Vaccine development against GBM meningitis is complicated by the pathogens capsular polysaccharide (PSA), an alpha 2-8-linked polysialic acid that is identical to the surface saccharide of the E. coli K1 capsular polysaccharide as well as to host structures, especially during fetal development. Despite effective antibiotic and supportive therapy, the mortality and morbidity of systemic infections, especially meningitis caused by GBM and Escherichia coli K1, remain unacceptably high. GBM continues to cause epidemics and outbreaks throughout the world, and E. coli K1 is a major cause of neonatal meningitis and kidney infections. With the goal of eventually providing a vaccine against these organisms, we examined evidence or the lack thereof for an association between PSA antibodies and autoimmune disease or effects on fetuses. Meningococci are classified into serogroups according to their CPs. Of the 13 reported CP groups, 5 (A, B, C, W135, and Y) cause almost all meningococcal disease. As essential virulence factors, the five group CPs inhibit the protective actions of complement;in addition, they function as protective antigens as evidenced by the fact that a critical level of serum IgG CP antibodies specifically induces both complement-mediated lysis of groups A, C, W135, and Y and opsonophagocytic killing of group GBM. Effective CP-based vaccines exist for groups A, C, W135, and Y, but none for GBM or E. coli K1. GBM causes more infections in infants and young children than do groups A, C, W135, or Y. Although PSA antibodies bind to many fetal and adult tissues in vitro, there is no evidence for in vivo binding or associated pathology. Efforts have been directed towards developing vaccines using non-capsular antigens, including outer membrane proteins, lipopolysaccharides, iron-binding proteins, and other antigens identified by examining the organisms DNA. Many of these antigens are polymorphic, heterogeneous, and subject to antigenic variation and may not be representative of all GBM. Furthermore, none will be useful against E. coli K1. Based on the performance of the Haemophilus influenzae type b, Salmonella typhi (Vi), pneumococcal, and group C meningococcal (GCM) conjugate vaccines, we developed a PSA conjugate that induced protective levels of serum IgG antiPSA. It is simple to produce and easy to standardize and should be close to 100 percent effective at all ages. Its performance in laboratory mice and primates has been confirmed. Few studies have compared severity of infection and outcome among meningococcal serogroups, and published studies of sequelae of meningococcal meningitis do not mention autoimmune diseases, such as Guillain-Barr syndrome, multiple sclerosis, etc. In the absence of epidemiological or clinical evidence to associate pathology with PSA antibodies, we conducted a retrospective cohort study of meningococcal patients to examine evidence for autoimmunity. The entire Danish population constituted our study cohort of 7,467,001 individuals followed for autoimmune disease between 1977 and 2004. GBM meningitis was diagnosed in 2,984 individuals, and the control population was 914 patients with GCM meningitis. Ratios of incidence rates of autoimmune diseases provided a measure of relative risk. Patients with GBM meningitis, either in comparison with people with group C meningococcal meningitis or those with no history of meningococcal meningitis, exhibited no increased risk of autoimmune diseases. We also studied this cohort for possible increased risk of preterm or stillbirth to women with previous GBM disease and whether their first-born children were at increased risk for birth defects. We found no such associations. Our findings suggest that systemic infection with GBM is not associated with autoimmune diseases or with immunoreactive diseases that may affect the health of offspring for up to 31 years after meningococcal disease.
| Gottfredsson, Magnus; Reynisson, Ingi K; Ingvarsson, Ragnar F et al. (2011) Comparative long-term adverse effects elicited by invasive group B and C meningococcal infections. Clin Infect Dis 53:e117-24 |
| Robbins, John B; Schneerson, Rachel; Xie, Guilin et al. (2011) Capsular polysaccharide vaccine for Group B Neisseria meningitidis, Escherichia coli K1, and Pasteurella haemolytica A2. Proc Natl Acad Sci U S A 108:17871-5 |
| Howitz, Michael F; Simonsen, Jacob; Krause, Tyra Grove et al. (2009) Risk of adverse birth outcome after group B meningococcal disease: results from a Danish national cohort. Pediatr Infect Dis J 28:199-203 |
