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If an avian flu pandemic does break out, public health agencies will need to generate millions of vaccine doses very quickly: The United States alone plans to vaccinate 20 million people. That's why Protein Science is aiming to chop the time needed to produce an influenza vaccine from six-to-eight months down to a few weeks. The company has come far enough along that its novel influenza vaccine will likely reach the market in fall
2007.
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Change has been a long time coming for this field. The current mainstay of vaccine production is a 50-year-old process in which the virus is grown in chicken eggs, which must be ordered months in advance. This process takes at least half a year and has numerous other flaws. For example, highly virulent strains of influenza (e.g., potentially pandemic strains) are lethal to chick embryos and cannot be grown in
eggs.
One answer is to develop influenza vaccines using cell culture. While no cell-culture-based influenza vaccine is yet on the market, such vaccines for diseases such as polio, hepatitis, and chickenpox have been approved in the United
States.
Most cell culture influenza vaccine developers use whole, live, influenza viruses in cell lines derived from sources such as dog kidneys, monkey kidneys, or human retinas. The process is similar to egg-based manufacturing
-- infect, grow, harvest, kill, package -- but much
faster.
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Caterpillar Power
Protein Sciences is doing the same thing, but with an uncommon cell source
-- the ovaries of a caterpillar, the fall armyworm (Spodoptera
frugiperda). Yes, a
caterpillar.
And there is another twist. In its expresSF system, Protein Sciences does not use whole influenza virus. Instead, just the gene for a particular influenza protein is inserted into a baculovirus. Caterpillar cells in bioreactors are then infected with the recombinant baculovirus and produce the
protein. |
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This Baculovirus Expression Vector System, or BEVS, is well known as an effective way to quickly generate large quantities of recombinant proteins: It is much faster than generating a cell line encoding that same protein. By using BEVS, new versions of protein drugs can be made in weeks, rather than months or years. Protein Sciences became a leader in the field when one of the process's inventors, Gale Smith, joined the company as chief scientific officer. The original intent was to use the approach to make HIV vaccines. That turned out to be much more daunting than expected, so in early 1990s, Protein Sciences started working on an influenza
vaccine.
FluBlØk, Protein Sciences'
BEVS-based influenza vaccine, is based on the same immunological principle as traditional whole, killed influenza vaccines: Certain proteins that stud the coat of the virus can ÒteachÓ the immune system to recognize and attack specific viral invaders. The most important of these proteins is hemagglutinin, or HA, which helps the virus infect cells. Genetic variation in HA and another protein, neuraminidase (NA), defines the seasonal strains of influenza. The potentially pandemic strain of avian influenza causing global concern at the moment is H5N1. The vaccine uses three recombinant HA (rHA) proteins derived from current circulating influenza viruses that are selected by the World Health Organization and the Center for Disease Control on an annual
basis.
Being able to avoid the use of live influenza viruses is one of the BEVS biggest advantages. The prospect of expressing just the non-infectious, rHA protein in insect cells is vastly preferable to bioreactors full of deadly live pandemic influenza viruses. Moreover, the rHA is an exact match to currently circulating strains, while the influenza strains grown in cell culture or eggs are slightly different due to being adapted to grow in cells that influenza normally does not
infect.
In 1997, there was an outbreak of avian influenza in Hong Kong, infecting thousands of chickens as well as 18 people, six of whom died. Researchers tried to make a vaccine using chicken eggs, but the embryos died before any virus was produced. The strain's unprecedented virulence made an egg-based influenza vaccine out of the question, so the National Institutes of Health requested that Protein Sciences generate a vaccine using BEVS. That process took just eight
weeks.
Although the Hong Kong outbreak petered out without becoming a pandemic, the vaccine effectively protected study chickens against the virus. Subsequent human clinical trials, the first to test a vaccine against avian influenza, showed immune responses (e.g., antibodies against HA) in people after two doses administered three to four weeks
apart.
Seven clinical trials, mostly in the elderly, have shown that recombinant HA generates strong immune responses against influenza (see Table, page 28). A pivotal proof-of-principle Phase III clinical trial tested two different dosages of FluBl¿k in 460 healthy adults from 18 to 49 years old in the 2004-2005 flu season. Results were even better than Protein Sciences had hoped: 71 percent of people were fully protected against influenza in the low-dose group and 100 percent in the high-dose group. Nobody in the high-dose group got the flu. As a result of this study, FDA qualified FluBlØk for accelerated approval, and the product could be approved in
2007.
Cell-culture-based flu vaccines will likely become commercially available within the next year: Protein Sciences aims for FluBlØk to be one of the first. If the feared avian flu pandemic does arise, the company also hopes to play a key role in defending against it. If that happens, many people may start seeing caterpillars in a whole different
light.
Gordon Kelley
is a freelance science writer in Eugene, Oregon, and Manon Cox is COO of Protein Sciences.
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