Research Magazine 2010

Building a Better Vaccine

Richard Goldstein

Richard Goldstein

Streptococcus pneumoniae—a bacterium that can cause pneumonia, meningitis, and a host of other invasive infections, resulting in the deaths of between two and three million children each year—is a master of disguise. Its outermost surface is covered by a capsule made up of sugars, and can come in any of 91 different capsular variants, or serotypes, depending on the composition of the sugars. The large number of serotypes—each with a different antigen that must be recognized by the body’s immune system in order for the bacteria to be destroyed—has so far thwarted efforts to develop a vaccine effective against all capsular variants of S. pneumoniae, also called pneumococcus.

Professor of Pediatrics Richard Goldstein hopes to change that, soon. A molecular geneticist by training, he is bringing a thorough knowledge of evolutionary mechanisms to bear on the search for a novel pneumococcal vaccine target, with support from the Hartwell Foundation and the National Institutes of Health.

The existing vaccine, Prevnar-13, offers protection against 13 of the most common and virulent S. pneumoniae serotypes. It is an extraordinary accomplishment, says Goldstein, who cites Prevnar co-inventor Porter Anderson as one of his heroes, but unfortunately it may not offer a permanent solution.

“Prevnar-13 responds to the most prevalent serotypes responsible for invasive pneumonia in North America,” Goldstein explains. “But the dark cloud is, subtract 13 from 91 and what do you get? The others are still out there. The question then becomes, will those other serotypes step in to replace the 13 covered by Prevnar?”

The answer appears to be yes. Epidemiological evidence suggests that the highly variable S. pneumoniae is capable of circumventing vaccines, through an increase in infections by non-vaccine serotypes. “But a broadly efficacious 91-valent vaccine is quite unlikely,” says Goldstein. “It’s too complicated to manufacture, and too costly to attempt.”

Instead, Goldstein intends to identify and characterize a new category of vaccine target, called a “common surface protein”—that is, an antigenically accessible protein universal to all of the otherwise variant capsular types of S. pneumoniae.

To do so, he is surveying pneumococcal DNA for genes that might code for such common proteins, then determining which of these genes are resistant to mutation, and thus “conserved” throughout the species. “If it’s not conserved across the species, it’s not a good vaccine target,” says Goldstein, because it leaves nature with a vacuum to fill. “The goal of the common protein strategy is not to allow for that vacuum.”

Goldstein is currently examining what he calls “chromosomal cold spots”—regions of pneumococcal chromosome where variation is tolerated. “Mutations do occur,” Goldstein says. “However, those mutations are lethal. Any bacterium with that mutation is naturally purged from the population.”  The hope is that one or more of these “cold spots” will prove to encode a highly promising vaccine target.

To test whether a particular cold spot is conserved across the species, Goldstein has amassed a unique collection of over 1,000 pneumococcal isolates from around the globe and organized them by genetic-relatedness into a vast phylogenic tree. The phylogenic tree serves as a template of S. pneumoniae species evolutionary diversity.

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The larger the tree, the more accurate a picture of species evolutionary diversity it provides. “There’s no one in the world who has the collection I have, and even so, it is not yet robust enough,” says Goldstein, who recently received hundreds of additional isolates from Africa and South Asia, thanks to collaborators at the Centers for Disease Control and Prevention and in Karachi, Pakistan. “A phylogenetically organized collection, that’s the key thing.”

The task before him amounts to a monumental and painstaking process of collation, but Goldstein is eager to take it on, driven by a strong desire to prevent and alleviate suffering caused by S. pneumoniae. “More than two million children die a year of pneumococcal infections,” he says, and those who survive can be left with serious, lasting health problems. “Of course children in poor, developing countries suffer the most. But this is a real problem in the United States too because of serotype replacement.”

Goldstein dreams of recreating Porter Anderson’s remarkable success with another vaccine, for Haemophilus influenzae type b (Hib), which has resisted serotype replacement for more than two decades and led to a 99 percent drop in deaths and serious complications from Hib since the early 1980s. “I always wanted to ask him, ‘How does it feel to get up in the morning? To know you’ve saved millions of children’s lives?’” If the common protein strategy proves successful, Goldstein just might find out.