SARS: Preparing for Round Two

If it returns, drug and vaccine makers hope to be ready

World health officials declare that the SARS epidemic has been stopped dead in its tracks. But in industry and government research labs, the work is just beginning. Scientists are rushing to develop diagnostic tests, drugs, and vaccines against the virus that has already killed more than 800 people. The hope is that these new weapons won't ever be needed. But the realistic expectation is that SARS is far from being beaten. "I think we're in a race not only to fight the ongoing disease, but also to be ready when it comes back -- which it will," warns Dr. Anthony S. Fauci, director of the National Institute of Allergy & Infectious Diseases. "This is not going away anytime soon."

In their own labs, and in partnership with the government, drug and vaccine makers are investing millions of research dollars to meet the challenge. If the disease strikes again, they hope to be in a position to fight back -- and to reap a share of the profits. Already, there are diagnostic tests on the market, potential drug candidates, and innovative approaches to vaccines. But researchers have also learned that tackling SARS could be a high-stakes business. Based on experience with a related cat disease, there's worry that a vaccine could make the virus more dangerous instead of preventing the illness. The recent U.S. outbreak of monkey pox in the Midwest, from pet prairie dogs, and the ongoing risks posed by West Nile virus are also stoking concerns about emerging diseases.

New threats aside, the fact that the SARS virus appears to lurk in animals such as the civet cat in China has convinced many scientists that the microbe probably will jump to humans again and again. And the next time SARS comes around, the consequences could be worse. "This is a virus with incredible pandemic potential," declared Dr. Mark R. Denison, a corona virus expert at Vanderbilt University, at a SARS conference at the National Institutes of Health in Bethesda, Md., on May 30. "It scares me."

Even if the disease makes only a mild reappearance next winter, public health officials foresee a possible nightmare. Emergency rooms will fill up with flu sufferers, as usual. But since the early symptoms of flu and SARS are similar, how will doctors and nurses spot the few SARS victims in time to isolate them and prevent an epidemic? "Rapidly identifying people with the disease is key," says Dr. Thomas P. Monath, chief scientific officer at British-American biotech Acambis (ACAM ) PLC. That means there's a big market for SARS diagnostics -- and a race to develop quick and easy tests. One of the first to jump in: Germany's Artus, which has a deal with Abbott Laboratories (ABT ) to sell its test in the U.S. and elsewhere.

Meanwhile, a host of companies, from Merck (MRK ) & Co. to AVI BioPharma (AVII ) Inc., are tapping their own labs for possible SARS treatments. AVI is designing new pieces of RNA -- the genetic material at the virus' core. These bollix up the microbe's machinery. And in tests of more than 200,000 chemicals, government and industry scientists have found drugs that seem to slow the virus down, including interferon and an extract of licorice root.

The best weapon against a virus like SARS would be a vaccine, however. At the very least, drug company execs figure there will be a sizable market in vaccinating health-care workers, who were hit hard in the recent epidemic. That's why many companies are jumping into the fray. "This is going to be a horse race," says Acambis' Monath.

There are already several competing approaches to vaccine development, each with fiercely partisan champions who are quick to criticize other tacks. Typically, vaccines are harmless variants of a microbe or pieces of it. Once in the body, the vaccine prompts the immune system to make antibodies -- roving molecules that recognize and stick to intruders such as viruses and bacteria. Sometimes, the vaccine also triggers an army of killer T-cells. So when the real bug infects a person, the immune system is primed to fight it off.

In a SARS-related cat disease called feline infectious peritonitis, however, vaccines backfire. Yes, they prod the immune system into making antibodies. But when the antibodies attach to the intruder, they make the microbe more potent. How? By enabling it to attack additional types of cells. "If SARS is like feline infectious peritonitis, then we definitely have a problem," says Ralph S. Baric, corona virus geneticist at the University of North Carolina at Chapel Hill. "Every vaccine that was tried failed."

Baric and many others hope that SARS will be different. But that leaves the question: What's the best vaccine strategy? The simplest approach is to grow a vat of the virus, then kill it to make a vaccine. "We can do that in the lab, and we are doing it now," says Fauci. But experts point out that killed corona virus vaccines haven't worked well in related animal diseases, that growing big lots of a deadly microbe like SARS is dangerous, and that viruses that escape being killed could start new epidemics. "It would be a nightmare," says Tony Ford-Hutchinson, Merck's vice-president for basic research. "It's a very naive approach."

A more sophisticated tack is to genetically engineer a weakened version of the live virus. UNC's Baric, for instance, has developed a clever way of recreating the genes of a virus, allowing him to design variations. "We can jimmy the entire genome with the goal of making it less virulent, but very immunologically robust," Baric explains. Live vaccines have proven effective against diseases such as polio and yellow fever. But there's always a risk that weakened viruses could mutate to become deadly again -- or harm people with impaired immune systems.

That's why companies such as Protein Sciences Corp. are banking on a potentially safer method. The small Meriden (Conn.) biotech has a method for rapidly making proteins in insect cells. Now, it's beginning to churn out large quantities of the "spike" protein found on the outer surface of the SARS virus. The protein will soon be tested in animals to see if it stimulates a protective immune response, though there are many skeptics. Viral protein vaccines have worked in hepatitis-B, but in general, they "have not proven as successful as everyone hoped," admits Vice-President and COO Manon M.J. Cox.

There may be a way to combine safety with effectiveness. At Merck, GenVec (GNVC ), Acambis, and other companies, scientists are constructing harmless viruses to be used as delivery vehicles for SARS genes. When these "vectors" are injected, the viral genes stimulate the body's own cells to make viral proteins. In other diseases, this has prompted a stronger immune response than injecting the proteins directly.

One encouraging twist: Normally, vaccines prevent disease. But since SARS typically takes a week to develop rather than a few days, Merck scientists and others hope that a vaccine could also be used after a patient is already infected. If given early enough, it could jump-start the immune system, taming SARS before it causes serious damage.

These efforts could be for naught if SARS is really gone for good. "It's a strange position to be in: deciding to commit to developing a vaccine, while at the same time hoping you never have to use it," says Stephen Albert Johnston, a geneticist at the University of Texas Southwestern Medical Center at Dallas who is working on a vaccine. But the benefits of making the effort go far beyond SARS, experts say, since the lessons learned will help speed responses to future disease threats. As much as we might wish otherwise, SARS is probably coming back. So we'll need the very best weapons we can devise.

By John Carey in Washington

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