As vaccine-makers gear up for the winter flu season, one biotech company is reporting success with an alternative method of developing a flu preventative that it says could work more effectively and be produced more quickly than traditional inoculations prepared in fertilized chicken eggs.

This moves Rockville, Md.–based Novavax, Inc., a step closer to submitting its seasonal flu vaccine candidate to the U.S. Food and Drug Administration (FDA) for approval, and at the same time helping the company move forward with its efforts to develop a vaccine against the H1N1 "swine" flu. The company's vaccine approach in both cases is to use viruslike particles (VLPs) containing surface proteins that make the VLPs resemble a virus, thereby eliciting the proper immune response—even though the VLPs lack the genes needed to replicate themselves.

To prepare a vaccine made in fertilized chicken eggs, scientists crack the shell and inject the influenza virus into the fluid surrounding the embryo. Ideally, the embryo is infected and the virus multiplies. After several days of incubation the eggs are opened and the virus is removed, purified and used to make the vaccine, as a 2004 Scientific American article points out. (The VLP approach bypasses the steps needed to adapt virus strains to grow in eggs.)

There are, however, several drawbacks to this "chicken and egg" approach, which dates back more than 50 years. In order to produce 300 million doses of vaccine, egg-based production would require some 900 million eggs, according to the U.S. Department of Health and Human Services. An outbreak of avian flu in particular could put eggs in short supply, restricting the amount of vaccine that could be produced. In addition, vaccine-makers that use eggs cannot begin developing new vaccines that target new virus strains until the U.S. Centers for Disease Control and Prevention (CDC) creates a live-virus reference strain for these companies to work with, a process that could take several weeks.

Novavax says it can develop a prototype vaccine without the aid of a virus reference strain. Instead, it uses information the CDC posts in the Global Initiative on Sharing Avian Influenza Data (GISAID) database, launched in 2006 by a number of science institutes and universities worldwide (including WHO, the CDC and the Max Planck Institute for Informatics) to encourage data-sharing in response to the global spread of the H5N1 avian flu. The company claims its VLP approach allows it to manufacture a vaccine to match a particular virus strain in about three months.

Novavax says that during Phase IIa of seasonal flu vaccine testing, which began in May, it was able in the majority of people tested to surpass the FDA's requirements for producing enough antibodies to protect the body from the H3N2, H1N1 and B viruses—all of which were common enough a year ago to be used to develop flu vaccines for the 2008 to 2009 flu season. The vaccine was most effective against H3N2, increasing antibody titers (a measure how much antibody is produced after vaccination) fourfold in more than 81 percent of who received it, according to the company.

The vaccine was less effective against the B strain (where a boost in titers was registered in more than 62 percent of participants) and H1N1 (where the boost was seen in more than 57 percent). The study included 221 people ages 18 to 49 who received either placebo or VLP vaccine.

"The success of this trial gives us the support that we need for Phase III," says Penny Heaton, Novavax's chief medical officer and vice president of development. "It's very encouraging." The company plans in October to conduct a separate test specifically to study the seasonal flu vaccine's effectiveness among 480 elderly participants (a demographic often encouraged to get seasonal flu shots), and Phase III efficacy trials across a larger set of demographics are scheduled to begin early next year.

Heaton thinks the success of Novavax's Phase II seasonal flu trial is encouraging for the company's efforts to also develop a vaccine for the H1N1 virus. Phase II trials for that vaccine candidate are set to begin within the next two months, so it will not likely be available to combat the current swine flu outbreak, which could kill as many as 90,000 Americans and land up to 1.8 million in the hospital, according to the President's Council of Advisors on Science and Technology (PCAST).

The advantage of Novavax's approach is that a vaccine can be made rapidly and in high volume, compared with the egg-based approach that's used today, says Ted Ross, an associate professor of microbiology and molecular genetics at the University of Pittsburgh's Center for Vaccine Research (CVR). "In the Novavax system, you generate a vaccine that looks just like the virus without being infectious," he adds.

This approach makes the FDA especially cautious. "Even though they're inactivating the virus, it's still there," says Ross, whose laboratory worked with Novavax during its preclinical studies, when the start-up was in need of laboratory facilities. Throughout the company's trials the FDA has been on alert for signs that a patient could have a bad reaction as a result of this vaccine-making approach.

Novavax is not the only company developing VLP-based vaccines, although it is ahead of the game in the category of flu vaccines. The only VLP-based vaccine to hit the U.S. market is Merck & Co.'s Gardasil, which won FDA approval in June as preventative against certain types of human papillomavirus (HPV), which could lead to cervical cancer. "This gave a huge boost to the VLP industry in that their vaccines could be approved," Ross says.

The current crop of seasonal flu vaccines, which contain H1N1, H3N2 and B flulike strains, are egg-based. "They're good, they're what we have," Novavax's Heaton says. "But there are improvements to flu vaccines that can be made that don't rely on our supply of eggs, and can do a better job for the elderly."