 . . . Fall 1997
When it comes to research, Hunein Maassab has the bug. The U-M epidemiologist still finds his subject—the influenza virus—as absorbing as when he started studying it some 40 years ago, as a Michigan graduate student.
Maybe it was the allure of being a young scientist in the heady days when vaccine research was really taking off. Maybe it was the challenge of going mano a mano with one of public health’s most persistent foes. Whatever sparked Maassab’s interest years ago has continued to burn inside him.
Licensed by the biopharmaceutical company Aviron, the vaccine should be available to the public in about two years. If that seems like a long wait, consider that it’s been 30 years since Maassab first tackled the problem. As a student of Thomas Francis Jr., founder of the Department of Epidemiology, Maassab had studied the disease-causing properties of the influenza virus. He was intrigued by the scientific puzzle, but also by the opportunity to help humankind through epidemiology, a specialty that applies lab work to public health concerns. And Michigan was the place for a young epidemiologist to be.
"At Michigan, the Department of Epidemiology was the hub, as it still is, of activity in the areas of infectious and chronic disease," Maassab recalls. He was one of the department’s first graduate students, starting his studies just a few years before Jonas Salk announced to the world from the U-M campus that his polio vaccine had been declared safe and effective. Salk and Maassab shared a mentor in Francis.
Vaccines were hot indeed when Maassab was starting his career, and the influenza virus seemed a deserving target. "Influenza has a very strong impact on the population, economically and healthwise," he says. Each winter, some 48 million cases of influenza occur in the United States. Although most of us experience flu as a miserable few days of fever, aches and chills, the illness exacts a larger toll. About 20,000 people die each year from influenza—most of them over age 65. In major epidemics, that number climbs to 40,000 or more.
The worst epidemic in modern times, in 1918, killed 20 million people worldwide, about 500,000 of them in the United States. Even in a more typical year, an estimated $4.6 billion is spent on direct medical costs related to influenza, and the cost of work days lost takes the bill even higher. The National Institute of Allergy and Infectious Diseases estimates that a severe influenza epidemic would cost at least $12 billion in medical costs and lost productivity.
Reason enough for Maassab to want to squash the bug he’d been studying. By the late 1950s, he had received his doctorate and joined the faculty, and his mentor, Francis, suggested he try to develop a "live" vaccine against influenza.
Live vaccines, on the other hand, are made with live viruses that have been weakened, and can elicit an immune response but can’t cause disease. Live vaccines, Maassab explains, generate stronger and longer-lasting immunity than their killed counterparts. They also work well in children, requiring fewer doses than a killed vaccine. Although children usually bounce back from the flu, they often pass the bug to parents or grandparents, who may get much sicker.
Maassab’s first step was to develop an attenuated strain of the influenza virus. One way of doing that is by breeding generations of virus at lower and lower temperatures. For reasons that aren’t completely understood, viruses become less virulent as they adapt to growing at colder temperatures.
Using a cold-adapted virus has an added benefit. The virus can’t live in the lower respiratory tract, where temperatures are warmer, but it does just fine in the cool nasal passages. That makes it ideal for a vaccine administered through a nasal spray. Not only is a nasal spray vaccine less painful than a shot, it provides front-line defense against flu viruses, which often enter the body through the nose.
Maassab spent about nine months developing the cold-adapted influenza virus and testing its effects on ferrets, animals that react similarly to humans when infected with the virus. His ferret work showed that the cold adapted virus could serve as the basis for a live vaccine, but that was only the beginning. Creating flu vaccines is tricky, because the influenza virus, like a master criminal, is constantly altering its identity through changes in proteins on its surface. If the virus being passed around this flu season is different enough from the one that made the rounds last year, your immune system will react too slowly to protect you.
To make matters worse, there are different strains of influenza virus, and being immune to one does not make you immune to the others. Medical experts have ways of predicting which strains will be prevalent in a given year and detecting altered forms of the virus as soon as they arise. Vaccine manufacturers can then tailor each year’s vaccine to the appropriate viruses.
Maassab’s challenge was to find a way of tailoring his vaccine to changes in the virus. He used parts of the attenuated virus, called the master strain, as the core. Each year, the core can be outfitted with a coat of proteins from the virus that’s making people sick. Maassab estimates it will take three to five weeks to update and test the live influenza vaccine each year, compared with three to four months for the killed version.
By the mid-1960s, Maassab had done all the ground work for the new vaccine—developing the harmless, cold-adapted virus and figuring out how to combine it in a vaccine with surface proteins from virulent viruses. Then came years of testing, first on ferrets, then on various groups of patients, to make sure the vaccine was safe and effective. The tests were done at other centers, with funding first from the Army and more recently from the National Institutes of Health and the Aviron company.
Now, with the influenza vaccine well on its way to being commercially available, Maassab has been bitten by another bug. While continuing to collaborate with Aviron on the flu vaccine, he’s also working on a vaccine for respiratory syncytial virus (RSV), which commonly infects infants. RSV usually causes mild, cold-like symptoms, but it can produce severe, even life-threatening illness. Worldwide, it is one of the leading causes of childhood deaths. Maassab hopes the vaccine will be ready for clinical trials within a year.
"Any kind of control or prevention of a disease for humans is a milestone," Maassab says. "When you develop a drug or a vaccine, then you feel like you have conquered the disease, in a sense. Besides the personal gratification, you feel you did something for the betterment of human endeavors."
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MAASSAB'S VACCINE SPRAYS
His single-mindedness paid off recently when clinical trials showed that a vaccine he developed was highly effective in preventing influenza in children. In the trials, only 1 percent of the 1,070 children who received the vaccine developed flu, compared to 18 percent of the children who did not get the vaccine. Best of all—from the kids’ point of view, at least—the new vaccine is administered as a nasal spray, not through a needle, and there are few or no side effects.
The approach made sense. It had been shown in 1941 that a vaccine containing the influenza virus could protect people against the disease. But those early attempts used dead viruses, as does the flu vaccine in use today. These "killed" vaccines contain whole viruses that have been inactivated and can no longer infect anyone.