Maryland-Based Research Lab Completes Study that is Likely to Lead to Development of Novel Meningitis B Vaccine
March 10, 2000
ROCKVILLE, MD -- Investigators at The Institute for Genomic Research (TIGR) today announced that they have determined the complete genetic blueprint for Neisseria meningitidis, the primary causative agent of bacterial meningitis. Hervé Tettelin led the team at TIGR that determined the order of all of the 2.27 million individual chemical base units making up N. meningitidis' DNA. This study, reported in the March 10 issue of Science, represents the 10th microbial genome sequencing project completed by TIGR.
Neisseria meningitidis (meningococcus), a Gram-negative bacterium, is a cause of life-threatening invasive bacterial infections, especially in young infants. The major diseases caused by N. meningitidis, meningitis and septicaemia, are a significant public health problem and are responsible for deaths and disability through epidemics in sub-Saharan Africa, and sporadic cases that are prevalent in many countries worldwide. Strains of serogroup B are a particular problem because they are a major cause of invasive disease in Europe and the USA and there is currently no effective vaccine. Sequencing the genome of strain MC58 (a serogroup B strain isolated from a case of invasive infection) provides an efficient means of acquiring data relevant to the detailed molecular characterization of this pathogen.
Detailed understanding of the bacterium's pathogenicity determinants was derived from the sequence, with the expert help from the team of E. Richard Moxon, Ph. D., head of the Molecular Infectious Diseases Group, Institute of Molecular Medicine, University of Oxford, UK. The sequence reveals that N. meningitidis contains many more genes that undergo phase variation than any pathogen studied to date, a mechanism that controls their expression and contributes to the ability of the organism to evade the human immune system. It also contains three major islands of horizontal DNA transfer, two of which contain gene coding for proteins involved in pathogenicity, the third island only containing coding sequences for hypothetical proteins.
In an accompanying paper, Chiron Corporation, which funded this work, also reported that it has used this detailed information on the microorganism's genetic structure to identify novel vaccine candidates against meningococcal disease. This is the first demonstration of the important role that genomics can play in the development of commercial products. "The completion of the genome sequence of Neisseria meningitidis represents a big step forward in the molecular understanding of an important human pathogen," states Claire Fraser, Ph.D., president of TIGR. "What makes this project unique is the fact that as the DNA sequence information was being generated at TIGR, our collaborators at Chiron were using this information in the search for new vaccine candidates".
"This project benefited to a great extent by the collaboration between groups of scientists with expertise in genomics, molecular microbiology, and immunology," says Hervé Tettelin, Ph.D., principal investigator for the project. "Our combined approach clearly demonstrates the ultimate power of genomics to rapidly impact human health". Using information derived from the DNA sequence, Chiron investigators were able to identify novel surface proteins in N. meningitidis. These newly discovered proteins behave differently from those previously identified and are present across a wide range of strains. Researchers have also shown that these proteins can stimulate an antibody response capable of killing the bacterium, a property known to correlate with vaccine efficacy in humans. Work is now underway to identify the most promising vaccine candidate(s) incorporating one or more of these surface-expressed proteins.
"Conventional research approaches to protect against different strains of meningococcal B disease have failed. A genomics-based approach is a completely novel paradigm for developing new methods of protection. Through this research we have a better understanding of the disease process. Using these insights, we are creating a vaccine capable of protecting against the broad diversity of invasive strains of this virulent microorganism," says Rino Rappuoli, Ph.D., vice president of research at Chiron's Italian facility, located in Siena.
A detailed description of the N. meningitidis genome is available through TIGR's Microbial Database on the World Wide Web at (www.tigr.org).