Immunization 2.0: Promising New Gene-Based Vaccines

Pathogens like West Nile virus show no respect for borders. But a new class of vaccines may soon keep them in check.

Paul Loebach volunteered to test a DNA vaccine for West Nile virus. His body’s response will help determine whether the vaccine is approved. PHOTOGRAPH BY ETHAN HILL

By Jonathan Gromer

By Ben Harder

Published in the September 2006 issue.

When Paul Loebach volunteered to have microscopic rings of foreign DNA injected into his body, his wife was none too pleased. That the genetic material came from the deadly Ebola virus might have had something to do with it. “My family thought I was crazy,” recalls the public health analyst from Rockville, Md. As if to prove they were right, he has since gotten several injections of West Nile virus DNA, too.

In both cases, medical investigators at the National Institutes of Health (NIH) in nearby Bethesda were mustering up volunteers to test promising new DNA vaccines. Loebach, 37, answered their call to bare arms. Unlike many current vaccines, which contain whole viruses, these gene-based vaccines have only snippets of viral DNA--just two genes, in the West Nile vaccine, out of seven--and those pieces are cooked up from scratch in a lab. “You can’t be infected because the [live] virus is not part of the production process,” says Barney S. Graham, chief of clinical trials at the NIH’s Vaccine Research Center. In essence, he says, the injection contains just enough “genetic information to enable the cell to make its own vaccine.”

Infectious diseases remain among the leading causes of death worldwide, and each year a new species of pathogen emerges. Swift development of vaccines is crucial to stopping potential epidemics. West Nile virus has swept through 48 states since it was first detected in New York City in 1999. Most infected people experience only mild symptoms, but when the virus enters the central nervous system, it can be deadly. There is also evidence that the virus has mutated into a second strain.

A DNA vaccine’s simplicity makes it versatile enough to take on a rapidly mutating foe, and cheap enough to deploy in developing countries. Scientists can swap in genes as a virus evolves, creating new formulas in a matter of days. Manufacturers need about nine months to produce large quantities of whole viruses for conventional flu shots, so DNA vaccines could quickly help defend against the deadly strain of bird flu, H5N1. And, DNA vaccines have a high tolerance for heat, so they can be distributed in places where refrigeration is unavailable.

Recipe for Resistance To create the West Nile vaccine, researchers produce a strip of DNA with the genetic code for two proteins that the virus uses to invade cells. They insert this into a loop of nonviral DNA called a plasmid, make many copies, and use a needleless, high-pressure “gun” to ram the plasmids into the arm muscle--on three occasions. (Studies suggest that more plasmids do their job when blasted into muscle cells than when injected by a needle.)

 

1-How a DNA Vaccine Is Made: Scientists extract single-stranded RNA from West Nile virus and convert it to double-stranded DNA. This is used to synthesize two genes that encode for proteins on the virus’s coat. The genes are stitched into a piece of nonviral DNA called a plasmid.

2-How the Human Body Responds: Once the vaccine is delivered, the plasmids direct muscle cells to manufacture the viral proteins. The proteins migrate to the cells’ surfaces and alert the immune system, which mounts a defense. Helper T cells spur the production of antibodies to disable the virus, and killer T cells mobilize to destroy any cells actually infected. ILLUSTRATION BY SCHWARZSCHILD

Each infected cell’s nucleus reads the viral DNA and makes proteins according to the genetic instructions. The proteins journey to the cell’s membrane and poke outward, raising “flags” visible to passing immune cells. Researchers expect the body’s response to be twofold: It will produce antibodies to target the foreign proteins, as it would with most vaccines, and stimulate white blood cells that will destroy compromised cells in the event of an actual infection. The two processes mimic how the body resists being reinfected with a virus it has already beaten.

At least that’s the theory. To confirm it, researchers sought out human guinea pigs. Willing subjects were excluded if they flunked any item on a laundry list of qualifications. No volunteer could have previously received a shot against yellow fever or Japanese encephalitis, two relatives of West Nile, because they would already have similar antibodies. Volunteers also had to live nearby so they could be monitored throughout the study. “You’re committing quite a bit of time on a regular basis for a year, or sometimes 18 months,” Graham says.

Acceptees are paid $50 or more for each clinical appointment. Says Loebach: “A round of golf a visit--that’s worth it right there.”

But Does It Work? Researchers examine the volunteers to determine whether their bodies develop the expected immune response. But the larger challenge could be proving that the vaccine actually protects them against the virus. To do so, researchers would normally vaccinate a

Bunch of people and watch to see if that group experiences fewer infections than an unvaccinated group. But illnesses from West Nile virus are still rare enough in the States--about one in 150,000 Americans were diagnosed last year--that such a study could take years and require hundreds of thousands of volunteers. Graham thinks there’s an easier way.

The Food and Drug Administration has yet to approve any DNA vaccine for use in people, but veterinarians already have one to protect horses from West Nile virus. Researchers proved the vaccine works by doing something too risky to try in humans: They exposed inoculated horses to the live virus. The animals didn’t get sick.

If studies show that people and horses develop comparable immune responses to the DNA vaccines for West Nile, Graham hopes the human vaccine will get the green light.

In the meantime, there will be a second trial for the West Nile vaccine that includes volunteers over age 50. Loebach won’t qualify for it, but he may be swinging by NIH for checkups anyway. Graham’s group is developing a DNA vaccine for HIV. “When I’m done with West Nile virus,” he says, “if they’re still doing the AIDS vaccine, I’ll probably volunteer for that.”