January 7, 2014 - By Tom Abate
James Swartz and his colleagues are working on an approach that they hope will make flu vaccines effective for multiple flu seasons.
Every year, the approach of flu season sets off a medical guessing game, with life or death consequences.
There are many different strains of flu, and they vary from year to year. So each season, health authorities must make an educated guess and tell manufacturers which variants of the flu their vaccines should target.
Even when this system works, flu-related illnesses kill 3,000 to 49,000 Americans annually, according to the Centers for Disease Control and Prevention. A bad guess or the unexpected emergence of a virulent strain can send the death toll higher than expected.
Against this backdrop, Stanford researchers report promising steps toward the creation of a universal flu vaccine, one that could be produced more quickly and offer broader protection than the virus-specific inoculants available today.
The researchers detailed their work in a paper published online Dec. 16 in the Proceedings of the National Academy of Sciences. The senior author was James Swartz, DSc, the James H. Clark Professor in the School of Engineering and professor of chemical engineering and of bioengineering. The lead author was postdoctoral scholar Yuan Lu, PhD.
Their approach arises from a better understanding of the structure of a key protein on the surface of the flu virus, and a new process for making vaccines based on that understanding.
Protruding from the surface of the flu virus are hundreds of copies of a protein called hemagglutinin. Each copy of hemagglutinin resembles a mushroom, with a head and a stem. The head of hemagglutinin helps determine the virulence of a given strain of flu.
Today's vaccines are based on inactivated viruses that contain the heads of hemagglutinin proteins. When a flu shot is injected into our bloodstream, our immune system sees the hemagglutinin head as a target and creates antibodies to fight what appears to be an infection.
Teaching the immune system to recognize a target is the essence of vaccination. If we are exposed to the flu after getting vaccinated, our immune system is primed to recognize and eradicate the invading virus before it can replicate sufficient copies to make us sick.
Swartz and his colleagues base their new vaccine approach on the understanding that, whereas the head of the flu virus varies from year to year, the protein stem remains more constant over time.
Theoretically, a vaccine based on the stem should be more broadly protective against different strains of flu, and perhaps offer universal protection. Moreover, because the stem remains relatively constant from year to year, once our immune systems produces antibodies against that antigen, multi-season protection might be possible.
But this approach remains experimental and has not yet been tested on patients.
The Stanford paper focused on the first step in developing such a universal vaccine: creating a protein stem fragment that could be injected into the bloodstream; in short, creating a target, or antigen, to attract the attention of the immune system and trigger an effective defense.
Lu, the lead author, outlined the process detailed in the PNAS paper.
The researchers began with a section of DNA that contained the instructions for making the protein structure for one important strain of flu, the H1N1 virus that caused the pandemic of 1918 and recurred in a milder form in 2009.
This DNA sequence defined the entire hemagglutinin protein, both head and stem.
The researchers then subtracted the DNA coding for the head. Thus, their edited DNA strand contained only the instructions for making the protein stem.
The Stanford team used a relatively new and experimental process to manufacture the viral stem. This process is called cell-free protein synthesis.
The advantage of this process is that it can produce proteins in a few hours versus a couple of weeks or even a couple of months, which is how long it takes to make proteins for flu vaccines using the practices that are approved for medical use today.
The researchers used this process to create and refine a viral protein stem that would be useful as an experimental vaccine antigen.
It took dozens of tries over two years, but eventually the researchers fed a DNA snippet into the process and created a soluble viral stem protein that could be a good antigen. That is what they report in the PNAS paper.
Many steps remain before the research community knows whether this viral stem approach yields a better flu vaccine. Next, Swartz and his team will attach their stem protein to a virus-like particle. The idea will be to create a bigger, better target with which to elicit an immune system response.
Should that prove successful, the new vaccine candidate would have to undergo safety and efficacy tests in animals and, eventually, large-scale human clinical trials.
Much is at stake. Recent estimates put the worldwide death toll from flu-related illnesses at between 250,000 and 500,000 persons per year.
"This is an important project for world health," Swartz said, noting that the vaccine must not only be broadly effective against different strains of flu but cheap to produce so that it can be widely distributed. "These are big challenges but we are committed to the effort."
The other co-author of the study was Stanford graduate student John Welsh.
The study was funded by the National Institutes of Health.
Stanford's Department of Chemical Engineering and Department of Bioengineering also supported the work. The Department of Bioengineering is jointly operated by the School of Medicine and the School of Engineering.
Stanford Medicine integrates research, medical education and health care at its three institutions - Stanford School of Medicine, Stanford Health Care, and Stanford Children's Health. For more information, please visit the Office of Communications website at http://mednews.stanford.edu.