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New genome sequence focuses search for type B meningitis vaccine

In this circular representation of the N. meningitidis genome each color denotes a different gene category.

Genome researchers often point out the landslide of medical applications that will emerge from their work. A report of the complete genome sequence of Neisseria meningitidis—the bacteria responsible for meningitis and septicemia—is actually accompanied by a report describing how scientists used the data to find vaccine candidates for groups B N. meningitidis. The two articles appeared in the March 10 issue of Science.

There are five groups of disease-causing N. meningitidis, designated A, B, C, Y, and W135. Group A is responsible for meningitis outbreaks in sub-Saharan Africa, while group B is responsible for meningitis in the United States and Europe. Vaccines exist for all groups except B.

People have attempted to make vaccines for group B N. meningitidis over the years, but it has been literally impossible, according to Rino Rappuoli, Vice President of Vaccine Research for the Chiron Corporation, and an author on both Science papers.

Over the past 18 months, as the sequence of the 2,272,351 building blocks of the N. meningitidis genome was being determined at The Institute for Genome Research (TIGR), in Rockville, MD, Rappuoliís team at Chironís Immunological Research Institute of Siena, Italy, sifted through the 2,158 computer-predicted genes for promising vaccine candidates. The N. meningitidis genome project was funded by the Chiron Corporation. The researchers looked for genes that make proteins located on the outside of the bacterial cell. These "surface proteins" are easily recognized by the immune cells and targeted for destruction. They found 350 proteins and made each one in the lab.

Each of these proteins was injected into a mouse to find the one that triggered the largest immune reaction—a characteristic of a good vaccine. Researchers found seven proteins, which triggered a strong antibody response to group B, and are also found in A, C, Y and W135 N. meningitidis. This suggests that a new vaccine developed from any of these seven proteins will protect against many types of N. meningitidis bacteria, says Rappuoli.

Four of the seven proteins might also be useful in a vaccine for gonorrhea because they are present in three types of N. gonorrhoeae.

Picking vaccine candidates from the entire repertoire of genes for an organism "will probably be the only approach used to find vaccines in the future, because the technique is so powerful and so fast," says Rappuoli. Before sequencing genomes became the trend, scientists analyzed proteins one by one and completed maybe two or three in a year, hoping the proteins were good for a vaccine, "often they were not," he notes.

Rappuoli anticipates that Chironís new vaccine will be put into clinical trials within the next year.

In addition to finding vaccine candidates, "the most striking feature of N. meningitidis from a genome perspective is that there are more contingency genes than any other bacterium or organism studied so far," says Hervé Tettelin, leader of the N. meningitidis sequencing project at TIGR. Contingency genes are thought to be critical to the bacteriumís ability to evade the hostís immune defenses because they have a high rate of mutation which helps the bacterium adapt to a wide range of host environments.

The genome sequence provides a fast track approach to finding vaccine candidates for a disease that had frustrated researchers for decades. It also provides another opportunity to understand the mechanism by which N. meningitidis, and other pathogens, cause disease.

See related GNN article
»Bacteria use quick-switch genes to dodge host defenses

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Tettelin, H. et al. Complete genome sequence of Neisseria meningitidis serogroup B strain MC58. Science 287, 1809-1815 (March 10, 2000).
Pizza, M. et al. Identification of vaccine candidates against serogroup B Meningococcus by whole-genome sequencing. Science 287, 1816-1820 (March 10, 2000).

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