PRESS-NEWS.org - Press Release Distribution
PRESS RELEASES DISTRIBUTION

Scientists create potential vaccine ingredient for childhood respiratory disease

The feat bolsters rational vaccine design approach that could also be applied to other challenging viruses including HIV and influenza

2014-02-06
(Press-News.org) Contact information: Mika Ono
mikaono@scripps.edu
858-784-2052
Scripps Research Institute
Scientists create potential vaccine ingredient for childhood respiratory disease The feat bolsters rational vaccine design approach that could also be applied to other challenging viruses including HIV and influenza

LA JOLLA, CA—February 5, 2014—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.

Folding from Loops

The new protein-design method represents a significant advance over previous methods.

"One approach we and others have taken has been to transplant a protein fragment of interest, for example one that mimics a particular structure on a virus, onto an existing protein 'scaffold,'" said TSRI Research Associate Bruno E. Correia, a member of the Schief laboratory at the time of the study and lead author of the new report. "While this approach often works well to mimic the structure of a viral epitope, it has never successfully induced neutralizing antibodies, and in some cases this method falls short of even producing viable vaccine candidates."

In these difficult cases, the scaffold structure fails to stabilize the transplanted fragment, resulting in an imperfect mimic of the virus and consequent loss of immune-stimulating properties.

The TSRI scientists wanted a way to design scaffold proteins from scratch—proteins that would fit around their functional fragments more naturally, and would do a better job of stabilizing them.

The result was a new software app, "Fold from Loops," for designing proteins that fold up around a functional fragment of interest. For a proof-of-principle demonstration, the scientists decided to attempt one of the most important current protein-design challenges: making a new protein that mimics a particular epitope on a virus, and thus can serve as a key component of a vaccine.

The Promise of Rational Vaccine Design

Researchers want to be able to stimulate antibody reactions against highly specific epitopes because some infectious agents seem unstoppable by traditional methods of immunization.

"The achievement announced today represents the confluence of recent technological advances in computational biology, structural biology and immune monitoring, and offers great potential for accelerating development of next generation vaccines against major global diseases," said Wayne C. Koff, chief scientific officer at IAVI, the International AIDS Vaccine Initiative, which helped to fund the studies.

Virtually all existing viral vaccines, for example, use whole (killed or weakened) virus particles or entire viral proteins to stimulate antibody reactions. These vaccines display virtually the same large set of viral epitopes that the immune system would encounter during a natural infection.

Yet some viruses, such as HIV and influenza viruses, effectively conceal their truly vulnerable epitopes during natural infections, displaying mostly "decoy" structures that change from one viral generation to the next. Only vaccines that can artificially stimulate large numbers of antibodies—against just the vulnerable epitopes—are likely to provide broad protection against such viruses.

Scientists know how to sift through blood samples of virus-exposed patients to find the rare, "broadly neutralizing" antibodies that hit those vulnerable epitopes. They also know how to map the precise atomic structures of these antibodies and their corresponding epitopes, using X-ray crystallography.

"What we haven't been able to do is to take that information about broadly neutralizing antibodies and their epitopes and translate it into effective, epitope-focused vaccines," said Correia.

A Candidate RSV Vaccine

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."

INFORMATION:

Other co-authors of the study, "Proof of Principle for Epitope-Focused Vaccine Design," were John T. Bates of Vanderbilt University, Rebecca J. Loomis of the Children's Hospital of Philadelphia Research Institute, Gretchen Baneyx of the University of Washington, Christopher Carrico of the Fred Hutchinson Cancer Research Center, Joseph G. Jardine of TSRI and the University of Washington, Peter Rupert and Colin Correnti of the Fred Hutchinson Cancer Research Center, Oleksandr Kalyuzhniy of the University of Washington and TSRI, Vinayak Vittal of the University of Washington, Mary J. Connell of the Children's Hospital of Philadelphia Research Institute, Eric Stevens and Alexandria Schroeter of the University of Washington, Man Chen and Barney S. Graham of the National Institute of Allergy and Infectious Diseases; Skye MacPherson, Andreia M. Serra and Yumiko Adachi of the University of Washington and TSRI; Margaret A. Holmes (deceased) of the Fred Hutchinson Cancer Research Center; Yuxing Li of IAVI and TSRI; Rachel E. Klevit of the University of Washington; Richard T. Wyatt of IAVI and TSRI; and David Baker of the University of Washington.

Funding for the research was provided by the National Institute of Allergy and Infectious Diseases (grants 5R21AI088554, 1UM1AI100663, 1R01AI102766-01A1, P30AI36214); the International AIDS Vaccine Initiative Neutralizing Antibody Consortium; the International AIDS Vaccine Initiative Neutralizing Antibody Center; the March of Dimes; the Bill and Melinda Gates Foundation; The Children's Hospital of Philadelphia; and the Fundação para a Ciência e a Tecnologia of Portugal.



ELSE PRESS RELEASES FROM THIS DATE:

Social media analysis shows the Garment District still rules New York fashion

2014-02-06
A new study shows New York fashion designers don't just flock ...

Quarks in the looking glass

2014-02-06
From matching wings on butterflies to the repeating six-point pattern of snowflakes, symmetries echo through nature, even down to the smallest building blocks of matter. Since the discovery of quarks, the building ...

A 'smoking gun' on the Ice Age megafauna extinctions

2014-02-06
It was climate that killed many of the large mammals after the latest Ice Age. But what more specifically was it with the climate that led to this mass extinction? The answer to this is hidden ...

Food insecurity leads to increased incidence of tuberculosis in Zimbabwe

2014-02-06
TORONTO, ON - The rise of tuberculosis (TB) in Zimbabwe during the socio-economic crisis of 2008-9 has been linked to widespread food shortage, according to a new study led ...

Paper offers insights into network that plays crucial role in cell function and disease

2014-02-06
A new research paper from the labs of University of Notre Dame researchers Holly Goodson and Mark Alber helps resolve an ongoing debate about the assembly of a subcellular network that ...

Will your child be a slim adult?

2014-02-06
Will your child be a slim adult? A novel new study published in PLOS ONE asked 532 international English speaking adults to submit or "crowd-source" predictors ...

Health Affairs examines successes and missing links in connected health

2014-02-06
You can successfully integrate technology into patient care, but it isn't easy. Just ask Kaiser Permanente Northern California (KPNC) ...

NASA sees Tropical Cyclone Edna affecting new Caledonia

2014-02-06
NASA's Aqua satellite spotted two storms in one image in the Southern Pacific Ocean as Tropical Cyclone Edna brushes by New Caledonia and an extra-tropical storm lingers west of New Zealand. New Caledonia warnings ...

Crossover sound

2014-02-06
We all learn in high school science about the dual nature of light - that it exists as both waves and quantum particles called photons. It is this duality of light that enables ...

Grasshoppers are what they eat

2014-02-06
PUBLIC RELEASE DATE: 5-Feb-2014 [ | E-mail ] var addthis_pub="eurekalert"; var addthis_options = "favorites, delicious, digg, facebook, twitter, google, newsvine, reddit, slashdot, stumbleupon, buzz, more" Share Contact: Beth Parada apps@botany.org American Journal of Botany Grasshoppers are what they eat New method to extract plant DNA from grasshopper guts improves understanding of plant-insect interactions VIDEO: This is a demonstration of grasshopper ...

LAST 30 PRESS RELEASES:

Pink skies

Monkeys are world’s best yodellers - new research

Key differences between visual- and memory-led Alzheimer’s discovered

% weight loss targets in obesity management – is this the wrong objective?

An app can change how you see yourself at work

NYC speed cameras take six months to change driver behavior, effects vary by neighborhood, new study reveals

New research shows that propaganda is on the rise in China

Even the richest Americans face shorter lifespans than their European counterparts, study finds

Novel genes linked to rare childhood diarrhea

New computer model reveals how Bronze Age Scandinavians could have crossed the sea

Novel point-of-care technology delivers accurate HIV results in minutes

Researchers reveal key brain differences to explain why Ritalin helps improve focus in some more than others

Study finds nearly five-fold increase in hospitalizations for common cause of stroke

Study reveals how alcohol abuse damages cognition

Medicinal cannabis is linked to long-term benefits in health-related quality of life

Microplastics detected in cat placentas and fetuses during early pregnancy

Ancient amphibians as big as alligators died in mass mortality event in Triassic Wyoming

Scientists uncover the first clear evidence of air sacs in the fossilized bones of alvarezsaurian dinosaurs: the "hollow bones" which help modern day birds to fly

Alcohol makes male flies sexy

TB patients globally often incur "catastrophic costs" of up to $11,329 USD, despite many countries offering free treatment, with predominant drivers of cost being hospitalization and loss of income

Study links teen girls’ screen time to sleep disruptions and depression

Scientists unveil starfish-inspired wearable tech for heart monitoring

Footprints reveal prehistoric Scottish lagoons were stomping grounds for giant Jurassic dinosaurs

AI effectively predicts dementia risk in American Indian/Alaska Native elders

First guideline on newborn screening for cystic fibrosis calls for changes in practice to improve outcomes

Existing international law can help secure peace and security in outer space, study shows

Pinning down the process of West Nile virus transmission

UTA-backed research tackles health challenges across ages

In pancreatic cancer, a race against time

Targeting FGFR2 may prevent or delay some KRAS-mutated pancreatic cancers

[Press-News.org] Scientists create potential vaccine ingredient for childhood respiratory disease
The feat bolsters rational vaccine design approach that could also be applied to other challenging viruses including HIV and influenza