Molecular mimics of meningococcal lipo-oligosaccharides as vaccine candidates

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Despite encouraging progress in the development of glycoconjugate vaccines against serogroup A and C meningococci, the development of an effective vaccine against serogroup B organisms remains a problem. Serogroup B meningococci cause more than 50% of cases of meningococcal disease in the UK. However, the serogroup B polysaccharide is poorly immunogenic. It mimics human cell surface carbohydrates and the poor response it elicits may be explained by immune tolerance. The safety of a vaccine that broke tolerance to epitopes expressed on human cells is questionable.

Consequently, the vaccine potential of alternative surface structures as epitopes for serogroup B is being investigated. The objective will be to develop molecular mimics to the LOS of group B Neisseria meningitidis as candidate vaccines for safe and effective protection against this organism in adults and infants. LOS is a major outer membrane component essential for the survival of the organism. The project will provide a proof in principle of this approach by focusing on the L3,7,9 LOS immunotype, which is associated with invasive disease. Several anti-L3,7,9 monoclonal antibodies are available as reagents for these studies. We will use a multidisciplinary approach to: 1) obtain idiotypically cross-reactive antibodies against LOS using molecular mimics that may stimulate a T-dependent response. Several peptide mimics have been isolated and their vaccine potential will be evaluated in animal immunogenicity trials; 2) clone the DNA encoding these peptide mimics into a suitable expression system for use as a DNA vaccine; 3) engineer higher affinity recombinant Fab fragments and use them to isolate additional idiotypically cross-reactive peptides from a peptide phage-display library, and test these for their vaccine potential.