Maassab

FluMist: Laboratory Dreams

by Deborah Gilbert

As a breed, young bench scientists are patient, analytical, and meticulous. They present cool, thoughtful faces to the world.

But under their white lab coats, many harbor romantic, idealistic hopes. They believe that with luck, perseverance, and often, a little help from their friends at the National Institutes of Health, they will achieve a breakthrough, a medical holy grail, that could change the world for the better. In the meantime, little wins along the way nurture their hopes and keep them at their microscopes.

University of Michigan epidemiologist Hunein “John” Maassab, 76, could not possibly have foreseen, however, in 1956—when, as a newly minted PhD, he entered the virology laboratory of the renowned Thomas Francis Jr.— that his own triumph, now dubbed FluMist, would take nearly 50 years to complete.

FluMist

Last winter, on December 12, 2002, the United States Food and Drug Administration Advisory Committee on Vaccines and Related Biological Products announced that Maassab’s innovative, trivalent, cold adapted influenza vaccine, FluMist, which uses live but weakened viruses and is delivered in a nasal spray, was “safe and effective for healthy people aged 5 to 49.” After decades of basic research and clinical trials, the years of dedication were finally paying off.

Dedication, tenacity, and perseverance are traits that pop up whenever colleagues discuss Maassab’s work. School of Public Health Dean Noreen Clark describes Maassab as part of “a proud tradition of vaccinology at Michigan. His work is characterized by creativity, innovation and a tenacious interest in bringing to fruition influenza prevention.”

Fawwaz T. Ulaby, UM vice president for research, expresses similaradmiration. “I’m impressed by the dedication and perseverance of Professor Maassab,” he says, remarking on “the long years of research required to bring his unique vision of a flu
vaccine to this point.”

Maassab, however, is matter-of-fact about his tenacity. “I focused on this goal for so long because we had many successes along the way. The work was challenging.”

The Power of a Suggestion

Maassab’s pursuit of a live-virus flu vaccine (as opposed to the traditional “killed virus” vaccine) began in 1956 after he completed his dissertation on influenza. This bold scientific mission was first suggested by his mentor, Thomas Francis Jr., founder
and first chair of the UM Department of Epidemiology, who during World War II had led the U.S. Army’s flu vaccine program. Francis is credited with isolating the Type A and Type B viruses and developing the first killed-virus influenza vaccine for U.S. troops.

Word of Francis’s enormous success transformed the School of Public Health into a “mecca” for public heath physicians and virologists, according to Maassab. Scientists worldwide petitioned to spend a year or two in Francis’s lab. Indeed, Jonas Salk, developer of the Salk polio vaccine, trained for six years with Francis.

However, despite the success of Francis’s vaccine, “the killed-virus vaccine was not completely effective,” Maassab explains. “Some people who got the killed virus vaccine were not protected. They got the flu.”

Hence the suggestion that Maassab try to develop a vaccine using live viruses. The expectation was that an attenuated, live-virus vaccine, which could elicit an immune response in the nasal epithelium but wouldn’t cause the disease, might be more potent and reliable than the killed-virus vaccine.

Pandemics Fell Millions

Maassab’s pursuit of the live-virus vaccine was also inspired by epidemiological history. The first 20th-century influenza pandemic occurred in 1918, just eight years before Maassab was born in Damascus, Syria. Dubbed the Spanish Flu, it was a catastrophe that felled 20 to 40 percent of the world’s population and left 20 million dead. About 500,000 Americans died in the pandemic. Unusually and inexplicably, that swine flu epidemic wiped out thousands of working-age adults. “In fact more U.S. troops died from the disease than perished in World War I,” Maassab notes.

Thus Maassab came into a worldwhere influenza was not “just the flu.” It was a virulent and fearful disease.

The century’s second pandemic, the Asian Flu, hit in 1957 when Maassab was a burgeoning research scientist. And the third, the Hong Kong Flu, swept the world in 1968. That epidemic infected 50 million Americans and killed 70,000.

Maassab also was encouraged by the dramatic announcement of the success of the Salk polio vaccine in 1955. The national field trials of Jonas Salk’s killed-virus polio vaccine, which included nearly 1.8 million U.S. children in a massive double-blind
study, was headquartered at UM and orchestrated by Prof. Thomas Francis Jr.

As a graduate student research assistant in 1955, Maassab had recorded some data from the polio vaccine trials, and he was in the audience in Rackham Auditorium, along with 500 scientists from all around the world and 150 frenzied reporters, when Francis announced that the vaccine worked. It was a thrill for everyone there, especially for the younger scientists in the room who were embarking on their careers.

Isolating the Enemy

Maassab’s first challenge was to isolate an influenza virus that he could culture successfully, which he ultimately named the Type A–Ann Arbor virus. That was accomplished in 1960. Then he used that virus to develop an attenuated strain of the
original. Genetic engineering wasn’t even a glimmer on the scientific horizon in the 1960s, so Maassab turned to Charles Darwin’s tried and true “technology,” patiently breeding gen-dishes at successively cooler and cooler temperatures.

Why the cooler temperatures? First, the attenuated, cold-adapted virus does not replicate well in the warmer temperatures of the lower respiratory tract, so it does not set off a full-blown case of the flu.

On the other hand, the attenuated virus does replicate well in the cooler nasal passages—the entry points for our respiratory tracts. Once sprayed inside the nose, the attenuated virus triggers the growth of protective antibodies in the mucus membranes, establishing a first line of defense against the flu virus, which, Maassab notes, “is an airborne pathogen.” Equally important, since the protection is established in the nasal passages, people are much less likely to spread the flu when they sneeze or cough.

Responding to the Virus’s Disguises

Maassab developed the weakened, cold-adapted viruses by 1967, and that year he published a paper in the distinguished journal Nature, which described the adaptation of an influenza virus for growth at low temperatures. The next step was a greater
challenge. The influenza virus is constantly altering its identity by changing the proteins on its exterior coat—in effect, shifting its disguise so the body’s immune system doesn’t immediately recognize that it’s under attack by the flu again. Maassab’s challenge was to develop a vaccine that could be adapted quickly to these shifting disguises.

His solution was to use parts of the attenuated virus as the permanent core of the vaccine—the master strain or donor strain—which could then be “retrofitted” with a new coat of proteins each year that matched those in the current year’s strains. This step was accomplished in the 1970s, with the support of the National Institutes of Health.

But Would It Work?

“At the end of the 1970s and beginning of the 1980s, the National Institutes of Health funded clinical trials to test the efficacy and safety of the new vaccine,” Maassab remembers. “During this time, NIH also tested to make sure that the genetic
characteristics of the virus did not change in people receiving the live virus vaccine. They also confirmed that a person receiving this live-virus vaccine could not transmit the virus to other people.”

In 1984, Maassab’s research got a massive boost when the NIH awarded him a five-year, $2 million grant to continue his work on the vaccine. Dr. Brian Murphy, a research scientist at the National Institute of Allergy and Infectious Diseases, collaborated
with Maassab from 1975 to 1993. Over the years, using Maassab’s master strain, the two of them made 40 to 50 different cold-adapted viruses, worked out how to use the influenza A and B donor viruses, and determined the genetic basis of attenuation in the A virus.

“John’s cold-adapted virus was an excellent virus. Excellent in that it always provided a satisfactory balance between attenuation and an ability to induce an immune response,” Murphy explains. “It was extremely consistent.”

Murphy remembers their collaboration fondly. “John was one of nicest men I have ever worked with. He was always helpful, enthusiastic and never political. He realized early on that we were working on a long-term problem but his character—his dedication—supported this kind of work. He did his share of the work, on time. And he always got along well with a wide variety of individuals.” In short, every scientist’s dream of a collaborator.

Coming to Market

A whole new chapter in the saga of Maassab’s live-virus vaccine began with the process of obtaining Food and Drug Administration approval and bringing the vaccine, now to be developed in a nasal spray, to market. The nasal spray would be a special
boon to children—the most frequent carriers of the flu—who hate shots.

To begin with, the University of Michigan licensed worldwide rights to develop the vaccine to Wyeth-Ayerst Laboratories in 1991. At that point, Maassab became an interested advisor, watching as the government and the biotechnology industry began
efforts to bring his innovative vaccine into the real world.

That same year, 1991, Wyeth-Ayerst and the National Institute of Allergy and Infectious Diseases signed a cooperative agreement to further develop the vaccine. By 1995, the agreement with Wyeth-Ayerst had been terminated. The UM then licensed the master strain and vaccine development rights to Aviron, a small biotechnology company in Mountain View, California.

In 1995, Aviron was awarded a cooperative research and development award from NIH to continue clinical development of Maassab’s vaccine through Phase III clinical trials. By this time the vaccine had been tested in more than 7,000 people spanning a broad age range.

In 1996, a small clinical trial conducted at the University of Rochester School of Medicine demonstrated the efficacy of the vaccine, which provided 85 percent protection from the flu compared to just 71 percent offered by the traditional killed-virus vaccine.

Then in 1997, NAID and Aviron announced in the New England Journal of Medicine that, in a study of 1,602 children at ten sites across the nation, the live, attenuated-virus vaccine provided 93 percent protection against influenza and an unexpected
98 percent protection against ear infections. Very impressive statistics, indeed.

In 1998, Aviron filed a product license application for “FluMist” with the Food and Drug Administration. Two years later, NAID reported in the February 2000 issue of the Journal of Pediatrics that, in an unexpected twist, after a 1997–1998 study of more than 1,300 children, researchers discovered that although the trivalent vaccine had not been designed to protect against the unexpected A/Sydney virus that turned up, the vaccine was 85 percent effective against that particular virus as well.

In July 2001, the FDA’s Vaccines and Related Biological Products Advisory Committee conducted two days of hearings on the vaccines and concluded that the vaccine was effective but asked for more information about its safety in children. MedImmune, a large biopharmaceutical company, purchased Aviron in January 2002.

“FluMist is a great example of how a small set of people—hard-working, creative, persistent and bold-thinking people—bridged a public-private collaboration to work toward bringing a valuable technology into the marketplace to improve our quality of life,” says Kenneth J. Nisbet, director of UM Technology Transfer.

In December 2002, the FDA advisory committee reported that the vaccine was safe and effective for healthy people ages 5 to 49, although they are still considering its safety in very young children. Maassab’s mission is almost accomplished, and the
public health holy grail—a medical breakthrough—is nearly in reach. Stay tuned.

This story appeared in the U-M School of Public Health's Findings magazine in Spring 2003. Maassab died in 2014.

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