in 09, a global collaboration of scientists, public health agencies and businesses ran to make a vaccine against a pandemic flu virus, but the majority was not ready until the pandemic had peaked. Now, researchers have developed an alternative, faster strategy when a pandemic influenza virus surfaces: Just squirt genes for the protective antibodies in the nose of people. The method, which borrows ideas both gene therapy and vaccination, but neither-protects mice against a range of influenza virus in a new study.
James Wilson, a leading gene therapy researcher at the University of Pennsylvania, credits the idea of a meeting with Bill Gates in April 2010. Wilson had investigated whether a harmless gene therapy virus tool called adeno-associated virus (AAV) may be used as gene delivery vehicle to treat hereditary diseases such as cystic fibrosis and hemophilia. Gates, whose foundation focuses on global health, "asked if the approach of AAV-mediated could be used in the context of a pandemic or emerging infection," recalls Wilson.
Wilson was intrigued by the idea. Build off of animal studies by researchers from AIDS and his own work with cystic fibrosis, he wondered whether an AAV designed could deliver genes encoding antibodies to influenza to cells lining the airways of people . If it worked, these so-called epithelial cells produce antibodies to the flu right on the site where the virus is trying to establish an infection.
A key problem early on was to decide which antibodies to make, because there are many different flu strains; a one-size-fits solution would be ideal. Then, in a 2011 paper Science immunologist Antonio Lanzavecchia in Biomedicine Research Institute in Bellinzona, Switzerland, reported the isolation of a "neutralizing antibodies" rarely able to fight many strains flu.
Wilson and colleagues designed to carry AAV gene rare antibody. When they delivered the virus into the noses of mice and ferrets, the epithelial cells of the animals produced antibodies wish they were then "challenged" the animals with a range of dangerous flu virus that no single vaccine can outsmart, including H5N1, which kills birds and humans and the H1N1 that caused the infamous 1918 pandemic . As they report today in Science Translational Medicine , antibodies provided strong protection against the disease in most cases.
"It is a excellent study, "Lanzavecchia said, noting that much credit must be given to researchers who first published a similar experience with the AIDS virus in 02." This is a new application of an approach initiated by other groups " he said. "The main question is: How do you use this approach is the prevention of gene therapy for sustainable flu?"
The problem, he explains, is that the strategy is different from the vaccination, in which the immune system of the body produces antibodies and remembers how to do it for years, even decades . In this case, AAV acts as a Trojan and leads epithelial airway cells to make antibodies; the question is how long they will continue to do so.
Philip Johnson, a molecular virologist at the Children's Hospital of Philadelphia, Pennsylvania, who did the work earlier and with AAV antibodies against the simian version of the AIDS virus, showed in an experiment monkey published in Nature Medicine in 09 that its vector has worked for over a year. However, AAV came up short in about 3 months in a monkey of experience in the study of Wilson. Johnson said a key difference is that it injected into a muscle, which has long-term cells, while the vector Wilson sprayed into the nose. Airway epithelial cells that the method relies on are continuously poured, he said.
Wilson agreed that three months of protection is "not optimal" during an influenza pandemic. He is currently working on ways to increase the sustainability and said his goal is 6 months. But the goal is not to make the vector always produce antibodies, he said. That's partly because of security concerns. Wilson led a famous gene therapy study with an adenovirus vector that killed a patient, Jesse Gelsinger, in 1999, a major setback for the entire field. Although AAV has never caused harm to a human being, there is always the unknown with artificial viral vectors.
Wilson sees his work as an interim measure until researchers understand how to make a vaccine that elicits neutralizing antibodies. But now, despite intense efforts, researchers have been unable to develop a vaccine that triggers the production of these powerful molecules. "We still have a ways to go," he said, "and until that happens, we'll just keep plugging away at it."
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