Basic Ability

Developing a new, safer smallpox vaccine is a national priority. But vaccine development takes a long, long time. ASU virologist Bert Jacobs has a head start on the competition.

A successful virus must adapt quickly to overcome obstacles built by its host’s defenses. A germ’s ability to mutate rapidly is a major reason why humans struggle—and often fail—to fight off the nasty little bugs that make us sick. A good scientist also faces new challenges and obstacles. Like the tiny viruses under the microscope, the scientists who can adapt quickly to new situations are often the most successful.

When Bert Jacobs arrived at Arizona State University more than 20 years ago, he never imagined that he would work on applied projects such as vaccine development or cancer treatments. He was committed to conducting basic research on viruses, the kind of studies that add to our general knowledge of biology.

Jacobs’ work grew out of a lifelong curiosity about science.

“I’ve been interested in science ever since I can remember,” says Jacobs, an ASU professor of life sciences. “My older brother is a chemist, so we had chemistry sets around the house all the time. I became more interested in biology from high school on. I want to know how living things work.”

After college, Jacobs focused his curiosity on the interferon system, one of the body’s main defenses against disease. Interferon is a protein produced by animal cells when they are invaded by viruses. Interferon signals healthy cells to produce an enzyme that counters the infection.

“One way to look at the interferon system is to study how viruses evolved resistance to interferon,” Jacobs explains.

Jacobs studied interferon-resistant viruses to learn their tricky techniques. He began by studying reovirus, but switched to vaccinia virus because it was easier to manipulate genetically.

Vaccinia virus is a close relative of the virus that causes smallpox. Scientists use vaccinia to make the vaccine used to prevent smallpox. By the time Jacobs started working with vaccinia, however, smallpox vaccines were a thing of the past. The vaccine was so successful that smallpox no longer exists in nature. Jacobs’ choice of virus to study became purely academic.

That changed on September 11, 2001, when terrorists attacked the United States and killed more than 3,000 citizens. The country began gearing up to prepare for any kind of terrorist activity—including bioterrorism, or germ warfare.

Stopping Smallpox
Smallpox is a potential weapon in the bioterrorist’s arsenal. Because the disease was eliminated, people no longer receive the smallpox vaccine, which is unpleasant and sometimes dangerous. But the virus still exists in laboratories. If a stolen lab sample was unleashed on the public, it could sicken and kill millions of unprotected people.

Developing a new, safer smallpox vaccine has become a national priority. But vaccine development takes a long, long time. Jacobs has a head start. He already has a good understanding of how vaccinia virus works in the body.

“We isolated genes from vaccinia that allow it to counteract the body’s defenses. Through our basic studies we were able to remove genes that counter our defenses. Does that make a better vaccine? It turns out that yes, it does,” Jacobs says.

The current smallpox vaccine is a live virus vaccine. When injected with vaccine, the body produces antibodies to vaccinia that will also recognize and kill smallpox. However, because the vaccine includes live virus, there is a chance the virus will replicate and cause illness or even death. Children and people with weak immune systems are most at risk from problems caused by the vaccine.

Children are particularly susceptible to encephalitis as a result of the vaccine. Encephalitis is a brain infection that causes death in half of all cases. Immune compromised people face the risk that the virus will replicate out of control. Although vaccinia is not the same disease as smallpox, it can sometimes be fatal to these weakened individuals.

These complications are rare. But even the “normal” side effects of the vaccine can be painful. People receiving the shot often develop a red welt and blistering at the inoculation site. Some suffer flu-like symptoms such as fever and swollen glands.

Most vaccines in use today are made with either killed viruses or parts of viruses (known as subunit vaccines). These types of vaccines are much safer than live vaccines. Unfortunately, vaccinia does not work as a killed or subunit vaccine.

“The immune response involves both producing antibodies and making cells that can kill the virus. Killed vaccines usually give good antibody responses but not good cell-mediated responses,” explains Jacobs.

The cell-mediated response, however, is critical in stopping certain viruses. Vaccinia is one of them.

“So we’re stuck with a live vaccine for smallpox,” Jacobs says.

He and his colleagues want to make the live vaccine safer. They tackle the problem from two different angles. One way is by engineering the vaccine so that any complications can be treated easily with tetracycline, a common antibiotic.

“Problems occur when vaccinia replicates in the wrong place or you’re immune compromised,” Jacobs says. “We are engineering the virus to stop replicating when treated with tetracycline.”

A prototype of this vaccine is currently being tested. The ASU team’s second approach is to develop an attenuated—or less virulent—strain of the virus.

“The vaccinia virus at high doses will kill mice. We’ve engineered mutations into vaccinia so it doesn’t kill them. But it still gives them a good immune response. It’s still a live virus, but less live,” Jacobs says.

The trick to attenuating the virus lies in a gene called E3L. Jacobs has studied E3L for years. E3L holds the key to vaccinia’s ability to resist interferon.

Jacobs discovered that E3L is essential in causing disease. If the gene is disabled, the vaccinia virus becomes harmless.

“E3L is the gene we’ve been working on for 20 years,” says Jacobs. “It’s kept us going for a long time—a single gene!”

Viral Tools
Understanding how viruses evade the immune system can help us prevent them from attacking our cells. But now, scientists are trying to use viruses as tools for healing. For example, the adaptability that makes viruses so difficult to get rid of can come in handy when they are used to attack cancer cells.

How can a virus kill a cancer cell without harming the healthy cells around it? Once again, Jacobs says, the answer can be found in the interferon system.

“The interferon system is one of the body’s main defenses against viruses. It’s also one of the body’s main defenses against cancer,” the ASU scientist explains. “As cancer cells grow, the interferon system starts killing them. But cancer cells eventually develop resistance to the interferon system. Those cancer cells are then susceptible to being killed by viruses that would normally be killed by interferon.”

In other words, the cancer cells can’t be killed by the interferon system, but they also can’t use it to their own advantage.

Other scientists have used mutated viruses in attempts to target and kill cancer cells. Jacobs realized that the mutant vaccinia viruses he was making had similar properties to these anti-cancer viruses. He decided to test them.

Researchers put human cancer cells into four mice to produce tumors on the left and right sides of the body. Then they injected a low dose of the mutated vaccinia virus into the right side. The tumor on the right disappeared.

When the researchers injected a higher dose on the right, the virus destroyed the tumor on both sides of the body.

“It gives hope that we can treat metastases, tumors that grow from cells that spread from the initial cancer site. Even when we don’t know where they are in the body,” says Jacobs.

Although more research is needed, initial results with the mouse studies are promising. The team saw complete regression of the cancer in seven out of eight tumors, and partial regression on the eighth.

“Needless to say we’re really excited!” says Jacobs. “Our viruses can be engineered to do lots of different things. That’s an advantage. We can use that as a starting point and add different things to make them better, more specialized.”

Jacobs is quick to point out that vaccine development and cancer treatments are just some of the applications that can grow out of basic research.

“You’ve got to have a basic understanding of a system before you can engineer it in ways that are useful for humanity,” Jacobs says. “You never know what important findings will grow out of basic research. We started out doing basic biology about 20 years ago. If you’d told me then that we’d be spending half our time now on vaccines I’d have said you were crazy. But we haven’t abandoned our basic research, either.”—Diane Boudreau