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Avian Flu Vaccine Falls Short in Trial

Times Staff Writers

Setting back plans to shield the nation from a potential bird flu pandemic, the first study of a human vaccine showed that even a massive dose failed to protect nearly half of those inoculated, according to a study released today.

The vaccine for the avian flu strain known as H5N1 was far less effective than the standard seasonal flu vaccine, which protects 70% to 90% of the people who get the shot, according to the study in the New England Journal of Medicine.

The experimental bird flu vaccine required 12 times the dose of the seasonal inoculation. That in effect would cut down the nation’s stockpile of the vaccine, purchased for about $160 million, to approximately 4 million courses -- enough to inoculate only some healthcare and vaccine workers.

The current pandemic flu plan, issued by the U.S. Department of Health and Human Services in November, calls for enough vaccine for 20 million people, though it does not set a timetable for acquiring the shots.

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“It’s disappointing in that it takes so much,” said Robert Webster, a virologist at St. Jude Children’s Research Hospital in Memphis, Tenn., who has been studying this particular strain of bird flu since it emerged in 1997. “We have to ... find ways to do better, to get more bang for the buck.”

Dr. Anthony Fauci, who heads the National Institute of Allergy and Infectious Diseases, acknowledged that the current vaccine “cannot be the answer to where we want to be.” He said, however, that the study did demonstrate that the vaccine was partially effective and safe to use.

“It’s a bit of muted good news in that we’re going in the right direction, but the sobering news is we have a long way to go,” he said.

Developing a human vaccine for bird flu has been the cornerstone of the nation’s efforts to deal with a potential pandemic.

The virus, which originated in Asia, rarely infects people, but scientists fear a mutation could make it more easily transmissible, sparking a pandemic.

Since 2003, the World Health Organization has recorded only 186 human cases. But H5N1 is clearly lethal: 105 of those people died.

In the last two months, the virus has been detected in birds in Europe, Africa and the Middle East.

Experts believe it could arrive in North America as early as this summer, carried by migrating birds into Alaska or northeastern Canada.

The Department of Health and Human Services has funded studies of more than 30 candidate vaccines. Results from some of these studies are expected to appear in the next six to 12 months.

The study reported today, which was funded by the National Institute of Allergy and Infectious Diseases, involved 451 healthy adults who were injected with vaccine made by French drug maker Sanofi Pasteur.

The patients received either placebos or dosages that ranged from 15 to 180 micrograms, split into two injections given 28 days apart. The standard dose for seasonal vaccine is 15 micrograms for each of three flu strains.

The researchers could not expose any of the subjects to the disease, so they later tested antibody response to gauge the effectiveness of the vaccine.

Two separate tests found that 54% and 58% of the people who received the highest dose had the same level of protection provided by a seasonal flu shot.

But the remaining subjects who got the highest dose -- 46% and 42% in the two tests -- fell below that level, meaning that they failed to reach the standard of protection.

Of those given lower doses, fewer than half were protected from the virus.

“We certainly hoped it would be better,” said lead author Dr. John J. Treanor of the University of Rochester in New York.

But he said that even people who were not fully protected might have enough immunity to reduce the severity of the illness.

Sanofi spokesman Len Lavenda acknowledged that the results were disappointing.

“We’re not satisfied with the level of protection, and we’re working diligently to improve the immune response,” he said.

Nonetheless, Sanofi is in discussions with the Food and Drug Administration about obtaining approval of its vaccine, Lavenda said.

The high doses needed cause serious problems for the nation’s pandemic planning.

Dr. Wendy Keitel, an infectious disease specialist at Baylor College of Medicine in Houston who is leading a trial of another Sanofi vaccine, said requiring two shots was impractical.

“Two high doses are quite problematic if you think about vaccinating people in a pandemic,” she said.

The massive doses also would strain the world’s manufacturing capacity, which at best can make bird flu vaccine for only 75 million people each year.

That is “really a no-go,” said Ripley Ballou, a research vice president at GlaxoSmithKline, which is also developing a vaccine. “It is just not even conceivable that all the manufacturers in the world could produce” enough to meet the demand in case of a pandemic.

The Sanofi vaccine is made in the traditional manner, using an altered virus grown in chicken eggs -- a process considered slow and inefficient.

“This is slide-rule technology,” said Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota. “We need to be dealing with a modern vaccine.”

British-based Glaxo and Sanofi have announced plans to build or expand factories, which could add hundreds of millions of doses of the pandemic flu vaccine to the global supply. But the added capacity won’t be available for several years.

To stretch the supply, researchers are experimenting with the use of a drug additive, known as an adjuvant, that could boost the effectiveness of the vaccine. The adjuvant works by making the vaccine more easily perceptible by the immune system.

The concept isn’t new. Childhood vaccines against tetanus and bacterial meningitis contain adjuvants. Most trials of adjuvants use alum, a mixture of aluminum salts.

Emeryville, Calif.-based Chiron Corp., which has also made millions of H5N1 doses for the U.S. stockpile, is testing an adjuvant derived from shark oil that it now uses in seasonal flu shots in Europe. The adjuvant isn’t approved for use in the U.S.

Glaxo will announce plans today to launch clinical trials using different adjuvants with experimental avian flu vaccine.

Sanofi has already tested a bird flu vaccine with an adjuvant that produced a “good immune response” and would meet European standards for licensing seasonal flu vaccines, Lavenda said.


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