Could DNA Vaccines Undermine Immunity?

Vaccines of live pathogens have saved countless lives, but living vaccines are not totally stripped of their ability to kill and maim: About eight vaccine-induced polio cases occur per year in the United States, for instance. Now it turns out that one scheme for averting these hazards--making vaccines from nothing but a bit of the pathogen's DNA--carries a risk of its own. A group of researchers from the U.S. Food and Drug Administration (FDA) has found that DNA vaccines can have the perverse effect of "tolerizing" the immune system, perhaps weakening any future response to the real pathogen.

DNA vaccines, which are now in early clinical trials, consist of a bit of DNA containing a gene for a marker protein from the pathogen. The idea is that when the DNA is injected into muscle tissue, it works its way into cells, where it is incorporated into the cellular DNA. The cell produces the protein encoded by the vaccine, then shuttles it to the cell surface, where the host's immune system recognizes it as foreign and mounts an immune response. The body thereby "learns" to recognize the pathogen and mount a strong response to it in the future.

But research published in this month's issue of the Journal of Clinical Investigation shows that newborn mice, instead of being immunized to the protein encoded by a DNA vaccine, actually learn to tolerate it. In fact, when later injected with the same protein, they developed no antibodies to it at all. George Klinman, an FDA immunologist and lead author of the report, speculates that dangling the protein in front of the immune system in an unusual setting--on a muscle cell--might be what triggers the inappropriate response. The finding raises the possibility, he says, that a DNA vaccine "could convert someone who normally would be able to clear a pathogen--albeit they might get sick first--to someone who can't clear it at all."

That could be a serious concern for vaccine developers, says John LaMontagne, director of the division of Microbiology and Infectious Disease at the National Institute of Allergy and Infectious Diseases. Klinman's finding adds to growing concerns about the risk of inducing tolerance by giving vaccines to newborns, who have immature immune systems. Newborns are often the target group in Third World immunization campaigns, because birth is when they are most likely to get medical attention. "We have to be thinking about [tolerance] all the time," says LaMontagne.

Klinman does see a bright side. A DNA vaccine's tolerizing effect could potentially be used to combat autoimmune diseases--such as some forms of diabetes and arthritis--in which the immune system attacks and destroys its own tissues. Says Klinman: "One of the directions my research is going is: Can we apply this in a positive sense?"