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To Make a Vaccine, First Sequence a Genome
The fight against group B strep starts with its genome sequence
Edward R. Winstead

Featured Article.

Since the mid-nineties, most pregnant women in the U.S. have been screened for infections by group B strep bacteria. This pathogen lives primarily in the vaginal tract and can cause life-threatening infections in newborns as they pass through the birth canal. The bacterium also preys on adults with a chronic illness such as diabetes or cancer.

This summer researchers evaluated the practice of screening pregnant women and concluded that fewer newborns have been infected by group B strep in recent years. But that was only part of the story: The same period saw an increase in newborn infections by other types of bacteria. Many of these pathogens were resistant to antibiotics used against group B strep.

Electron micrograph of group B strep.

Are the trends related? Has the use of antibiotics against group B strep caused a shift in the type of pathogen responsible for newborn infections? Without more studies, the questions cannot be answered.

But whatever the answers may be, it's clear that new strategies are needed to combat group B strep and antibiotics will not suffice. One solution would be a vaccine for women who are pregnant or might become pregnant.

Such a vaccine now seems within reach, because the genome sequence of group B strep, also known as Streptococcus agalactiae, has just been published. The study identified hundreds of proteins that are potential targets for vaccines, and a handful are now being tested in mice at Chiron Corporation of Siena, Italy.

‘You cannot develop vaccines against a bacterial pathogen without the genome.’

The pathogen was sequenced at The Institute for Genomic Research (TIGR) in Rockville, Maryland, in collaboration with Chiron and the Channing Laboratory in Boston, Massachusetts. Chiron provided funding and has expertise in developing vaccines, while the Channing Laboratory has decades of experience working with group B strep.

Group B strep is one of the last major human pathogens to be sequenced. Hervé Tettelin of TIGR and his colleagues have also sequenced its cousin Streptococcus pneumoniae, and another group recently sequenced Streptococcus pyogenes. All three pathogens cause invasive disease in humans, but they colonize different parts of the body.

"We have identified virulence factors that are specific to each streptococcal species and that are shared by all three," says Tettelin. "Having the genome sequences of more and more pathogens has allowed us to exploit the power of comparative genomics."

Chiron and TIGR teamed up a few years ago to sequence Neisseria meningitidis, the bacterium that causes meningococcal disease. This pioneering use of the genome in vaccine development, done in collaboration with researchers at the University of Oxford, yielded three proteins, or antigens, that Chiron plans to test in human vaccines next year.

"Based on the success of the Neisseria meningitidis project, we have decided to follow the same strategy for developing vaccines for other pathogens, including group B strep," says Guido Grandi, who heads the Biochemistry and Molecular Biology Unit of Chiron in Italy.

Detail from a circular representation of the S. agalactiae genome. View full

Sequencing the genome of a pathogen "is an extremely effective approach for developing vaccines," says Grandi. "The group B strep project began two years ago, and we now have protein candidates that we think could elicit protective immunity in humans."

Whether the proteins will lead to working vaccines remains to be seen. But during the first stage of vaccine development, when the goal is to identify promising targets and uncover clues about the pathogen's biology, the genome seems to be the place to start.

"We're very excited to have the genome," says Michael R. Wessels, a researcher at Channing Laboratory. "It is a huge resource for understanding how the bacterium causes disease, and the information can be used to develop vaccines."

The sugar 'coat' that surrounds the bacterium and protects it from host defenses has been the main focus of vaccine research to date. Now, with the genome, researchers can target proteins on the cell surface that may be critical in allowing the pathogen to enter human cells and cause disease.

"One of the really interesting things to come out of this study was a large number of predicted surface proteins, many of which were not known previously," says Wessels.

‘No one knows how group B strep made the jump from cows to humans.’

Since the Neisseria meningitidis genome was published in 2000, Chiron and TIGR have modified their strategy of selecting targets. In addition to computational methods, they now analyze patterns of gene expression and determine where proteins are expressed in the bacterium. The result has been additional candidates that were not initially found through the computer analysis of sequence data.

"Once you have the genome, you can use a combination of different strategies to pin down all the possible vaccine candidates—genomics and proteomics and microarray studies," says Rino Rappuoli, vice president of vaccine research at Chiron.

"You cannot develop vaccines against a bacterial pathogen without considering the genome," adds Rappuoli. "The genome is part of today's science. For any research about bacteria today, you always start with the genome."

Malaria researchers, for instance, are using the genome sequence of the malaria parasite in their ongoing efforts to identify targets for a vaccine. And TIGR is collaborating with researchers in Kenya to develop a vaccine against the cattle parasite Theileria parva. The parasite is now nearly sequenced, and the researchers are evaluating potential vaccine targets.

"Chiron has set a new trend in vaccine development," says Vishvanath Nene of TIGR, who is working on the Theileria parva project. In the past, vaccine candidates have been discovered one at a time through 'fishing expeditions.' "Genomics takes the opposite approach," Nene says. "You start with all the genes and ask: How many have the potential to be vaccine antigens?"

The group B strep genome, published in Proceedings of the National Academy of Sciences, includes a comparison of the sequenced strain and 19 others. (Group B strep comes in nine forms known by their particular sugar coat.) The researchers found considerable genetic variation—a finding that is relevant because vaccines should be effective against an array of strains.

Neisseria meningitidis.

Type V, the sequenced strain, was chosen because in the last decade or so it has emerged as a leading human pathogen, responsible for about a third of the group B strep infections. But it was only recognized in the late eighties, and is rarely if ever found in collections of group B strep from decades ago.

Over the last ten to fifteen years, however, type V strains have become quite common. They are now the most common isolates infecting non-pregnant adults and among the top three serotypes among infant infections.

"There clearly has been a shift in the prevalence of type V strains in clinical isolates in the last three decades," says Wessels, "and we don't yet understand the reasons for that."

Streptococcus agalactiae was originally isolated in cows in the 1930s and for several decades was considered a pathogen of cows. But about thirty years ago doctors began noticing an increase in the prevalence of group B strep-related conditions in infants.

"No one really knows how group B strep made the jump from cows to humans," says Michael J. Cieslewicz of the Channing Laboratory. "We hope in the future to sequence bovine isolates and compare them to human isolates, then focus in on those differences."

Group B strep infections in cows are still a problem. "The infection in cows is treatable with antibiotic therapy," says Cieslewicz, "but a number of farmers and consumers do not want antibiotics in their milk or meat." A bovine vaccine would be a welcome development.

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Tettelin, H. et al. Complete genome sequence and comparative genomic analysis of an emerging human pathogen, serotype V Streptococcus agalactiae. Proc Natl Acad Sci USA. Published online August 28, 2002.
Schrag, S.J. et al. A population-based comparison of strategies to prevent early-onset group B streptococcal disease in neonates. N Engl J Med 347, 233-239 (July 25, 2002).
Stoll, B.J. et al. Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants. N Engl J Med 347, 240-247 (July 25, 2002).
Pizza, M. et al. Identification of vaccine candidates against serogroup B meningococcus by whole-genome sequencing. Science 287, 1816-1820 (March 10, 2000).
Tettelin, H. et al. Complete genome sequence of Neisseria meningitidis serogroup B strain MC58. Science 287, 1809-1815 (March 10, 2000).

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