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Stanford Report, September 24, 2003

Grant will fund study of influenza as agent of bioterror

By MITZI BAKER

Researchers at the medical center received last week a five-year, $15-million grant to study the flu virus and how to guard against it if it were to be unleashed as an agent of bioterrorism.

Stanford is one of five centers to receive funding from the National Institute of Allergy and Infectious Diseases, one of the National Institutes of Health, to study the human immune response to possible agents of bioterrorism. Funding for all centers totals $85 million.

The Stanford team, which spans a number of departments, will focus on how the immune system of adults and children reacts to influenza, the virus that causes the common flu. By understanding how the immune system offers protection against influenza, researchers hope to improve protective vaccines against the virus if it were to be used — perhaps in a modified form with increased infectivity — with the intent of causing widespread illness and death.

Potential agents of bioterrorism include anthrax, smallpox and the plague, but influenza has characteristics that could make it a weapon, said Ann Arvin, MD, the Lucile Salter Packard Professor of Pediatrics and professor microbiology and immunology, who is the principal investigator for the study. Some of its destructive qualities include highly efficient person-to-person transmission, its potential for being aerosolized (which can magnify the area of exposure) and its ability to cause life-threatening, or at least incapacitating, illness.

"Influenza is one of the only pathogens that knows how to cause significant disease, year in and year out in all age groups of the population," said study co-director Harry Greenberg, MD, the Joseph D. Grant Professor and professor of microbiology and immunology. He said it has a highly efficient mechanism of mutating that allows it to re-infect people and cause severe acute respiratory illness, especially in children and the elderly.

"Three times in the last century, it has played a particularly nasty trick and changed into a virus to which no one had immunity and caused a worldwide pandemic that killed millions," Greenberg said. "No one knows how to reproduce a pandemic, but we are close to knowing how to reproduce the sequence of the virus that caused the 1919 pandemic."

While influenza vaccines already exist, the way in which the vaccines protect the respiratory tract in humans is poorly understood. The objective of the flu study is to use the immunity that develops following vaccination as a model for in-depth analysis of immune response in the respiratory tract, said Arvin, who is also chief of infectious diseases at Packard Children’s Hospital.

An attenuated flu vaccine — created from live virus that has been weakened so that it is no longer infectious — has been approved this year for widespread use. The researchers will compare the attenuated vaccine, which is inhaled, to an injected vaccine containing a killed virus to observe differences between the two routes of administration. "We are studying two vaccines that we know work; these vaccines are licensed vaccines," Arvin said. "What we don’t know is how they work and what are the fundamental mechanisms.

"The idea is that if we understand the components of a really effective immune response to flu that protects the individual, then we can understand how to construct a better vaccine," Arvin said. "We know that the flu virus mutates every year and that’s how it can cause new infections. If we could understand how to provide immunity against proteins of the virus that don’t tend to mutate, it would be possible to think about a different vaccine design."

Another improvement could be the speed with which it works, she said. In a pandemic, an effective preventive measure would need to work within days, whereas current vaccines take weeks.

In addition, any discoveries the researchers make about influenza will help in understanding how the human immune system reacts to other pathogens. Many potential bioterrorism organisms, such as anthrax, could be disseminated via the respiratory system, said Greenberg, so it is crucial to understand how respiratory tract-specific immunity develops in humans. "We know a lot about what happens in animals, but it is not easy to give pathogens to people," he said. "We are optimistic that this will provide us with a unique opportunity to study the immune response generated following respiratory tract immunization."

In addition to Arvin and Greenberg, Stanford investigators involved as project leaders are Eugene Butcher, MD, professor of pathology; Mark Davis, PhD, professor of immunology and a Howard Hughes Medical Institute investigator; Cornelia Dekker, MD, associate professor of pediatrics; David Lewis, MD, associate professor of pediatrics; Elizabeth Mellins, MD, associate professor of pediatrics; and Peter Parham, PhD, professor of structural biology and of microbiology and immunology.

Other co-investigators are Daniel Bloch, PhD, associate professor of health research and policy; Patrick Brown, MD, PhD, professor of biochemistry; Yueh-hsiu Chien, PhD, professor of microbiology and immunology; Stanley Falkow, PhD, professor of microbiology and immunology; Xiaosong He, PhD, senior research scientist in the division of gastroenterology and hepatology; Garry Nolan, PhD, associate professor of microbiology and immunology; David Relman, MD, associate professor of medicine (infectious diseases and geographic medicine) and of microbiology and immunology; and Lawrence Steinman, MD, professor of neurology and neurological sciences.





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