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

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. Image 1 • MenA and Carba-MenA molecular dynamics simulations show conformational differences. • Carba-MenA analogue has more random and extended conformations than MenA. • Compact S-bend conformations of MenA are absent in the analogue. • Disaccharides are poor models of the conformation of longer chains. • Modeling can provide information for the design of optimal vaccines. [ABSTRACT FROM AUTHOR]