Scientists Look to Vaccines in the War on E. Coli

Shousun C. Szu, a scientist at the National Institutes of Health, says the best way to prevent people from being poisoned by deadly E. coli would be to vaccinate all infants against the bacteria. Graeme McRae, a Canadian biotechnology executive, says it would be more practical to inoculate cows instead. Vaccines for people and for cattle are just two approaches under development to prevent or treat food poisoning by the strain E. coli O157:H7. Right now, scientists can do little medically to fight the pathogen, which was responsible for two severe outbreaks last fall, one from contaminated bagged spinach and a second from tainted lettuce served in chain taco restaurants. The main approach has been to try to prevent contamination through careful handling, rigorous inspections and government regulation. Slaughterhouses have already sharply reduced contamination through practices like washing carcasses with hot water, steam or acids. Now the focus is on new procedures and regulations for the fresh-produce industry. Some researchers say medical approaches could eventually supplement food-processing measures. To pave the way, an advisory committee of the Food and Drug Administration met on April 12 to discuss how to run clinical trials of drugs to treat E. coli infections. On the animal side, a vaccine for cattle developed by Mr. McRae’s company, Bioniche Life Sciences, was approved in December for distribution to veterinarians in Canada. Studies have shown that the vaccine can reduce but not eliminate the E. coli shed into manure. Not only does that make the cows cleaner as they go into the slaughterhouse, but it could also conceivably reduce the risk that the germ will spread from a feedlot to a nearby produce field though water or wild animals. Cows and their manure are considered the major sources of the pathogen. “If we can reduce the likelihood that animals are going to carry the bacteria, then we might reduce over time what they put out into the environment,” said Guy Loneragan, a veterinary epidemiologist at West Texas A&M University, who has received financing from the beef industry. Other methods being tested include cattle antibiotics, an industrial chemical, bacterial-killing viruses and friendly bacteria to displace the evil ones. One big potential barrier is that ranchers and feedlots may have little incentive to pay for such treatments, because they do not make the cows grow faster. Nor do they keep the cows healthy, because O157 does not sicken the cows that harbor it. “The cattle industry is within pennies of making a profit or not,” said Carolyn Hovde Bohach, a professor of microbiology at the University of Idaho who is working on a different E. coli vaccine for cattle. “Would it be their responsibility to protect vegetables?” Efforts to develop drugs and vaccines for people also face barriers. Because outbreaks are rare and sporadic, for instance, it would be difficult to test such treatments in clinical trials. It might be hard to diagnose the infection in time to intervene medically. And any treatment would have to be very safe, because it would be given to children and because most people improve without any intervention. E. coli O157:H7 causes 75,000 cases of infection and 61 deaths in the United States each year, according to a 1999 estimate by the Centers for Disease Control and Prevention posted on its Web site. The actual number of confirmed cases has dropped since then, particularly in 2003 and 2004, but increased in 2005 and 2006, in part because of the outbreaks tied to spinach and lettuce. As few as 10 bacteria can make someone ill. The bacteria release one or two potent toxins that cause bloody diarrhea. In 15 percent of children younger than 10, and more rarely for adults, the infection causes hemolytic uremic syndrome, in which red blood cells are destroyed and the kidneys fail. In a small percentage of such cases, the syndrome proves fatal. Dr. Phillip I. Tarr, an expert at Washington University in St. Louis, says treatment is difficult because the bloody diarrhea that signals infection may not occur until three to four days after ingestion of the bacteria. By then, a patient could be well on the way to kidney failure. Antibiotics, the usual treatment for bacterial infection, only make things worse by killing the bacteria and releasing more of their toxin, Dr. Tarr said. He added that the sole treatment shown to reduce the severity of kidney problems was intravenous fluids. Other scientists are trying. Thallion Pharmaceuticals of Montreal and Teijin Pharma of Japan have separately developed monoclonal antibodies that can latch on to the toxin molecules and neutralize them. Monoclonal antibodies, a synthetic version of the body’s own infection fighters, are commonly used to treat cancer and other diseases. Thallion and Teijin have shown that the antibodies can protect laboratory animals from lethal doses and have conducted preliminary safety testing in people. But at the recent F.D.A. advisory committee meeting, both said it would be prohibitively expensive to test whether their drugs could prevent hemolytic uremic syndrome. Some outside scientists question whether a treatment that starts after the toxin is already in the bloodstream would be effective. Dr. Szu of the health institutes said a better approach would be to vaccinate people so their immune systems could dispense with the bacteria before they had a chance to multiply and release their toxin in the bloodstream. She and colleagues have developed a vaccine made of the complex sugar that is on the surface of the bacteria, the very O-type polysaccharide that gives O157 its name. The sugar is linked to a protein taken from another bacterium to make it more potent in stimulating the immune system. Dr. Szu and collaborators have tested the vaccine on adult volunteers and on children 2 to 5. The volunteers were not exposed to O157 — that would be unethical — but they developed antibodies to it. Moreover, when the bacteria were exposed in the laboratory to blood samples from vaccinated people, the microbes were killed. Dr. Szu said the next test would be in infants. The vaccine is years from the market. As with drugs, testing effectiveness would be difficult, and some experts say it may not make sense to vaccinate every child to protect a small number. “A lot of the economics of it would not be very favorable,” said James B. Kaper, an expert on O157 at the Center for Vaccine Development at the University of Maryland. Dr. Szu disagreed, saying, “All human lives are precious, especially if you talk to parents who lost their children.” The cattle vaccine developed by Bioniche is based on the work of B. Brett Finlay of the University of British Columbia, who helped discover how O157 bacteria attach themselves to the cattle intestines, where they can then multiply. The bacteria use a type of microscopic syringe to shoot proteins into the cells lining the intestine, and the cells erect a protein pedestal, to which the bacteria can bind. The Bioniche vaccine consists of proteins involved in the attachment. The idea is that the cow’s immune system would make antibodies to attack the proteins, thereby blocking the attachment. The bacteria could still pass through the cow and into manure. But if they could not colonize, their levels should remain low. Tests at the University of Nebraska found that the vaccine reduced by 70 percent the number of cows shedding O157 into their manure, said Rodney A. Moxley, a professor of veterinary science there. Mr. McRae, president of Bioniche in Belleville, Ontario, said the company would begin to distribute the vaccine in Canada in June or July after it increases manufacturing capacity. The approval there is conditional, and the company has to provide more data showing that the vaccine works. Mr. McRae said he hoped to obtain approval to sell the vaccine in the United States from the Agriculture Department this year. He said feedlots would be charged no more than $2.20 a dose, with two doses needed. Randall D. Huffman, vice president for scientific affairs at the American Meat Institute, which represents beef processors, said that the cost was “not trivial” and that the vaccine “might not be right for everyone,” because it was not 100 percent effective. Still, Mr. Huffman said, “If there is technology that is proven effective and is reasonable in cost, I think you’ll see it adopted.” His organization and the National Cattlemen’s Beef Association helped pay for the research on the vaccine and other approaches to reducing the shedding of O157. One approach already in use is probiotics, the idea that friendly bacteria fed to cattle will displace O157. The Nutrition Physiology Corporation of Guymon, Okla., sells a feed additive with lactobacillus, the same type of bacterium used in yogurt. The additive is sold to aid cattle digestion, but some studies suggest that it also reduces O157 in manure. An experimental approach is to feed cows sodium chlorate, a chemical used in the pulp and paper industry. This idea takes advantage of the fact that O157 has an enzyme that allows it to survive without oxygen, which is not true for most desirable bacteria. That enzyme will convert sodium chlorate to sodium chlorite, which poisons the pathogen. “It’s like a suicide pill to the E. coli,” said Robin C. Anderson, a microbiologist for the Agriculture Department in College Station, Tex. Dr. Anderson said the treatment did not harm the cow. Eka Chemicals, which makes sodium chlorate for the paper industry, is working to obtain regulatory approval for a cattle treatment. The antibiotic neomycin has also been shown to reduce O157 levels in manure. Using antibiotics in animals raises concerns of spurring development of human pathogens resistant to the medicines. Another approach being studied involves phages, viruses that infect and kill bacteria. Experts say multiple approaches might be used in parallel, because no single approach works perfectly. Michael T. Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, said he was skeptical about all the approaches. “What really is a concern to me about this issue is we always have a tendency to want high-tech responses to what in many cases are common-sense low-tech solutions,” Dr. Osterholm said. He is a consultant to Fresh Express, the leading seller of bagged salads, and is head of a committee that will disburse $2 million from the company for research on how the produce industry should handle E. coli. He said stringent safety procedures had kept that company from having any contamination incidents. In any case, even if a high-tech solution was desired, there does not seem to be a vaccine for spinach as there is for cattle. Greens are now often rinsed in chlorine solution, but that is not always effective because surface nooks and crannies can shelter the bacteria, said James Gorney, senior vice president for food safety and technology at the United Fresh Produce Association, a trade group. A possible alternative is to use a gas like chlorine dioxide instead of a liquid wash, Dr. Gorney said. Irradiation can also kill the bacteria. But he said the amount of radiation needed could damage fruits or vegetables. And some consumers object to the technique. “Any one of these technologies doesn’t offer us a pasteurization step,” Dr. Gorney said. “So we are left with prevention, prevention and prevention, preventing the contamination from ever occurring.”