Vanderbilt University researchers have received a five-year, $9 million grant from the National Institutes of Health (NIH) to design more effective flu vaccines and novel antibody therapies.
Current flu vaccines, weakened or inactivated forms of the influenza virus given as injections or nasal sprays, trigger immune responses against proteins on the viral “coat.” Because these proteins are constantly changing, like disguises they help the virus evade immune detection. That’s why flu vaccines are not 100 percent protective.
Vaccines could be “universally” protective if they induced immunity against highly conserved, unchanging places on the surfaces of proteins found in every flu virus, said James Crowe Jr., M.D., co-principal investigator of the grant with Jens Meiler, Ph.D.
Similarly, “universal” antibodies that recognize every strain of the influenza virus could be developed into the first effective, injectable antibody therapy against the flu, said Crowe, Ann Scott Carell Professor and director of the Vanderbilt Vaccine Center.
Despite widespread immunization campaigns, as many as 30,000 Americans die of complications of influenza each year. If a new strain emerges for which there is no effective vaccine or treatment, it could kill millions worldwide. “Flu is just a continual ticking time bomb,” he said.
In collaboration with scientists from The Scripps Research Institute in La Jolla, California, the Vanderbilt researchers are using a computer program named “Rosetta,” which predicts protein structure from the amino acid sequence. In this way they hope to design antibodies that hone in on influenza’s “Achilles’ heel.”
Rosetta was originally written in the lab of David Baker, Ph.D., head of the Institute for Protein Design at the University of Washington in Seattle. Meiler, associate professor of Chemistry and Pharmacology, and his Scripps colleague, William Schief, Ph.D., both trained in the Baker lab and helped to develop the software suite.
Computer-designed proteins with a well-defined function have tremendous potential for the development of “biologics,” a quickly growing class of therapeutics that reuse the building blocks of nature such as amino acids, sugars or nucleic acids, Meiler said.
Crowe said the project will be conducted in three phases.
At Scripps, Ian Wilson, Ph.D., chair of the Department of Integrative Structural and Computational Biology and a world-renowned crystallographer, and his colleague Andrew Ward, Ph.D., a world expert on electron microscopy, will generate structural data on antibodies developed in the Crowe lab.
Based on those data, Meiler is building models of therapeutic antibodies and Schief, professor of Immunology and Microbial Science at Scripps, is building models of potential vaccines. “And my group … tests all the designs,” Crowe said.
“We’re going to move vaccines from empiricism, in which we take the (virus) and we inactivate it or break it up into pieces, and just use it as is (to trigger an immune response), and instead we’re going to design synthetic flu proteins to be better than the natural infection,” he said.
“We couldn’t do it in the past,” Crowe continued. “But now we can design these vaccine candidates on the computer, we can synthesize them in the lab and we can make a molecule that never existed before, and that’s better than the virus that existed in nature for inducing immunity.”
The grant (AI117905) from the National Institute of Allergy and Infectious Diseases of the NIH will provide $1.8 million in fiscal year 2015-2016, of which $900,000 will support the work at Scripps.
