to the CPS. There are twelve meningococcal serogroups, five of which (A, B, C, Y and W) are responsible for the vast majority of disease in children and adults. Tetravalent conjugate vaccines against serogroups A, C, Y and W are available, however, outbreaks of a new serogroup X has led to the current development of a pentavalent conjugate vaccine (NmCV-5) that includes serogroup X. 

We have applied our established systematic approach [1] to modelling these six dominant Nm polysaccharide antigens and will present a comparison of their conformations and relative flexibilities. Structurally, the CPS can be grouped into three pairs: NmA and NmX are phosphodiester-containing homopolymers of amino sugars, NmB and NmC are homopolymers of sialic acid, whereas NmY and NmW are almost identical polymers of hexose-sialic acid. Our simulations reveal considerable differs within the pairs. For example, NmA CPS behaves as a flexible random coil which becomes less conformationally defined as the length increases, whereas serogroup X forms a more stable regular helical structure [2]; thus providing a rationale for why the MenAfriVac vaccine (containing serogroup A) would not be able to protect against serogroup X disease. Further, NmY CPS has a single dominant conformation, whereas W exhibits a family of conformations including the Y conformation; this in turn accounts for the different levels of cross-protection measured for the Y and W monovalent vaccines and the high serogroup W responses observed in HibMenCY-TT vaccinees [3]. Our latest conformational study also reveals significant differences in the conformations of the structurally similar NmB and NmC. Information on polysaccharide conformation and dynamics can provide valuable mechanistic insights into clinical observations on cross-protection between carbohydrate antigens and understanding of measurable polysaccharide solution properties/behaviour such as shape, viscosity, reactivity and processing characteristics important for vaccine development.

References: 
  1. Kuttel M.M.; Ravenscroft N. The Role of Molecular Modeling in Predicting Carbohydrate Antigen Conformation and Understanding Vaccine Immunogenicity, ACS Symposium Series , Volume 1290, pp 139-173, Carbohydrate-Based Vaccines: From Concept to Clinic, American Chemical Society, 2018. 
  2. Hlozek J.; Kuttel M.M.; Ravenscroft N. Conformations of Neisseria meningitidis serogroup A and X polysaccharides: The effects of chain length and O-acetylation. Carbohydr. Res. 2018, 465, 44-51.
  3. Kuttel M.M.; Timol Z.; Ravenscroft N. Cross-protection in Neisseria meningitidis serogroups Y and W polysaccharides: A comparative conformational analysis. Carbohydr. Res. 2017, 446, 40-47.

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