Since its introduction eight years ago, the childhood pneumococcal conjugate vaccine (Prevnar) has been effective at reducing the incidence of pneumococcal disease in the United States in people of all ages. But pneumonia, meningitis, and other infections caused by Streptococcus pneumoniae still kill about 1 million children worldwide every year. The cost of the vaccine and other barriers complicate its use in the developing world. New research led by HMS and HSPH researchers, published in PLoS Pathogens on Sept. 19, provides hope that there may be a better way to protect vulnerable children against these infections.
Though it has generally been assumed that antibody formation is the primary mechanism of natural immunity to pneumococcus, recent data have challenged this view. Very young children appear to develop resistance to most pneumococcal serotypes simultaneously, an indication of one rather than many individual immune responses.
“In 2005, we showed in mice that you can protect against pneumococcal colonization by a T cell–dependent, antibody-independent mechanism,” explained co–lead author Richard Malley, HMS associate professor of pediatrics at Children’s Hospital Boston. “We know that in children, from age 1 to 2, there is a 50 percent drop in incidence of pneumococcal disease, yet there is no measurable increase in concentration of anticapsular antibodies. The new paper shows that in children and also in adults, in response to pneumococcus, CD4+ T cells make a protein that enables them to help clear carriage of this extracellular pathogen.”
In addition to establishing a link to humans, Malley, co–lead author Marc Lipsitch, HSPH professor of epidemiology, and colleagues, including first author Ying-Jie Lu, HMS research fellow in pediatrics at Children’s, used a mouse model to elucidate a probable mechanism by which T cells provide immunity to nasopharyngeal pneumococcal colonization.
Four weeks after receiving a genetically altered whole-cell intranasal pneumococcal vaccine, the mice were challenged. Both immunized mice and those in the control group were colonized one day later by the bacterium. Four days post-challenge, nasopharyngeal carriage in the immunized mice was significantly reduced compared to the controls. Similar post-challenge results were observed in a group of mice that had been repeatedly exposed to live pneumococci but not in controls. Immunization with the whole-cell vaccine or prior exposure to S. pneumoniae accelerated clearance over a period of days, providing more evidence that a non–antibody-mediated form of immunity was at work.
To identify the specific CD4+ T cells involved, IFN-gamma, IL-4, and IL-17A-receptor knockout mice were immunized with the whole-cell vaccine. IFN-gamma– and IL-4–deficient mice exhibited significant protection against colonization; IL-17A-receptor knockout mice did not. Using more than one technique, the researchers confirmed that the primary source of IL-17A is CD4+ cells—specifically the Th17 subset. Through pneumococcal stimulation of tonsil cells from children and blood cells from adults, the research team, which included Jane Gross, HMS clinical fellow in pediatrics at Children’s, and Debby Bogaert, then a postdoctoral fellow at HSPH and Children’s, was also able to elicit IL-17A production in human cells. Since no IL-17A could be elicited from cord blood, it appears that prior exposure to pneumococcus triggers production of this cytokine.
Also described in the paper is an assay to measure pneumococcus-specific Th17 cells in humans, which can serve as a correlate of protection in future studies of the whole-cell pneumococcal vaccine that Malley’s lab has been developing. The potential advantages of a whole-cell vaccine include broad protection against all pneumococcal strains.
Malley and Lipsitch are working with a Brazilian manufacturer on a vaccine that will be suitable for human testing and is intended to provoke both antibody-dependent and serotype-independent immunity.
Conflict Disclosure: The investigators report no conflicts of interest.
Funding Sources: Program for Appropriate Technology in Health, the National Institutes of Health, Pamela and Jack Egan Fund
