UW research leads to life-saving vaccine against hepatitis B

UW Genetics Professor Ben Hall (left) in his lab with graduate student Salam Shaaban.

Imagine you just won the Lotto and—generous person that you are—you’re going to donate $1 million to help fight AIDS. Do you give it to 10 people with AIDS so they can try all the latest treatments? Buy condoms for free distribution? Spend it trying to develop a vaccine? Or give it to researchers who can’t say exactly how their work might lead to a cure, but who insist that first we need to understand a whole lot more about how the virus attacks the body?

Now imagine it’s 20 years ago and you’ve never even heard of AIDS. But you are worried about hepatitis B, a contagious disease than can wreak havoc on the liver. With your Lotto winnings you try to develop a vaccine against hepatitis B virus. Would you start by studying baker’s yeast?

Ben Hall did. The UW genetics professor certainly didn’t set out to develop a vaccine for hepatitis B when he began studying yeast genetics two decades ago. But that’s what rose out of his work, done in collaboration with then-postdoctoral fellow Gustav Ammerer and others. Through their yeasty discoveries, they have already saved millions of lives. They and their colleagues could banish a killer that takes up to four million lives annually.

Hepatitis B is 100 times more contagious than the virus that causes AIDS, and is spread in the same ways—through sex, infected blood, shared hypodermic needles, and from an infected mother to her newborn. Chronic carriers of the disease are at risk for developing liver conditions that can lead to cirrhosis and cancer.

About 300,000 new cases of hepatitis B are reported each year in the United States and more than 200 million people carry the disease worldwide. The virus kills about 14 people each day in the U.S. Hepatitis B is epidemic in some parts of the world, including Asia, Africa, the Pacific Islands, Alaska and in U.S. cities where drug use is prevalent.

One victim is Patrick Shapard. Twelve years ago, while Hall and Ammerer were working on yeast genetics, Shapard became infected with the hepatitis B virus. He doesn’t know how it happened. He didn’t start showing symptoms until four years ago, when extreme fatigue forced him to quit his job.

His condition has worsened to cirrhosis of the liver. “I’m tired all the time—24 hours a day,” he says. “I have a lot of joint pain and night sweats.” Because he has chronic hepatitis B, Shapard is not a candidate for a liver transplant, since the disease would attack a transplanted liver.

Shapard has two risk factors: he’s a gay man and his previous social service work with mentally handicapped adults sometimes exposed him to other people’s blood. There was no hepatitis vaccine 12 years ago. His advice on getting vaccinated now: “You’d be crazy not to.”

“With a focused campaign, hepatitis B could be eliminated in 20 to 30 years because the vaccine is so effective and safe—safer than flu or measles vac­cines,” says UW Medicine Professor Robert Carithers Jr., director of hepatology at the UW Medical Center.

The vaccine is now recommended for all school children in the U.S., and for college students as well. Federal law requires all health care workers and health science students who work around blood to be vaccinated.

The creation of the vaccine has not only saved millions from a devastating disease; it’s also helped hundreds of researchers at the University. Due to several patents, it brought in $7.8 million in 1993, nearly 90 percent of the royalties the UW earned last year from faculty discoveries. The royalties are shared by the inventors, their school or department and the UW. Some royalties travel overseas, since Ammerer is now on the faculty at the University of Vienna in Austria.

“This has made possible the UW’s royalty research fund, which awards research grants to faculty and puts a good deal of revenue into graduate student funding in our department,” says Hall. “That gives great satisfaction both to Dr. Ammerer and to me.”

“Sometimes we have tough times at the University,” he notes. Work leading to the vaccine was being done in the early 1980s, at the same time state budget cuts forced the UW to lay off faculty and staff. As chair of the genetics department during that period, he says, “I was keenly aware we needed outside sources of revenue.”

But making money isn’t why researchers like Hall come to work every day. The aim of basic research is to understand root causes and basic biological mechanisms. The practical applications aren’t immediately apparent.

There’s no poster child for basic research, which makes it tough to compete for scarce dollars. Some fear that, with the approach of health care reform and its focus on cutting costs, basic research might be shortchanged. Scientists are afraid that, as lobbyists and activists clamor for more dollars, more funds will be targeted to specific diseases.

There was no hepatitis B lobby clamoring for more funds for Hall’s basic research in yeast genetics. But it’s the knowledge gained in basic research like Hall’s that unlocks the secrets of diseases, allowing us to pave the way for treatments and prevention.

The path to a hepatitis B vaccine began decades ago in the uncharted territory of genetics. Hall wanted to understand how genes control living cells. Somehow the blueprints—the genetic information in DNA—are transformed into working drawings—RNA—which then direct the construction of proteins to build the living body.

In the early 1960s, working with the common gut bacteria E. coli, Hall helped figure out that DNA does its work by being copied in the form of RNA. Today, high school biology students know about this intermediate step, called “RNA transcription.” But 35 years ago it wasn’t clear even to Ph.D. geneticists how the blueprints in DNA get turned into working drawings.

DNA consists of strings of genes that carry informa­tion for all aspects of bodily growth and development. Some DNA information is a blueprint for the assembly of various proteins, while other information acts as “on” and “off” switches to control copying and reading of the genetic blueprint.

It’s this copying, or transcription, that turns the genetic blueprints of DNA into the working drawings of an RNA message. Current research in Hall’s lab focuses on this copying process in yeast in order to understand how one enzyme recognizes the “on” and “off” switches.

Much of Hall’s work on transcription involves “gene splicing”—separating and recombining chains of DNA molecules into new sequences that hold different instructions than the original sequence.

Back in 1980, Hall and Ammerer isolated one of the “on” switches in yeast DNA, determined where on the long string of genes the “on” switch begins and ends, and described it in detail.

The “on” switch activates a section of the genetic blueprint that is joined to it, making the yeast cell copy the blueprint’s protein. The scientists figured if they could insert blueprints from another creature next to a yeast “on” switch, they could turn the yeast cell into a factory for protein from “foreign” DNA.

Using enzymes, Hall and Ammerer cut, spliced and created the new yeast cell factory. At the time, they didn’t know their techniques and hardware might lead to a hepatitis B vaccine. Practicing basic research, their procedures were first tested on proteins without commercial importance—one from rats and one from fruit flies.

In order to extend and confirm those results, they collaborated with a group from the biotech company Genentech, led by Ron Hitzeman, with the goal of producing human interferon in yeast. Interferon occurs naturally in very small amounts in humans and other animals and is useful in combating many diseases, including some forms of cancer. Genentech had cloned the human interferon gene, which the group spliced together with the yeast “on” switch. Like magic, the yeast cells began producing interferon.

In 1981 the UW and Genentech jointly filed patent applications for the first genetic procedure that used yeast to produce non-yeast proteins beneficial to humans. Besides providing a new source for interferon, the experiments showed for the first time that yeast could manufacture useful proteins from human genes and viral genes.

Hall and Ammerer then turned their attention to hepatitis B. Again using enzymes to cut and splice, they combined the yeast “on” switch with a DNA blueprint necessary to construct the hepatitis B surface “antigen.” Antigens spur the immune system into action to protect against infection. Being vaccinated with the hepatitis B antigen prompts the body to produce specific antibodies, so if you are later exposed to the actual hepatitis B virus, you already have an antiviral line of defense in place.

Once again, Hall and Ammerer collaborated with scientists at another institution in order to move their work forward. In this case their partners were Pablo Valenzuela and William Rutter, researchers at the University of California, San Francisco (UCSF), who had cloned the gene for the hepatitis B protein. UCSF holds a joint patent with UW for the technology to make this protein in yeast.

Earlier attempts using E. coli to make the vaccine had failed. Yeast worked much better because the antigen molecules, along with fat molecules, clumped together in a very regular way to form particles of a distinctive size. “Such particles are exceptionally immunogenic,” Hall explains, “which means a little bit goes a long way. Consequently, very little material had to be injected into a human to give rise to immunity.”

The unexpected result—that yeast formed par­ticles of such potency—provided a surprising shortcut to vaccine development. It also meant that relatively little yeast-related material had to be purified out of the vaccine before it could be used in humans.

“I don’t think this work would have been nearly as exciting for us if we had not known that several groups were trying to do the same thing at the same time,” Hall said. “It’s much more fun to be breaking new ground.”

Since the FDA approval in 1986, sales of the vaccine have grown steadily, increasing four-fold in 1993. The general yeast-expression method and the hepatitis B virus technology were licensed by the Washington Research Foundation to two major pharmaceutical companies—Merck, Sharp and Dahme; and Smithkline Beecham.

In addition to the royalties paid to the University since 1988, last year the foundation made a $1-million gift out of its own revenue from Hall and Ammerer’s discoveries to establish endowed fellowships for graduate students pursuing interdisciplinary studies.

“It’s a stunning example of basic scientific research conducted here which has benefited both the campus and the wider community,” says Alvin Kwiram, UW vice provost for research. “Hall’s work has been highly significant in worldwide disease prevention. It shows what an important role research universities like the UW play.”

A shot in the arm will stop this killer

Five percent of the world’s population is in­fected with hepatitis B. About 14 people die each day in the United States from its conse­quences, yet there’s a safe, effective vaccine that can prevent this liver disease.

“It’s probably the safest vaccine ever pro­duced,” says Medicine Professor Robert L. Carithers Jr. “We have the tools to eradicate the disease.”

Hepatitis is an inflammation of the liver that prevents the organ from doing its job of filtering blood. Flu-like illness and jaundice often signal hepatitis, although many cases are without symptoms.

Hepatitis comes in several forms, each caused by a dif­ferent virus. Most people are familiar with hepatitis A be­cause of restaurant outbreaks caused by an infected person preparing food with dirty hands. Less familiar are hepatitis B, C, D and E.

Much more contagious than the AIDS virus, hepatitis B is spread in the same ways: through exchange of virus-con­taminated blood or body fluids. Intravenous drug users, sexual partners of infected people and health care workers are most likely to become infected, as are babies born to infected mothers.

Only 5 percent of adults infected with the hepatitis B vi­rus eventually develop life-threatening, chronic liver disease or cancer, but nearly 90 percent of the infants infected be­come silent carriers of the virus, says Carithers, who directs hepatology at the UW Medical Center.

Public health officials now recommend that all children be vaccinated and that pregnant woman be tested for hepatitis B.

The vaccine is most effective in infants, granting immu­nity in 98 to 99 percent of cases. By age 50, the effective­ness drops to 80 to 90 percent, Carithers says. For that reason he favors requiring—rather than just recommend­ing—that all children be immunized. He’s especially con­cerned that youngsters be vaccinated before their teen years.

“Many, many people are exposed to hepatitis B by age 18 or 20, presumably from sexual contact, IV drug use, tat­toos, ear piercing and other behaviors that teens engage in,” Carithers says.

About 800 sixth through ninth graders in two Seattle schools are getting free hepatitis B vaccines in a project co­ordinated by UW research fellow Bradley Stoner and funded by the federal Centers for Disease Control (CDC).

In another CDC-funded project that will start July 1, hepatitis B vaccine will be available – at no cost – to high-risk adolescents in settings such as juvenile detention, the King County Jail, the Sexually Transmitted Disease Clinic at Harborview Medical Center, and at community clinics and drug and alcohol treatment centers with adoles­cent clients. Stoner says disease rates skyrocket in the 14- to 20-year-old age group.

The prevalence of hepatitis Bin the U.S. population is about five cases in 1,000 people. The situation worldwide is much bleaker. Roughly 10 percent of people in Southeast Asia and Africa are chronic hepatitis B carriers. “Liver can­cer due to hepatitis B is the number one cancer killer of men in the world,” Carithers says.