20 October 2005
Global Demand Grows for Bird Flu Vaccine
Pandemic prompts new look at traditional vaccine production methods
By Cheryl Pellerin
Washington File Staff Writer
This is the second in a series of articles on human and avian flu and vaccines.
Washington – Demand is growing for a vaccine to protect against the spreading H5N1 strain of bird flu, but many experts say it will take months to develop an effective vaccine and they question the ability of manufacturers worldwide to produce enough vaccine if a pandemic occurs.
The World Health Organization (WHO) has confirmed 118 human cases of H5N1 infection in four Asian nations, resulting in the deaths of at least 61 people and more than 150 million birds.
To cause a pandemic among people, the H5N1 strain would have to mutate in such a way that it would be easily transmitted from person to person.
If that were to occur, said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health, the need to produce enough vaccine for large numbers of people would stress an already weak flu vaccine production capacity.
“The global vaccine capability is tenuous,” Fauci said in an interview with the Washington File, “in fact, the whole enterprise is rather fragile.”
Under the best circumstances, developing and producing influenza vaccines is a long, complicated process that starts with international disease surveillance led by the WHO Global Influenza Surveillance Network, established in 1952. (See related article.)
In the United States, the Centers for Disease Control and Prevention (CDC) are part of that process.
Every year, flu experts at CDC and the U.S. Food and Drug Administration (FDA) examine surveillance data – including information on which flu viruses are circulating and how they are mutating – and decide the virus strains against which the latest flu vaccine should protect.
The agencies then submit their recommendation to an expert committee, the FDA’s Vaccines and Related Biologicals Products Advisory Committee, which helps determine the vaccine’s final composition.
CDC and WHO usually recommend the same flu vaccine formulation.
“There are three viruses in the vaccine,” said Raymond Strikas, associate director for adult immunization at CDC’s National Immunization Program.
“There’s nothing magic about that number,” he added, “except that for the last 25 years or so, three types of viruses have circulated in any one year.”
The three kinds of flu viruses are influenza types A, B and C. Influenza A viruses have subtypes because they mutate much faster than influenza types B and C.
Influenza A viruses infect people, birds, pigs, horses, seals, whales and other animals, but wild birds are their natural hosts. Only certain influenza A subtypes – H1N1, H1N2 and H3N2 – are in general circulation among people.
H1N1, H3N2 and influenza B strains are included in each year's influenza vaccine. Such a mix of strains, Strikas said, “offers the best combination for addressing public health risk for disease and balancing that with the ability to make a lot of vaccine.”
Inactivated (killed) whole viruses, or parts or subunits of the killed virus, go into the vaccine.
When flu vaccine formulations are finalized, WHO collaborating centers prepare and distribute the candidate vaccine strain to manufacturers.
Viruses that go into flu vaccines have been grown the same way for more than 50 years – in fertilized (embryonated) chicken eggs.
“These are not eggs you buy in the store,” Strikus said, “these eggs have embryos in them and the virus grows well there.”
Eleven days after fertilization, each chosen flu virus – the strains are grown separately – is injected into the egg and allowed to accumulate in the fluid around the embryo.
The virus infects the embryo and multiplies. After several days of incubation, a machine opens the egg and harvests the virus.
The virus then is purified, chemically killed and used to produce the vaccine. On average, it takes between one and two eggs to produce one dose of annual flu vaccine.
The entire process takes at least six months and uses about 100 million eggs in the United States alone.
“Large commercial facilities and laboratories have used eggs for many years,” Strikus said, “but it’s become easier to isolate viruses like the avian influenza virus in cell culture than in eggs for no other reason than the avian virus is lethal to eggs.”
Cell culture involves growing animal or human cells in the laboratory in a nutrient solution.
The virus is injected into the cells, and cells and viruses multiply. Then the cells’ outer walls are removed and the virus is harvested, purified and inactivated.
Egg-based production of flu vaccines is well established and cost effective, but because of the need for so many eggs and a lengthy production time, this process could not produce enough vaccine to protect adequately the human population in the event of a pandemic.
“If we were to switch to cell culture methods,” said Andrew Pekosz, assistant professor of molecular microbiology at Washington University School of Medicine in Missouri and a NIAID-funded researcher, “then the bottleneck of how many eggs you have is no longer there.”
“There’s a lot of manufacturing capability allowing us to do very large-scale cell-culture experiments and to mechanize and optimize that process,” he added.
“Industry already uses cell culture to generate a wide range of therapeutic compounds,” Pekosz said. “So it’s just a matter of taking a technology that’s already out there and applying it to influenza, rather than coming up with a whole new infrastructure designed specifically for influenza vaccines.”
An alternative production method in the case of H5N1 is to grow the viruses initially in cell culture, then transfer them to eggs for more growth.
“That’s what was done for the H5 vaccine,” Strikus said, at Sanofi Pasteur, the vaccine division of the French Sanofi-Aventis Group.
Sanofi-Aventis in Pennsylvania and Chiron Corp. in California received NIAID contracts in 2004 to produce and clinically test a vaccine based on H5N1.
Sanofi is testing a prototype vaccine on 400 people and says it will have results by the end of the year, and Chiron is developing two vaccine candidates for different strains of the H5N1 virus.
The U.S. Department of Health and Human Services, Strikus said, also has a contract with Sanofi-Aventis to develop cell-culture techniques for eventual commercial production. Major vaccine producers worldwide also are working to develop cell-culture methods.
“The current method of generating human influenza vaccines is perfectly acceptable for our normal influenza seasons,” Pekosz said. “But if we talk about a pandemic influenza virus, in a best-case scenario we have a year’s notice, in a worst-case scenario we have a couple weeks’ notice.”
In that worst-case scenario, he added, “the current way of making influenza vaccine will not work when applied to a pandemic influenza.”
For more information on U.S. and international efforts to combat avian influenza, see Bird Flu.
This is the second in a series of articles on human and avian flu vaccines. See also “New Flu Season Begins as Chance of Pandemic Looms.” The third will describe evolving trends in flu vaccine production.
(The Washington File is a product of the Bureau of International Information Programs, U.S. Department of State. Web site: http://usinfo.state.gov)
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