Study of Bird Flu Vaccine Indicates Long Road Ahead; But Human Tests Are Important First Step

By JOHN FAUBER, KAWANZA NEWSON and SUSANNE RUST

Results from the first rigorous clinical trial of the bird flu vaccine for humans suggest that existing manufacturing methods could not produce enough vaccine to protect most Americans.

Doctors say the trial of the H5N1 flu vaccine is a first step in preparing the country for a devastating pandemic that could kill as many as 2 million Americans, but it also reveals how vulnerable the nation is, at least in the near future.

“Basically, it’s back to the drawing board,” said Gregory Poland, a professor of medicine and infectious disease at the Mayo Clinic College of Medicine in Rochester, Minn. “We’ve been puttering around since 1997 (when the first H5N1 human cases emerged) and there still is not a viable (vaccine) candidate.”

The study, reported today in the New England Journal of Medicine, also underscores the need for vaccines that can provide broad immunity to multiple strains of flu. Researchers hope that such a vaccination could be taken once, or every 10 years, providing resistance to not only seasonal flus, but possible pandemic flus as well.

Several groups are developing such “universal flu vaccines,” said Gary Nabel, director of the Vaccine Research Center at the National Institute of Allergy and Infectious Disease, a branch of the National Institutes of Health. None of these would be on the market for at least five years, he said.

A universal vaccine is just one goal in what has become a frantic field of research, slapped out of its slumber by an injection of billions of dollars in federal funding.

Scientists and drug companies also are looking at new ways of making vaccines, including producing them in dog kidney cells, or using DNA vaccines. These methods, theoretically, could produce larger amounts of vaccine quicker than the old-fashioned method of making vaccine in chicken eggs.

Earlier this month, Gov. Jim Doyle announced the establishment of a $9 million Institute for Influenza Viral Research in Madison. The site, which will be built in existing space at the University Research Park, will serve as a national hub for genetic research studies on influenza viruses and provide critical information needed to fight the deadly strain of bird flu that’s circulating globally.

Because pandemics strike roughly three times every 100 years, and the last one occurred in 1968, some infectious disease experts say we are in a race against the clock.

As many as 30 H5N1 vaccine trials are going on now, said Poland, who also wrote an editorial accompanying the study.

Despite the effort, it will likely be a few years before enough of any vaccine can be produced to protect the U.S. population from a pandemic, he said.

An important wake-up call’

However, Anthony Fauci, director of the National Institute of Allergy and Infectious Disease, said the vaccine trial was important because it was the first properly tested human vaccine against the H5N1 virus, which has been infecting bird populations around the world.

“What this paper shows is you can make a vaccine against bird flu,” said Fauci, whose institute funded the study. “It also points out a lot of weaknesses in the system. It’s an important wake-up call.”

Yoshihiro Kawaoka, a world-renowned flu expert at the University of Wisconsin-Madison, said the study provided researchers with a baseline upon which to compare future trials.

“This vaccine was produced the same way the annual, seasonal flu vaccines are produced,” he said.

If they had manufactured the vaccine in a different way, or introduced elements that made it more potent, it wouldn’t have provided the baseline researchers need to make comparisons.

Since 2003, more than 100 people worldwide about half of those who developed symptoms have died from H5N1. Most of these people have had close contact with infected poultry. The disease has not been able to jump easily between people.

Large doses appear effective

The study reported today involved 451 healthy adults who received two shots of an H5N1 influenza vaccine in the arm, one month apart. The killed virus used in the vaccine was isolated from a patient in Vietnam who was infected by a chicken.

Among those given the highest dose of vaccine two 90-microgram injections 54% developed an antibody level that most likely would be protective against the virus, compared with 22% of people who received two 15-microgram shots.

The typical seasonal flu vaccine is one shot designed to protect against three different circulating flu strains, using 15 micrograms of each virus strain. Such shots normally provide protection in 70% to 90% of those vaccinated, doctors said.

The big problem in producing the H5N1 vaccine for mass inoculations is that demand would far outstrip the world’s vaccine production capacity.

With the double 90-microgram dose used in the trial, about 37 million courses of the vaccine could be produced with existing capacity, Poland said.

“Even at that, only half the people would have protective levels of antibodies,” he said.

One hope is that by adding substances known as adjuvants that enhance the immune reaction to the vaccine, the dosage of vaccine needed can be substantially reduced.

Adjuvants such as aluminum and a derivative of cholesterol are being tested.

If adjuvants can enhance the immune response by a factor of only two, they won’t be of much help, said Fauci. But if they provide tenfold improvement, “then you’re in good shape,” he said.

Lead author John Treanor said the trial’s results don’t necessarily mean that the people who didn’t receive the highest dose weren’t protected, too.

“Protection” was an arbitrary designation based on what is known about antibody levels with seasonal flu, he said.

“These are all things that will be hard to know until we learn more about the disease,” he said.

A different strategy

One strategy to boost response, though highly debated, would be to begin adding some of the circulating strain of H5N1 into the seasonal vaccine to familiarize the immune system to the virus and hopefully enhance the response to any variant that might appear in the future, said Kelly Henrickson, a professor of pediatrics and infectious disease expert at the Medical College of Wisconsin.

“As we learn from studies, say maybe elderly need more or children need less, we would just adjust doses accordingly,” he said.

In the last year, there has been a lot of attention paid to bird flu, Henrickson said.

“Did I wish it had happened a decade ago? Sure,” he said. “But that doesn’t take away from the good response now.”

Despite the caution Fauci and others expressed, William Schaffner a flu expert and head of the preventive medicine department at Vanderbilt University Medical Center in Nashville, Tenn., who was not involved in the study said we should look at the study with a “glass half-full, not half-empty,” attitude.

“This is the first bird flu vaccine to be tried in the first human trial. So, this is a biggie,” he said. It shows that the vaccine was safe even at extremely high doses and that there were no more reactions to this vaccine than to the seasonal human flu vaccine some people receive every year.

“This is the first step in developing something that will give us better and better bird flu vaccines,” he said.

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