Immunology
Body Builds Defense
Against Pneumococcus
Without Antibodies
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Body Builds Defense Against Pneumococcus Without Antibodies
New Vaccine that Stimulates T Cells May Satisfy Unmet Need of Developing World
The key to defeating Streptococcus pneumoniae is traditionally thought to be antibodies, and antibodies are the weapon used by current pneumococcal vaccines. But a new study led by Richard Malley and Marc Lipsitch suggests that the natural process of keeping the bacterium from colonizing the surface of nasal passages may be independent of antibodies. The finding, published in the March 29 Proceedings of the National Academy of Sciences, points to new ways of designing vaccines against pneumococcus that may be practical for the developing world, where one million children die of pneumococcal infection every year.
Photo by Graham Ramsay
According to work by Richard Malley (left) and Marc Lipsitch, pneumoccocal vaccines may be able to sidestep specific antibodies and activate T cells instead.
S. pneumoniae colonizes many people without doing harm, but in children and immunocompromised or elderly adults, it can cause pneumonia, meningitis, and ear infections and is the most lethal bacterium in the United States. The bug is a dangerous package wrapped in a sugar coat. The polysaccharide capsule that surrounds pneumococcal cells is their primary form of protection and, according to the common view, also the key to their defeat. During infection or asymptomatic colonization, the body produces antibodies to the capsule, and it was assumed that these antibodies are the primary cause of immunity. The catch is that S. pneumoniae is highly diverse—the sugar coat comes in 90 known varieties, and each one elicits distinct antibodies.
Negotiating
Curves of Infection
Vaccines developed for pneumococcus have shown that antibodies against
the capsule can prevent infection. The current vaccines consist of several
polysaccharides
linked to a protein from another virus, representing the capsules of the
most common serotypes of the bacterium.
But a study published in the January PLoS Medicine by Lipsitch, HSPH associate professor of epidemiology, Malley, HMS assistant professor of pediatrics at Children’s Hospital Boston, and their colleagues presents evidence in humans suggesting that specific antibody responses, though effective, do not play a role in naturally acquired immunity in children.
They looked at the incidence of pneumococcal disease in infants and toddlers from a U.S. data set. Young children gradually lose their susceptibility to disease as they are exposed to each pneumococcal strain and produce antibodies against them. Or so it was thought. If that were the case, the incidence curves for infection by each strain should differ, depending on how common the strain is in the children’s environment. Instead, the researchers found, the incidence of each strain follows a very similar curve, peaking at about one year and then tapering off.
| The results “suggest—with all the usual caveats of animal models—that the natural way that individuals become immune to carrying pneumococcus may be by a mechanism that hasn’t been appreciated before.” |
The team then immunized mice with a vaccine that Malley’s lab has developed, containing whole killed pneumococcal cells stripped of their sugar coats. “We’re eliminating what makes the 90 types different from each other,” Malley said. “The immunity we’re eliciting is not due to immunity from the capsule.” The vaccine was able to provide long-lasting immunity, even when administered to animals that lacked the ability to produce antibodies of any kind. The antibody-deficient mice were also protected from bacterial colonization when they were previously exposed to live pneumococci.
Since antibodies were not needed for immunity to the bacteria, the team investigated whether T cells were involved. They found that knocking out CD4 cells, but not CD8 cells, blocked the protective ability of the vaccine. Lipsitch said that the results “suggest—with all the usual caveats of animal models—that the natural way that individuals become immune to carrying pneumococcus may be by a mechanism that hasn’t been appreciated before.”
Questioning
the Antibody Defense
No one would doubt the effectiveness of the current polysaccharide vaccine,
which has been on the market for about four years. In fact, a recent
study in Gambia showed that the vaccine worked even better than expected,
preventing
pneumococcal infections and preventing one childhood death for every
200 children vaccinated. But the vaccine has drawbacks; it is relatively
costly
to produce
and cumbersome to deliver, since it requires refrigeration and sterile
needles. And the few serotypes of pneumococcus represented by the vaccine
are not
the same types found in developing countries, where the vaccine is most
needed. By immunizing large numbers of people against a select group
of serotypes,
the vaccine also puts selective pressure on the bacterial population,
encouraging the types not represented in the vaccine to proliferate.
“Antibodies are sufficient to protect against disease. We’re wondering if they’re necessary,” Malley said. He was approached several years ago by Porter Anderson, a scientist at the University of Rochester with expertise in vaccine development, who is a co-author on the PNAS paper. Under Anderson’s mentorship, Malley began to explore ways of developing a cheaper vaccine for pneumococcus that would be more appropriate for use in developing nations. To do that, Malley wanted to learn from the events taking place on the surface of nasal passages, where pneumococcus colonizes. “We were more interested in mucosal immunity and the mechanisms of naturally acquired immunity,” he said. The current study offers support for Anderson and Malley’s whole killed vaccine, which has the advantage of working indiscriminately against all serotypes. Malley said that a vaccine could also be based on a combination of specific bacterial components to elicit CD4 responses.
The study brings up a more fundamental riddle as well. As an evolutionary biologist, Lipsitch is interested in figuring out why the pneumococcal polysaccharide coat comes in so many varieties if it is not the key to evading the acquired immune response. “Why is it we have this incredibly diverse population out there? We thought we had the problem solved, but now our data suggest that more work is needed to answer the question.”