Meningococcal Research Laboratory

Background on meningococcal disease and vaccination
Meningococci are Gram-negative bacteria that cause serious disease worldwide. The organism can be subdivided based on distinctive capsular polysaccharides. Strains with five different capsular groups, designated A, B, C, W135 and Y cause most serious disease. In sub-Saharan Africa, epidemics caused predominantly by group A strains occur every five to ten years (Jodar et al, Lancet 2003). In the United States and Europe, the last major meningococcal epidemics were in the 1940s. However, the organism remains the most common cause of bacterial meningitis in children and young adults. Each year there are approximately 3000 cases of meningococcal disease reported in the United States (caused predominantly by group B, C and Y strains) and 7700 cases in Western Europe (mostly group B and C strains). Approximately half of these cases are meningitis. In New Zealand, an epidemic of group B meningococcal disease has been ongoing for more than a decade.

In the United States and Europe, infants and young children are at highest risk of acquiring disease. Young adults housed in close quarters, for example, military recruits and college students living in dormitories, also are at increased risk. Despite an increased understanding of the pathogenesis of meningococcal disease and the availability of appropriate treatments, the overall mortality rate from meningococcal disease remains at 10% to 15%, and an additional 10% to 20% of patients develop permanent sequelae. These sequelae include limb amputation resulting from gangrene, extensive skin scarring requiring grafting, or cerebral infarction and loss of hearing and cognitive function.

Vaccines offering protection against meningococcal disease have been available for more than 30 years but even in 2002 there is no formulation that offers comprehensive protection against strains from all of the pathogenic capsular groups. Meningococcal capsular polysaccharides form the basis of the currently licensed bivalent (A and C) and tetravalent (A, C, W135 and Y) vaccines. The principal limitations of the currently available polysaccharide vaccines are that they are not effective in children and do not provide long term immunity in adults. Recently developed polysaccharide-protein conjugate vaccines for prevention of disease caused by group C vaccines were introduced in the United Kingdom in late 1999. These conjugate vaccines overcome many of the limitations of the older plain polysaccharide vaccines and are now widely used in European countries and Canada. Their use in the UK has virtually eliminated group C disease in the population under 20 years of age that was targeted for immunization. Vaccine manufacturers are currently developing multivalent meningococcal polysaccharide-protein conjugate vaccines that contain capsular groups A, C, Y and W135. However, the multivalent vaccines will still not provide protection against group B organisms , which account for 30% of disease in the U.S. and up to 80% in Europe (reviewed in Jodar et al, Lancet 2002)

The group B capsular polysaccharide is structurally identical to a carbohydrate widely distributed in human tissues. Thus, efforts to develop a capsular-based vaccine have been hampered by poor immunogenicity of the polysaccharide and the risk of eliciting autoantibodies. Surface-exposed noncapsular antigens also can elicit protective antibody but a major limitation of this approach has been antigenic variability and the resulting failure of vaccine candidates to elicit broadly protective bactericidal antibody responses. Our laboratory is investigating several novel approaches to identify new vaccine candidates for prevention of all N. meningitidis disease, including group B strains. These approaches include molecular mimetics, novel conserved proteins discovered during the N. meningitidis group B MC58 genome-sequencing project (Pizza et al, Science 2000), and improved vesicle vaccine.