In the U.S., before the advent of the pneumococcal conjugate vaccine, known as Prevnar, S. pneumoniae caused more than 7 million ear infections each year, half a million episodes of bacterial pneumonia, and life-threatening cases of meningitis and bacteremia. Prevnar is made up of material from the outer capsule of each of the seven pneumococcal strains most common in the U.S. This material triggers recipients' immune systems to produce so-called anticapsular antibodies specific to those strains. However, Prevnar doesn't work against many pneumococcal strains in the developing world, where pneumococcus kills nearly 1 million children annually, and it is expensive and difficult to manufacture, leading to chronic shortages. Moreover, in several studies, use of pneumococcal conjugate vaccines caused non-vaccine strains to become more common, raising concerns that Prevnar could eventually become ineffective even in the U.S. Of 90 known pneumococcal strains, Prevnar only covers seven.
Lipsitch and Malley first conducted epidemiologic studies in unvaccinated toddlers in the U.S., Israel, and Finland. As they reported in January in the online journal PLoS Medicine, the incidence of invasive disease from almost all pneumococcal strains fell by nearly half between 1 and 2 years of age. Yet, anti-capsular antibody concentrations increased only slightly, suggesting that a mechanism other than antibody to the pathogen's outer capsule may be conferring natural protection against pneumococcal disease.
What then might provide this protection? Looking at the first step of pneumococcal disease, colonization of the nose and throat, Malley and Lipsitch were able to elicit long-lasting immunity to pneumococcus in mice independently of any antibodies. In the current (March 29) Proceedings of the National Academy of Science, they report that when mice were exposed to live pneumococci, or to a whole-cell vaccine developed in Malley's lab, they were highly immune to pneumococcal colonization -- even if they were genetically unable to make antibodies. Moreover, mice exposed to a single pneumococcal strain became immune not just to that strain, but to others. The immunity appeared to arise from an effect on the immune system's CD4+ T-cells, since mice that lacked these cells did not develop immunity.
"Textbooks say that naturally-acquired protection against pneumococcal disease depends on the development of antibody against the capsule of the bacterium," says Malley, who is also an assistant professor in pediatrics at Harvard Medical School. "We were surprised to find that protection was independent of not only antibody to the capsule, but also antibody of any specificity."
Overall, their findings suggest that while antibodies are sufficient for protection against pneumococcal disease, they may not represent the natural mechanism of protection.
"An interesting observation is that HIV-infected children, whose CD4+ cells are depleted by the virus, are at about a 200-fold higher risk for pneumococcal disease," Malley adds. "Our experiments in mice may provide an explanation for that vulnerability."
The whole-cell vaccine developed by Malley's lab could potentially protect against all pneumococcal strains, Malley says. The vaccine, made of killed pneumococcal cells, was shown to prevent colonization and invasive disease when given to animals in the form of nose drops. Malley believes the vaccine stimulates CD4+ T-cells to identify components of pneumococcus that are identical in every strain and to provide protection at the earliest stage of infection, when pneumococcus is colonizing the nasal passages.
The whole-cell vaccine, or a derivative of it, would be a boon for the developing world, because it is inexpensive, covers all pneumococcal strains, and does not require refrigeration. Malley and colleagues are now working to define precisely how the whole-cell vaccine works immunologically, and determine what parts of the killed bacterium provide the actual protection. The ultimate goal is to test the vaccine in adult volunteers, and eventually in children.
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