Fighting the bird flu, fast

Special to The Times

IF the bird flu afflicting poultry flocks in Asia starts spreading efficiently among people, many millions could die. We have no natural immunity to this virus, and no effective vaccine is available. And even if we did have a potent bird flu shot, vaccine production is such a slow, unwieldy process that vaccine makers couldn’t produce sufficient supplies fast enough to avert a catastrophe.

Health researchers are trying to tackle this problem -- to prepare for the H5N1 bird flu threat and for other lethal strains that might crop up. And they are making some headway. A couple of experimental bird flu vaccines in clinical trials can be made much more swiftly than the conventional influenza vaccines we get shots of each flu season.

One approach entails using cells in a lab fermenter to quickly churn out the viruses needed to make a vaccine. (Normally, flu vaccines are made by growing viruses on millions of chicken eggs.) Another method uses just one gene of the virus, instead of the whole flu virus, to stimulate a protective immune response.

“These methods could shorten the window of time it takes to make the avian flu vaccine,” says Terrence Tumpey, a microbiologist and avian flu expert at the Centers for Disease Control and Prevention in Atlanta. “If we can make a vaccine in three months versus the six to eight months required now, that would save lives.”


So far, there hasn’t been an outbreak because bird flu is hard to contract: The H5N1 avian flu virus doesn’t migrate that easily from birds to humans, and when it does, it doesn’t spread readily among people. But public health officials worry that this might change -- causing disaster because the virus kills more than half of its victims.

Of the 265 people who are known to have been infected with H5N1 flu since 2003, 159 have died, according to the World Health Organization in Geneva. Were it to evolve into a more contagious strain because of the speed of air travel, health officials predict we could face a worse global flu pandemic than the one that struck in 1918, when a bird flu spread to humans and claimed at least 50 million lives.

Although this threat has lent urgency to the search for an effective avian flu vaccine, the path is littered with roadblocks. For starters, influenza viruses are notorious shape shifters: The H5N1 avian flu strains that recently emerged in Indonesia and China, for example, are different from the H5N1 culprit behind the initial 1997 outbreak in Hong Kong. That means researchers cannot stockpile bird flu vaccine, because even if a vaccine prevented infection from the original strain, it might not protect against new variants.

This is a problem because if the pandemic hits, the world will quickly need hundreds of millions of doses. Yet making flu shots takes six months or more if done conventionally -- namely, growing viruses in fertilized hens’ eggs, then collecting, killing and processing them into vaccine. It takes months to line up supplies of eggs and months more to incubate them. It’s virtually impossible to ramp up production quickly.


“The influenza viruses are a moving target, and keeping up with their variability is a perpetual challenge, which is why we’re exploring these new technologies,” says Dr. Gary J. Nabel, director of the Vaccine Research Center at the National Institutes of Health in Bethesda, Md.

The two novel ways of making vaccines could dramatically speed up vaccine production. Cell-based vaccines use mammalian cells (often ones originally derived from canine kidneys) instead of eggs. The cells are bathed in nutrients in big vats and are used as hosts for the growth of modified avian flu viruses that can be used in vaccines. This method reduces production time by about a month, and the cells can be frozen for stockpiling in case of emergencies.

Early tests of this method have yielded promising results. A 2006 clinical trial revealed that one cell-cultured avian flu vaccine triggered a strong immune response in 65% to 96% of human participants, depending on the strength of the doses they received.

The vaccine, developed by Baxter International of Deerfield, Ill., was tested on 270 healthy adults, each of whom received two shots spaced 21 days apart. What was especially encouraging is that the vaccine showed evidence of cross-protection against several H5N1 strains. Larger tests of humans are slated to start this year.


A similar cell-based vaccine is just beginning a clinical trial at the University of Maryland that will eventually include as many as 100 healthy volunteers.

Other experimental vaccines are speedier still -- shrinking production time from months to weeks. Two groups of scientists are working on methods that use the gene for a certain flu virus protein, hemagglutinin, to provoke an immune response.

Hemagglutinin was chosen because it normally sits on the outside of a flu virus and is one that the immune system recognizes and uses to neutralize flu viruses.

In one method, Nabel and colleagues at the NIH’s Vaccine Research Center spliced a bird flu hemagglutinin gene into a ring of DNA and then inserted it into bacteria. The bacteria were then incubated in fermentation tanks, becoming biological factories that made many, many copies of the gene.


In the vaccine method, the DNA is injected into a person’s muscle, where it enters cells and directs the formation of hemagglutinin. The immune system recognizes the hemagglutinin -- and now should protect against attack by any virus that carries a similar-enough hemagglutinin.

Another technology, under development by Dr. Andrea Gambotto, an immunologist at the University of Pittsburgh, uses the hemagglutinin gene in a different fashion. The gene is inserted inside the genome of a harmless, modified cold virus which is then reproduced in mammalian cells. The virus is injected into people, where it enters cells but does not spread or cause disease. Again, hemagglutinin is manufactured -- triggering a protective immune response.

In recent animal studies, these approaches were 100% effective in mounting protective immune reactions against various influenza viruses, including avian H5N1. Last December, the NIH team began human tests involving 45 volunteers. Gambotto plans to start clinical trials of his vaccine this year.

Even if all goes well, it will be several years before any of these experimental approaches become standard tools. “If an outbreak occurred within the next couple of years,” Nabel says, “we’d have to rely on conventional methods to make the hundreds of millions of doses we’d need.”




In development

At least four H5N1 bird flu vaccines are in development using the conventional method of growing influenza virus on eggs -- ones by Sanofi Pasteur, GlaxoSmithKline, Novartis and Chinese scientists. However, a viable bird flu vaccine using such methods won’t be on the market for at least another year, and all require two shots to stimulate a protective level of antibodies. In the event of a pandemic, existing production facilities could not produce enough vaccine for everyone.


One approach could stretch the supply of vaccine during a crisis. A turbo-charged version of GlaxoSmithKline’s bird flu vaccine (containing an immune-boosting additive called an adjuvant) raised a protective immune response in 80% of 400 volunteers at a far lower dose in trial results reported in 2006.

More tests are needed before it becomes available.

“We don’t have a perfect vaccine yet,” says Dr. Kenneth Zangwill of UCLA’s Center for Vaccine Research. “But if a pandemic comes knocking on our doors, I’ll take what we’ve got.”

-- Linda Marsa