Out of obscurity step our best hope for bird-flu vaccine

Out of obscurity step our best hope for bird-flu vaccine
Sunday, August 13, 2006
BY KITTA MacPHERSON AND ED SILVERMAN
Star-Ledger Staff

For years, the world's vaccine companies have labored in the shadows of the pharmaceutical industry, vilified by parent groups who claim childhood vaccines can cause neurological disorders like autism.

Now, almost overnight, these same companies have been thrust to the forefront of a massive campaign to produce a vaccine against pandemic flu. Not since Jonas Salk's work to find a cure for polio in the 1950s have vaccine scientists been so squarely in the vanguard of medicine.

The challenges are vast. The unanswered questions surrounding the influenza virus are profoundly difficult, the process for producing vaccines is slow and unwieldy, and the infrastructure needed to make major advances quickly has suffered from decades of neglect.

"I can't emphasize enough how daunting the task is to go about creating the industrial infrastructure to make hundreds of millions of doses in periods of months using technology that is on the drawing board," said Bruce Innis, vice president of clinical research and development for GlaxoSmithKline Biologicals in North Carolina.

But with avian flu spreading through flocks in Asia, Europe and Africa, raising the specter of a global pandemic, it's no longer a matter of choice.

The race is on.

INSUFFICIENT STOCKPILES
The influenza virus is one of nature's most talented chameleons. Its genetic matter allows for a constant reshuffling of genes.

This process, known as antigenic drift, alters the shape of its surface proteins in a way that can fool antibodies generated by the body to seek and destroy older versions of the flu virus.

Flu also is what scientists describe as a "superspreader." Its animal and human carriers are highly infectious before they even realize they are ill.

The bird flu virus known as H5N1 is a particularly lethal variant. Beyond wiping out millions of chickens and other birds, the virus has killed more than 130 people around the globe. Humans have no natural immunity.

The pathogen has not yet mutated to allow easy transmission between people, but government and industry scientists agree that society's defense system against such a threat is inadequate.

For starters, there is no surefire vaccine against the H5N1 virus. Even if there were, the ability to produce it quickly on a large scale is limited.

Officials at the federal Centers for Disease Control and Prevention have stockpiled new batches of H5N1 vaccine in an undisclosed location for safekeeping. But there is evidence the bird flu virus in circulation has mutated enough so that the vaccine supply may no longer provide protection, according to many scientists.

"We need a better vaccine -- clearly, one that works against multiple strains," said Anthony Fauci, director of the National Institute of Allergy and Infectious Disease. The agency, lead actor in the federal government's vaccine effort, funds research into bioterrorism countermeasures and treatments for diseases such as flu, AIDS and immune disorders.

The existing vaccine stockpile is also much too small to protect the general population. Of the 4 million doses available, one-third would be given to the military and the rest would be severely rationed.

"No matter how you slice that one, we don't have a large enough stockpile," Fauci said.

Traditionally, flu vaccines are grown in millions of fertilized chicken eggs, a process that can take six to nine months. Such a lengthy production cycle gets in the way of responding quickly to mutating flu strains.

Science and technology are not the only factors that have held back the field.

For many years, the inventions produced by vaccine companies were not viewed by the pharmaceutical industry as life-saving instruments, but as unprofitable commodities. Unlike treatments for chronic illnesses, which can reap billions for drug companies, vaccines could block an illness with a single shot.

Industry mergers and corporate decisions to leave the business because of low profits ended up reducing the size of the specialized, century-old field. Controversies, such as concerns over side effects and additives such as thimerosal -- which is at the center of the debate over childhood autism -- pushed the industry further to the margins.

Now, nearly overnight, the ground has shifted.

A BOOM IN THE MAKING
The global vaccine business is surging, according to a report by Richard Bernstein, chief investment strategist at Merrill Lynch. He forecasts double-digit growth rates over the next decade.

There are several reasons: New research techniques have created fresh opportunities for manufacturers; the demand for protection against bioterrorism has increased; developing nations have sought to raise immunization rates; and there has been a new emphasis on vaccines to treat, not just prevent, disease.

But clearly the biggest factor has been the avian flu outbreak.

The U.S. National Institutes of Health is pouring tens of millions of dollars into basic research on flu vaccines in both private industry -- mainly biotechs -- and academia. The effort has not been dampened by a report issued earlier this month by federal scientists that found it would not be so easy for the virus, genetically speaking, to mutate and spread among humans.

That report "provides meaningful information," said José Galarza, a vaccine scientist at TechnoVax Inc. in Tarrytown, N.Y. But scientists can't rule out the possibility that the right mutation could produce a true pandemic form, he said, and it's "necessary that we maintain surveillance."

The NIH's parent agency, the Department of Health and Human Services, is funneling more than $1 billion to major drug firms such as Novartis, GlaxoSmithKline and Sanofi-Aventis to enhance manufacturing capacity, support new construction and speed the conversion from egg-based vaccine creation to a process known as rapid cell-culture. This technique allows for the proliferation of animal cells infected with flu virus, nimbly producing the key content of vaccines.

Developing new kinds of weapons against pandemic flu requires massive investment and a sturdy infrastructure -- acres of property, huge plants and highly trained personnel.

Faced with this task of creating this arsenal, scientists, engineers and production experts are under unprecedented pressure to reinvent and scale up their most basic manufacturing processes -- and to stretch their thinking beyond available technologies.

There have been some promising developments already:

Breakthroughs in fundamental genetic science. The flu has been well-studied, from X-ray images of the virus in crystalline form to wholesale genetic sequencing. Such techniques have revealed secrets such as the virus' detailed surface structure and chemical patterns responsible for many of its key features. "We now have better technologies to make better vaccines both for the regular influenza vaccine and also against pandemics," said Peter Palese, a pioneering vaccine researcher at the Mount Sinai School of Medicine in New York.

"Broad" vaccines: An inoculation that provides a degree of immunity to a range of flu viruses is being developed by several biotech companies, including Novavax of Malvern, Pa.; Vical in San Diego; Protein Sciences in Meriden, Conn.; and PowderMed in Oxford, England. And some scientists even hold out hope for a "universal vaccine," a drug that in theory could protect a person against almost any pathogen it recognizes. Though years away, such a product is scientifically feasible, according to experts like Gary Nabel, director of vaccine research for the National Institute of Allergy and Infectious Diseases.

Improved boosters: Molecules known as adjuvants, which normally boost the body's immune response when added to a vaccine mix, are showing some promise in protecting humans against different versions of the flu virus. Glaxo last month reported its adjuvant-enhanced pandemic flu vaccine is more effective than any other vaccine to date.

Revitalized cell-culture technology: Scientists are taking a technique already used to produce other kinds of vaccines and tweaking it. Using cells taken from monkey or dog organs and growing them in lab dishes, scientists are infecting them with bird flu virus and growing those in huge vats laced with growth media. All the major pharma companies are experimenting with the technique.

Enlarged capacity: Sanofi is building a new cell-culture plant at its Swiftwater, Pa., facility; Novartis also is expanding, building a new facility in Europe and another one in Holly Springs, N.C.; and Glaxo will be tripling the capacity of its Quebec vaccine plant and doubling that of a European factory. With more capacity and a faster manufacturing process, these companies are hoping to dramatically improve their ability to respond to a pandemic.

ON A MISSION
Some industry analysts speculate that big pharma and smaller biotech firms eventually may form strategic alliances for vaccine discovery and invention to capitalize on collective strengths.

"They could become knights in shining armor," said Mark Ravera, an industry analyst with Strategic Pharma in Chatham. "Because, if bird flu shows up, the general public would probably be grateful these companies had the foresight and made the investment to fight this disease."

Those who have stayed with the science are feeling a sense of mission. "I feel honored to be part of this effort and I'm excited that I can do something important," said Norbert Klein, a vaccine manufacturing executive with Novartis in Marburg, Germany. "What we are coming up with is a much more robust technology. It has very distinct advantages for future developments."

The prize, for the public and the companies who will profit, will be, if not a universal treatment, then at least broader protection against a killer that can mutate with abandon, rendering custom-tailored vaccines useless. And the technologies developed for new types of seasonal and pandemic flu vaccines could be used to fight other diseases, opening up potentially lucrative markets.

"It's a foot race all right, with everyone out there toe-to-toe waiting for the big break," said Richard Bright, vice president for vaccine development for Novavax, one of several fledgling biotechs in the hunt. "And someone is going to get it."


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