Turning Genes Into Vaccines

They may prevent-and treat-killers like AIDS and cancer

Dr. Margaret A. Liu knows what it's like to play to an audience. As a Paris-trained classical pianist, her performances once drew enthusiastic crowds. Now, as a leader in research on a new class of vaccines at Merck & Co., Liu is again packing them in. Scientists come by the hundreds to hear her presentations on a technology that could be one of the most important advances in vaccine research since Jonas E. Salk and Albert A. Sabin conquered polio.

The new approach offers promise for preventing or treating diseases that have eluded traditional vaccines. They include malaria, tuberculosis, AIDS, and cervical cancer. Merck, American Home Products, French vaccines giant Pasteur Merieux Serums & Vaccins, and others are spending hundreds of millions on the technology that uses snippets of genetic code to induce powerful defenses against disease. In animals, the approach has been very promising. And this spring, two so-called DNA vaccines--one for influenza and another for AIDS--began human testing.

"REVOLUTION." The technique has its hurdles. Some key technical challenges remain to be solved before the vaccines can be made widely available. And regulatory problems that inevitably arise in the face of new products could delay their approval. Yet many researchers remain optimistic over the long run. "We're on the verge of a revolution," says Dr. Stephen L. Hoffman, director of the malaria program for the U.S. Naval Medical Research Institute.

The development and sale of vaccines has grown to be a highly competitive $3.6 billion-a-year industry. Just a decade ago, it was thought of as a low-margin commodity business. A key factor in the industry's growth was the passage of legislation in the mid-1980s that shielded vaccine makers from lawsuits arising from rare but serious side effects. The industry's main players now see only growth on the horizon as managed-care outfits push cost-saving preventive medicines. "If you get recommendations from groups like the American Academy of Pediatrics to give [a vaccine] to every baby, that's a huge market--and you don't have to do any advertising," says Dr. C. Jo White, a senior scientific adviser for the Connaught Laboratories Inc. unit of Pasteur Merieux.

SMITTEN. Sensing opportunity, innovative newcomers have surged into the field with fresh science and big marketing hopes. Alliances have been formed: American Home Products Corp. has pledged at least $100 million to underwrite DNA vaccine research by Apollon Inc. of Malvern, Pa., and Merck is likely to spend at least that much in deals with Vical Inc. of San Diego.

Of the various approaches now being studied, DNA vaccines are among the most impressive--and still the furthest from commercialization. Although the technique remains unproven in humans, scientists are smitten with its power and simplicity. This past February, more than 400 researchers turned out for a National Institutes of Health international meeting on DNA vaccines--10 times the number who came to a similar meeting just two years ago in Geneva. "Scientifically, it's a very exciting time for my group and for me," says Liu.

Enthusiasts describe DNA vaccines as third-generation technology. The first generation includes polio and measles vaccines, which use a weakened or killed virus to provoke an immune response. Researchers would spend years searching for viruses potent enough to trigger protection but not so potent that they caused disease. For many diseases, the search was unsuccessful.

More recently, genetic engineering has allowed scientists to make large quantities of key proteins from viruses or bacteria. When injected, the proteins induce an immune response. These vaccines--including SmithKline Beecham's and Merck's big-selling hepatitis inoculations--don't carry the risk of infection but can be costly to make. Another limitation of these so-called subunit vaccines--in the case of HIV, in particular--is that they induce only a partial immune response.

The idea of DNA vaccines, as pioneered by Vical scientists in 1989, is to activate the body's defenses by injecting genes that hold the recipe for an antigenic part of the organism--that is, the part of the organism that provokes an immune response. Once inside the body, the genes are taken up by cells that begin churning out foreign proteins. When manufactured by the body's cells, these proteins are configured in a way that triggers a complete immune response without any risk of infection. Then, when a virus or bacteria invade, the body is primed to respond, and it kills off the invader.

BREAKNECK. Research on DNA technology has accelerated at a breakneck pace since about 1990, when Vical scientists showed they could get mice to produce foreign proteins--a key step in the working of a vaccine--simply by injecting DNA into their muscles. In the past year, Merck researchers, working with Vical, have triggered powerful immune responses by immunizing monkeys with DNA that codes for proteins of the flu, herpes simplex, and AIDS viruses. These experiments have all but vanquished earlier fears that the DNA-based vaccines might fail in primates.

More support for the technology came from the lab of David B. Weiner, a researcher at the University of Pennsylvania who is working with Apollon on an AIDS vaccine. Because HIV contains only RNA, Weiner uses DNA culled from infected cells in his vaccine. In recent studies, Weiner reported that a DNA-based AIDS vaccine "stopped the virus completely" in healthy chimps who were subsequently infected with HIV. He cautions that this doesn't mean the vaccine will work in humans. But the technology "has enormous flexibility because we can rapidly test very different combinations of genes and gene products to boost immune responses."

Weiner and Liu both caution that the first generation of DNA vaccines could easily fall short. Examples of promising technologies that succeed in animals but fail in humans are common. Because vaccines are intended for use in huge populations, even minor unexpected side effects can have important public health consequences, dashing developers' hopes. One worry is that the DNA won't be adequately absorbed by cells. Researchers are devising various technical schemes to remedy that.

Besides the technical challenge, DNA vaccines may be tough to sell to regulators. Researchers are still uncertain about the long-term health effects of injecting foreign DNA into humans. According to James F. Young, senior vice-president of R&D at MedImmune Inc. in Gaithersburg, Md., regulators have a "phobia" about DNA-based therapies. "We'd rather invest our Rsuperscript&D dollars in some products we can get to market more quickly," he says.

Despite the hurdles, other drugmakers are attracted by the long list of ailments that are targets for DNA vaccines. Apollon and American Home are working on a vaccine for herpes simplex that is expected to go into human tests later this year. A vaccine against the human papilloma virus, which causes genital warts and cervical cancer, could begin human trials as soon as next year. Meanwhile, Merck and Vical are pursuing the same targets, plus a couple of forms of hepatitis, influenza, and tuberculosis. Pasteur Merieux has allied with Vical to fashion vaccines against tick-borne Lyme disease, malaria, and the ulcer-linked H. pylori bacteria.

While vaccines have traditionally been used to prevent disease, some say the new vaccines may also help treat it. Weiner found, for example, that his HIV vaccine could reduce the amount of virus in an already infected chimp. Apollon has another vaccine in the works to treat T-cell lymphoma. Human tests began in February. Other targets for Apollon include treating autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.

Winning approval to market DNA vaccines will take years of testing and evaluation. So, except for an AIDS vaccine--which would certainly be fast-tracked if it proves successful--products from the DNA-based technique are at least 5 to 10 years off. If the DNA vaccines prove to be as powerful as their proponents claim, disease prevention--and the vaccine industry--will never be the same.

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