Annually changing flu vaccines with their hit-and-miss effectiveness may soon give way to a single, near-universal flu vaccine, according to a new report from scientists at The Scripps Research Institute and the Dutch biopharmaceutical company Crucell.
They describe an antibody that, in animal tests, can prevent or cure infections with a broad variety of influenza viruses, including seasonal and potentially pandemic strains.
The finding, published in the journal Science Express on July 7, 2011, shows the influenza subtypes neutralized with the new antibody include H3N2, strains of which killed an estimated one million people in Asia in the late 1960s.
"Together this antibody and the one we reported in 2009 have the potential to protect people against most influenza viruses," said Ian Wilson, who is the Hansen Professor of Structural Biology and a member of the Skaggs Institute for Chemical Biology at Scripps Research, as well as senior author of the new paper with Crucell's chief scientific officer Jaap Goudsmit.
Tackling a Major Shortcoming
Wilson's laboratory has been working with Crucell scientists since 2008 to help them overcome the major shortcoming of current influenza vaccines: They work only against the narrow set of flu strains that the vaccine makers predict will dominate in a given year, so their effectiveness is temporary. In addition, current influenza vaccines provide little or no protection against unforeseen strains.
These shortcomings reflect a basic flu-virus defense mechanism. The viruses come packaged in spherical or filamentous envelopes that are studded with mushroom-shaped hemagglutinin (HA) proteins, whose more accessible outer structures effectively serve as decoys for a normal antibody response. "The outer loops on the HA head seem to draw most of the antibodies, but in a given strain these loops can mutate to evade an antibody response within months," said Wilson. Antiviral drugs aimed at these and other viral targets also lose effectiveness as flu virus populations evolve.
"The major goal of this research has been to find and attack relatively unvarying and functionally important structures on flu viruses," said Damian Ekiert, a graduate student in the Scripps Research Kellogg School of Science and Technology who is working in the Wilson laboratory. Ekiert and Crucell's Vice President for Antibody Discovery Robert H. E. Friesen are co-first authors of the Science Express report.
By sifting through the blood of people who had been immunized with flu vaccines, Goudsmit and his colleagues several years ago discovered an antibody that bound to one such vulnerable structure. In mice, an injection of the antibody, CR6261, could prevent or cure an otherwise-lethal infection by about half of flu viruses, including H1 viruses such as H1N1, strains of which caused deadly global pandemics in 1918 and 2009.
The Crucell researchers approached Wilson, whose structural biology lab has world-class expertise at characterizing antibodies and their viral targets. Ekiert, Wilson, and their colleagues soon determined the three-dimensional molecular structure of CR6261 and its binding site on HA, as they reported in Science in 2009. That binding site, or "epitope," turned out to be on HA's lower, less-accessible stalk portion. The binding of CR6261 to that region apparently interferes with flu viruses' ability to deliver their genetic material into host cells and start a new infection. That antibody is about to begin tests in human volunteers.
The Missing Piece
Crucell researchers subsequently searched for an antibody that could neutralize some or all of the remaining flu viruses unaffected by CR6261, and recently found one, CR8020, that fits this description. As the team now reports in the Science Express paper, CR8020 powerfully neutralizes a range of human-affecting flu viruses in lab-dish tests and in mice. The affected viruses include H3 and H7, two subtypes of great concern for human health that have already caused a pandemic (H3) or sporadic human infections (H7).
As with the CR6261 project, Ekiert and colleagues were able to grow crystals of the new antibody bound to an HA protein from a deadly strain of H3N2, and to use X-ray crystallography techniques to determine the antibody's structure and its precise epitope on the viral HA protein.
"It's even lower on the HA stalk than the CR6261 epitope; in fact it's closer to the viral envelope than any other influenza antibody epitope we've ever seen," said Ekiert.
Crucell is about to begin initial clinical trials of CR6261 in human volunteers, and the company expects eventually to begin similar trials of CR8020. If those trials succeed, aside from a vaccine the two antibodies could be combined and used in a "passive immunotherapy" approach. "This would mainly be useful as a fast-acting therapy against epidemic or pandemic influenza viruses," said Wilson. "The ultimate goal is an active vaccine that elicits a robust, long-term antibody response against those vulnerable epitopes; but developing that is going to be a challenging task."
Other authors of the paper, "A Highly Conserved Neutralizing Epitope on Group 2 Influenza A Viruses," are Gira Bhabha and Wenli Yu from Scripps Research; Ted Kwaks, Mandy Jongeneelen, Carla Ophorst, Freek Cox, Hans J.W.M. Korse, Boerries Brandenburg, Ronald Vogels, Just P.J. Brakenhoff, Ronald Kompier, Martin H. Koldijk and Wouter Koudstaal of Crucell Holland BV, Leiden, the Netherlands; Lisette A.H.M. Cornelissen of the Central Veterinary Institute, Wageningen University, Lelystad, the Netherlands; and Leo L. M. Poon and Malik Peiris of the Department of Microbiology, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
The research was supported by the US National Institute of Allergy and Infectious Diseases, National Institutes of Health; the US Department of Energy; and by Crucell Holland BV.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neuroscience, and vaccine development, as well as for its insights into autoimmune, cardiovascular, and infectious disease. Headquartered in La Jolla, California, the institute also includes a campus in Jupiter, Florida, where scientists focus on drug discovery and technology development in addition to basic biomedical science. Scripps Research currently employs about 3,000 scientists, staff, postdoctoral fellows, and graduate students on its two campuses. The institute's graduate program, which awards Ph.D. degrees in biology and chemistry, is ranked among the top ten such programs in the nation.
Mika Ono | EurekAlert!
Transport of molecular motors into cilia
28.03.2017 | Aarhus University
Asian dust providing key nutrients for California's giant sequoias
28.03.2017 | University of California - Riverside
The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.
To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
28.03.2017 | Life Sciences
28.03.2017 | Information Technology
28.03.2017 | Physics and Astronomy