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Biomedicine

Flu Vaccines Hit a Wall

As new influenza strains emerge, researchers struggle to speed vaccine development.

Making a vaccine against seasonal influenza is a constant catch-up game. Scientists must predict which of the constantly mutating virus strains will be most virulent six months in the future, the amount of time it takes to manufacture the vaccine. The system has worked well enough for the regular flu. But when new, virulent strains emerge–including the current, rapidly spreading swine flu (H1N1)–the traditional approach falls short. Even as consumers clamored for a vaccine, it took seven months and around 48,000 confirmed U.S. cases before the first H1N1 vaccines were shipped to hospitals around the country.

Attacking influenza: Scientists hope that new technologies for making vaccines will lead to quicker availability of vaccines against the human strain of H1N1 that originated from the swine flu virus, shown here.

Influenza vaccine production has not changed substantially since it was first introduced in the 1940s. The new H1N1 vaccine took so long to make because it was manufactured using the usual technique–vaccine specialists identify and isolate the most virulent strains, weaken them, genetically adapt them for growth in birds as well as in mammalian cells, and then inject them into fertilized chicken eggs, where the virus can reproduce without killing its host. Once inactivated, the viral proteins can then be made into a vaccine. Add quality control and distribution, “and it is a five-to-six-month process, at its best,” says Gregory Poland, director of the Mayo Clinic’s Vaccine Research Group, in Rochester, MN.

Researchers are working hard to develop faster production methods for seasonal flu vaccines as well as for “universal” vaccines that could guard against almost all influenza strains, including swine and avian. But both are a long way down the road. “There is really nothing in the pipeline that will guarantee the production of vaccine in much less than six months,” says Robert Webster, an infectious disease and viral immunology expert at St. Jude Children’s Research Hospital in Memphis, TN.

Some companies, including Novartis and Baxter International, are working on flu and other vaccines that could be grown in cell culture rather than in eggs–a method that has the potential to halve time to production. The time-consuming steps of tweaking the virus strains so they’ll grow in bird rather than mammalian cells, and weakening them so that they can reproduce without killing the egg, would no longer be required. And manufacturers would no longer be dependent on the available egg supply. “With cells, you can grow them up, freeze them, and bring them out when you need them,” Poland says. “You can make as much or as little as you want.”

Both Novartis and Baxter have clinical trials under way, and Baxter just received European marketing approval for its H1N1 vaccine. But the process could take much longer in the U.S. because the cell-culture method itself has not been approved by the Food and Drug Administration. Companies will have to go through testing and manufacturing inspections that will cost on the order of about $500 million each, says Poland.

Other researchers are looking beyond single strains of influenza and into the possibility of creating a vaccine that can protect against almost all versions of the virus. Polio and measles vaccines given in childhood confer a lifetime of immunity because the viruses they protect against change very little from year to year, but the flu virus mutates fast, changing its outer proteins almost completely every season. However, researchers have found a few stable regions on the virus that they believe could be used to create a vaccine that could guard its recipients against nearly all strains of influenza, including those most likely to cause a pandemic.

Theraclone Sciences, based in Seattle, has a proprietary technology that can create an entire immune history from a person’s blood sample. The end result is a personalized antibody library covering every ailment the individual has successfully fought off. The company has previously used this technology to identify antibodies against HIV and is now turning to influenza, examining blood from patients who successfully fought off some of the most lethal flu viruses. By studying how the patients’ antibodies react to H5N1 influenza, Theraclone scientists found that the most effective antibodies bound to a spot that appears conserved among all viral strains, a specific location on a known surface protein called M2.

Researchers will look at the crystal structures of these antibodies and then use them as templates to reverse-engineer a vaccine that would prompt the human immune system to produce them. “Finding these antibodies is a very important advance, and I think researchers are excited that they finally have the tools to be able to do the analytical work around the biology of these pathogens,” says David Fanning, Theraclone’s president and CEO. “We may be able to come up with immunogens that bind to the broadly neutralizing antibodies. But whether they’re capable of eliciting the same or similar antibodies on vaccination is really the big unknown right now.” Theraclone is beginning an $18 million collaboration with Tokyo-based Zenyaku Kogyo pharmaceutical company to look for conserved flu antibodies and develop subsequent vaccine candidates.

Perhaps the most exciting but challenging prospect for a universal vaccine lies in DNA-based vaccines–sequences of DNA that, when taken up by cells and expressed as proteins, prompt an immune response. DNA vaccines can be made and modified quickly, are cheap to produce, and have a long shelf life. The major hurdle in developing these vaccines is getting the right cells to take up enough DNA to elicit immunity. Inovio, a company based in Blue Bell, PA, is working to solve this problem through a process called electroporation, in which a small electric shock disrupts a cell membrane long enough for designer DNA fragments to slip through. Recent studies by the company have shown that consensus genes, synthetic sequences that look similar enough to certain components in a variety of viruses, can prompt a broad immune response against multiple strains of flu.

Despite the promise, vaccine researchers still have a long road to travel. “There’s lots of exciting things out there,” Webster says. “But the first thing with vaccines is safety. You must always be sure of their safety.”

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