But in the case of the coronavirus responsible for deadly severe acute respiratory syndrome (SARS), collaborating researchers at the University of North Carolina and Vanderbilt University have found that accelerating the rate of mutations cripples the virus's ability to cause disease in animals. In addition, they say this finding may allow scientists to explore a new option for creating safer live vaccines.
A collaborative study, published Nov. 11 in Nature Medicine, demonstrates a SARS-coronavirus, altered to lack the ability to "proofread" (correct mistakes in replication), begins to mutate much more rapidly and becomes unable to cause disease in mouse models. In effect, the alteration creates a profoundly weakened or attenuated SARS virus.
This work may offer reassurance at a critical time. Public attention was recently heightened regarding a novel human coronavirus that sickened at least two with respiratory and kidney disease, killing one in the Middle East. The SARS outbreak in 2002 and 2003 caused 50 percent mortality in older adults. A rapid and effective international response ended the outbreak in just four months. The final tally: 8,422 cases of SARS, resulting in 916 deaths.
"We originally thought that the virus might find a way to fix the mutations we engineered or work around them as viruses often do. That didn't happen, and in this case, the attenuated viruses replicated well enough and long enough to generate a protective immune response, even in immunocompromised animals, so it works wonderfully as a vaccine in an animal model," said Rachel Graham, Ph.D., a research associate at UNC, who led the research.
The study is the culmination of more than a decade of collaboration between the laboratories of Mark Denison, M.D., Craig-Weaver Professor of Pediatrics and professor of Pathology, Microbiology & Immunology at Vanderbilt University School of Medicine, and Ralph Baric, Ph.D., professor of Microbiology, Immunology and Epidemiology at the University of North Carolina at Chapel Hill's Gillings School of Global Public Health. The researchers' aim is to better understand how coronaviruses, which also cause the common cold, evolve and spread between species.
Denison's lab developed the attenuated SARS virus by disabling a unique exoribonuclease (or ExoN) protein, referred to as a proofreading protein. Previous Vanderbilt studies had shown that disabling ExoN knocks out the virus's ability to correct mistakes, increases mutations twentyfold, and stops its ability to cause disease, at least in the lab setting. Graham, formerly a graduate student in Denison's lab, was able to continue the work in animal models as a postdoctoral scientist in Baric's lab.
Coronaviruses are RNA viruses known to have the largest genomes in the RNA viral world. It is now understood that the ExoN proofreading protein allows coronaviruses to maintain their expanded genomes, with many proteins evolved to help them survive and spread. But deactivation of ExoN creates a particularly enticing potential approach to vaccine design.
"Live vaccines in general confer broader and longer-lasting immunity, but the risk of live vaccines is they could potentially revert back to virulence as happened with the live polio vaccine in immunocompromised people," Baric said. "Our evidence is exciting because a more permanently attenuated virus might be safer. We believe that related approaches can be applied to other important human and animal viruses, resulting in safer vaccines."
To test the likelihood of reversion to virulence, researchers allow a virus to grow in a host that lacks immunity. In the current study, even in very young, very old and immunocompromised animals, the virus did not kill and could persist for a long time without showing signs of a return to virulence.
"In contrast to science fiction, where mutations are evil and endanger the world, our studies demonstrate that viruses have evolved to tightly control their mutation rates, and changing that rate is detrimental to virus survival and disease in nature," Denison said. "Since all coronaviruses have the ExoN protein, this method for attenuation could be broadly applicable in coronaviruses."
"If we can't have a vaccine ready to administer that works for all coronaviruses, then we at least have a strategy for fast production of a functional vaccine for any new epidemic coronavirus that might arise. That's a key take-away point of our paper and what makes it so important in the face of current events," Graham said.
Carole Bartoo | Vanderbilt University Medical Ce
Study suggests possible new target for treating and preventing Alzheimer's
02.12.2016 | Oregon Health & Science University
The first analysis of Ewing's sarcoma methyloma opens doors to new treatments
01.12.2016 | IDIBELL-Bellvitge Biomedical Research Institute
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy