As a child, John Wherry enjoyed taking apart machines, including his father's treasured toy train. Now, as an immunologist, he's dismantling perhaps the most intricate machine of all—the human immune system—to develop a vaccine that provides lifelong immunity against influenza. There's no time to waste, given the threat of a global pandemic triggered by mutations in the deadly bird flu virus that have emerged in Asia, Africa and Europe. Wherry and co-workers are racing to create a prototype for the vaccine by 2011.
The drawback of current flu vaccines is evident every fall and winter when people have to line up for a flu shot. Current vaccines typically use killed or inactivated flu viruses to stimulate the immune system to generate antibodies against proteins on the surface of those viruses; the antibodies recognize the virus as an invader and clear it from the bloodstream. But because two or three different influenza virus strains are usually circulating around the world at any time, and because their external proteins evolve rapidly, public-health specialists have to formulate new flu vaccines every year; the antibodies generated by last year's shot won't necessarily neutralize this year's bug. Moreover, the immune systems of elderly people don't always produce sufficient antibodies in response to conventional vaccines; many of the 36,000 influenza deaths in the United States each year are elderly people who had been vaccinated.
Wherry, based at the Wistar Institute in Philadelphia, hopes to overcome those problems with a vaccine made in part from a live virus—a disabled common cold virus with pieces of cloned flu virus inserted into it. In theory, it will stimulate a deep, long-lasting defense called cellular immunity, which involves something called a memory T cell, a kind of white blood cell partially formed in the thymus gland in response to a foreign virus or bacterium. Unlike current vaccines, a T cell reacts to the stable proteins inside an influenza virus as well as to its ever-changing surface proteins. And once a T cell has formed, it perpetuates itself for generations. Unlike antibodies, T cells are capable of destroying cells that have been invaded and colonized by viruses.
"If we can train the T cells to effectively recognize the internal proteins for influenza virus, and be maintained long-term," Wherry says, "it might be possible to create a vaccine that protects against all strains of flu." But designing a vaccine to target memory T cells is a thorny task, and public-health authorities were not much focused on developing new flu vaccines until they faced the bird flu threat and bioterrorism scenarios involving killer influenza viruses. In fact, Wherry and his co-workers' flu vaccine work is backed by a $10 million federal anti-bioterrorism research grant.
Wherry, 36, grew up north of Philadelphia in rural Bucks County, the son of a lawyer and a homemaker. By high school, he knew that he wanted to be a biologist. He became fascinated with immunology at Penn State University and went on to study memory T cells as a graduate student at Thomas Jefferson Medical College in Philadelphia. During a postdoctoral fellowship at Emory University in Atlanta, he helped discover why some memory T cells, after being activated by an infection or vaccination, grow weaker: they sprout a receptor that blocks a signal telling them to fight. Wherry and his colleagues were able to restore the vitality of deactivated memory T cells—in mice—by interfering with that receptor, called "programmed death 1."
Wherry aims to find out if the same findings apply to people. "And if one of these things is operating, it's a potential target for a vaccine or therapy." As he envisions it, a new flu vaccine might contain both a bit of the influenza virus' internal workings, to stimulate memory T cells, and another ingredient to maintain the cells' vigor by undermining PD1. "We're enthusiastic," he says. "We're starting to see promising hints in mice. But translating these things to humans takes a tremendous amount of time and effort."
"My prediction is that in the next five to ten years, John will become a major player in the field," says Rafi Ahmed, an immunologist at Emory who has worked with Wherry.
"Eighty percent of these approaches fall flat," says Wistar's immunology chief, Dr. Hildegund Ertl. "Some people get discouraged by failure. What has impressed me about John is not only that he is a good scientist, he also clearly has the temperament to deal with setbacks."
Arthur Allen, of Washington, D.C., is the author of Vaccine: The Controversial Story of Medicine's Greatest Livesaver.