Modeling the conformations of Neisseria meningitidis serogroup a CPS and a carba-analogue: Implications for vaccine development

Hlozek, Jason and Ravenscroft, Neil and Kuttel, Michelle (2019) Modeling the conformations of Neisseria meningitidis serogroup a CPS and a carba-analogue: Implications for vaccine development, Carbohydrate Research, 486, Elsevier.

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Neisseria meningitidis is a major cause of bacterial meningitis worldwide, especially in Africa. The capsular polysaccharide is the main virulence factor and the target antigen for polysaccharide- and conjugate vaccines. Three tetravalent conjugate vaccines against serogroups A, C, Y and W have been licensed and the monovalent MenAfriVac® was introduced to address the high burden of serogroup A disease in the Meningitis Belt of sub-Saharan Africa. Three of these four vaccines are lyophilized due to the instability of the serogroup A antigen (MenA) in aqueous solution, resulting in a two vial presentation with concomitant additional costs for storage and distribution. Replacement of the saccharide ring oxygen with a methylene group is a promising approach to preparing a stable oligosaccharide MenA analogue (Carba-MenA) vaccine suitable for a liquid formulation. However, to be effective, Carba-MenA must elicit an immune response that is cross-reactive to the native MenA. Here we employ microsecond molecular dynamics simulations of ten repeats of MenA and Carba-MenA to establish that there are significant differences in the conformation and dynamics of these antigens in solution. Carba-MenA has a more random extended, conformation than MenA; MenA has a significant population of compact S-bend conformations that are absent in the analogue. We also find that the disaccharides are poor models of the conformational behaviour of longer chains. This information is relevant for the rational design of optimal analogues for conjugate vaccines.

Item Type: Journal article (paginated)
Additional Information: Article number 107838 Page number not yet allocated
Subjects: Applied computing > Life and medical sciences > Computational biology > Molecular structural biology
Computing methodologies > Modeling and simulation > Simulation types and techniques > Molecular simulation
Applied computing > Physical sciences and engineering > Chemistry
Date Deposited: 10 Nov 2019 19:48
Last Modified: 10 Nov 2019 19:48

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