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Scientists at The Scripps Research Institute (TSRI) have invented a new method for designing artificial proteins, and have used it to make key ingredients for a candidate vaccine against a dangerous virus, respiratory syncytial virus (RSV), a significant cause of infant mortality. The virus has been resistant to current vaccine-design strategies.
With the help of collaborating laboratories, the scientists were able to apply the new method, which uses a “rational design” approach to making vaccines focused on specific binding areas (epitopes) on the virus. The result was designer vaccine proteins that the scientists showed stimulate the production of the desired virus-neutralizing antibodies in rhesus macaques.
“This was a proof-of-principle demonstration of a technology that could be very useful against HIV, influenza and other highly variable viruses that have been difficult to stop using traditional vaccine-design strategies,” said William R. Schief, associate professor of immunology at TSRI.
The research is reported in by the journal Nature on February 5, 2014.
artificial proteins
For the test case, the team used the Fold from Loops software to design proteins that incorporate and stabilize a broadly neutralizing epitope on respiratory syncytial virus(RSV), a significant cause of infant mortality for which no preventive vaccine is yet available. Winnowing thousands of design possibilities down to four that seemed to have the best properties, the team turned them over to collaborating laboratories for preclinical testing and analysis.
In rhesus macaque monkeys, whose immune systems are quite similar to humans’, the designer “immunogen” proteins showed great promise. After five immunizations, 12 of 16 monkeys were producing robust amounts of antibodies that could neutralize RSV in the lab dish.
“It’s unusual to take a newly designed protein and immunize rhesus macaques with it,” said Schief. “We were fortunate to collaborate with Philip Johnson at Children’s Hospital in Philadelphia, whose laboratory performed those immunizations.”
Analyses of the animals’ immune responses were conducted at Johnson’s laboratory and at the laboratory of James E. Crowe, Jr., at Vanderbilt University Medical Center and in Barney Graham’s lab at the NIH/NIAID Vaccine Research Center.
At the laboratory of Roland K. Strong at Fred Hutchinson Cancer Research Center in Seattle, researchers performed X-ray crystallography of two neutralizing monoclonal antibodies produced by the macaques—antibodies that had never been described before—and confirmed that each hit the desired virus epitope.
Having proven the principle of epitope-specific design, Schief and his colleagues now hope to continue this line of research and produce a working RSV vaccine. “RSV is estimated to cause nearly seven percent of all human deaths worldwide in children ages one month to one year,” said Schief. “Beyond that, RSV sends millions of kids to the hospital and right now there is no licensed vaccine. So we are going to push hard to see if we can make a vaccine for infants and children using these new technologies. We’re also trying to improve this protein design method further and apply it to other vaccine projects including HIV and influenza vaccines.”
Source:
Medical Xpress
This entry was posted on Sunday, February 16th, 2014 (last updated)