Influenza: Curbing the Effects of a Possible Epidemic

BY MARK SHWARTZ

WINTER 2003 - The sudden and unexpected emergence of the SARS epidemic in 2003 serves as a stark reminder of how quickly respiratory viral infections can spread. While the SARS virus appears to have been contained for now, the more common influenza virus continues to cause major outbreaks of the disease every year.

Flu infections kill an average of 36,000 Americans annually and cause 114,000 hospitalizations. Very young children are among the most likely to suffer complications from influenza -- from sinus problems and ear infections to bronchitis and pneumonia.

David B. Lewis, M.D. (left), associate professor of immunology, and research associate Wenwei Tu, M.D., Ph.D., use protein molecules, called MCH tetramers, to monitor how B and T cells of the immune system respond to the influenza virus. Their work is part of a five-year anti-terrorism research project funded by the National Institutes of Health.

Although the flu vaccine has helped keep the number of serious cases in check, fundamental questions remain about how the vaccine actually works in children and adults. Now scientists from Packard Hospital and the Stanford School of Medicine are turning to biotechnology for answers. Their insights could lead to the development of new vaccines that will prevent both natural epidemics and artificial outbreaks manufactured by bioterrorists.

"We really don't know as much as we should about human responses to viral infections, or how those responses differ in children and adults," says David B. Lewis, M.D., an associate professor of pediatrics at Stanford.

Lewis and other Stanford researchers are collaborating on an ambitious five-year study designed to help scientists decipher the complex biological reactions that are triggered during an influenza invasion. The Stanford study, which is being directed by Ann Arvin, M.D., and Harry Greenberg, M.D., is one of several anti-terrorism research projects underwritten by the National Institutes of Health (NIH) in 2003.

"Most influenza deaths today occur among the elderly, but children -- especially if they're very young -- are frequently hospitalized," Lewis says. "The virus strain that circulates in a particular year differs from the previous one. This is a process of natural selection in which mutated virus strains that can re-infect people are favored. This explains why kids and adults need to receive a flu shot every season to be protected, and why the composition of the flu vaccine has to be constantly updated."

One of the viruses in circulation today is a descendant of the one that killed approximately 50 million people worldwide during the devastating influenza epidemic of 1918. "Back then, the highest risk of death was in adolescents and young adults, not the elderly, as it is in most years," Lewis says. "We really don't understand why that happened. All we know is that, in subsequent years, the virus changed, and its remnants didn't cause the same deadly outbreaks."

Some experts worry that a clever bioterrorist could re-create the 1918 scenario by developing a highly virulent virus strain and releasing it in a heavily populated area. "So the more we know about how the normal immune response works to control influenza, the better prepared we'll be," Lewis says.

Stanford scientists involved in the NIH study will focus their research on a class of white blood cells, known as B cells and T cells, that help orchestrate the body's immune system reaction; and on natural killer cells, which do not attack the virus directly but instead destroy the body's own infected cells.

About half of the NIH grant has been earmarked for the development of new biotech tools to monitor how these cells respond to an influenza infection. One device, called the tetramer chip, will use protein molecules, called MHC tetramers, to follow individual T cells that recognize influenza. The chip is being developed in the labs of Stanford scientists Mark Davis, Ph.D., and Patrick Brown, M.D.

The study also will compare how children and adults respond to two types of vaccine: the standard flu shot, which is made from dead virus proteins; and a new aerosol inhalant made from live viruses that have a very limited ability to replicate in the respiratory tract. Both vaccines work, says Arvin, chief of infectious diseases at Packard Hospital: "What we don't know is how they work. 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."

The solution to these and other immunological mysteries ultimately will come from new technologies, Lewis says: "We need to start applying these new technologies to pediatric diseases. We have to do it, because the potential for taking on common pathogens that have plagued children for centuries, as well as other difficult-to-treat chronic diseases that are immunologically mediated, is finally on the horizon. Not to seize the day would be a major lost opportunity for advancing children's health."