Using lipo-oligosaccharide modification to generate a novel vaccine to protect against serogroup B meningococcal disease
Dr Garth Dixon, Dr Jeremy Brown, Dr Peter Van der Lay, Prof Nigel Klein
- Start Date:
19 June 2009
Institute of Child Health, London, UK
Neisseria meningitidis remains a common cause of bacterial meningitis and septicaemia in children. Although conjugate capsular vaccines for serogroups A and C have been successfully developed, a safe and effective vaccine to serogroup B remains elusive. Serogroup B vaccine efficacy is correlated to the level of bactericidal antibodies induced. Current serogroup B vaccines in development are based on subcapsular outer membrane antigens, including detergent extracted outer membrane vesicles (D-OMV). Although D-OMV vaccines have had some success, a major problem is lack of induction of bactericidal antibodies in infants that are cross protective against sufficient number of meningococcal B strains.
One strategy is to harness the natural adjuvant properties of LOS (lipooligosaccharide) to strengthen protective responses to D-OMV vaccines, but native LOS stimulates large rises in cytokines and is therefore highly toxic. Our approach is to genetically alter the LOS structure of serogroup B meningococcus, via lipid A modification, to reduce its toxicity but preserves adjuvant activity, and to modify the LOS oligosaccharide to target uptake of OMVs by antigen presenting cells, specifically dendritic cells (DCs). This procedure will also obviate the requirement for detergent extraction of OMVs, which is normally performed to reduce the LOS content. Moreover, natural OMVs should facilitate presentation of a broad range of meningococcal antigens in their natural conformation that are usually altered or lost in detergent extraction, and this should enhance cross-protection across different meningococcal B strains.