Vaccine scientists say their "Holy Grail" is to stimulate immunity that lasts for a lifetime. Live viral vaccines such as the smallpox or yellow fever vaccines provide immune protection that lasts several decades, but despite their success, scientists have remained in the dark as to how they induce such long lasting immunity.

Researchers at Emory University and Georgia Tech have designed tiny nanoparticles that resemble viruses in size and immunological composition and induce lifelong immunity in mice. They designed the particles to mimic the immune-stimulating effects of one of the most successful vaccines ever developed — the yellow fever vaccine. The particles, made of biodegradable polymers, have components that activate two different parts of the innate immune system and can be used interchangeably with material from many different bacteria or viruses.

The results are described in this week's issue of Nature. The research was supported by the National Institutes of Health and the Bill and Melinda Gates Foundation.
These results address a long-standing puzzle in vaccinology: how do successful vaccines induce long lasting immunity? said senior author Bali Pulendran, Charles Howard Candler professor of pathology and laboratory medicine at Emory University School of Medicine and a researcher at Yerkes National Primate Research Center.  These particles could provide an instant way to stretch scarce supplies when access to viral material is limited, such as pandemic flu or during an emerging infection. In addition, there are many diseases, such as HIV, malaria, tuberculosis and dengue, that still lack effective vaccines, where we anticipate that this type of immunity enhancer could play a role.

One injection of the live viral yellow fever vaccine, developed in the 1930s by Nobel Prize winner Max Theiler, can protect against disease-causing forms of the virus for decades. Pulendran and his colleagues in the Emory Vaccine Center have been investigating how humans respond to the yellow fever vaccine, in the hopes of imitating it.

Several years ago, they established that the yellow fever vaccine stimulated multiple Toll-like receptors (TLRs) in the innate immune system. TLRs are present in insects as well as mammals, birds and fish. They are molecules expressed by cells that can sense bits of viruses, bacteria and parasites and can activate the immune system. Pulendran's group demonstrated that the immune system sensed the yellow fever vaccine via multiple TLRs, and that this was required for the immunity induced by the vaccine.

TLRs are like the sixth sense in our bodies, because they have an exquisite capacity to sense viruses and bacteria, and convey this information to stimulate the immune response, explained Pulendran. We found that to get the best immune response, you need to hit more than one kind of Toll-like receptor. Our aim was to create a synthetic particle that accomplishes this task.
Emory postdoctoral fellow Sudhir Pai Kasturi worked with Niren Murthy, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, to create tiny particles studded with molecules that turn on Toll-like receptors.
Given the ability of these nanoparticles to tune T and B cell responses, I anticipate they will be the focus of numerous vaccine developments in the future, said Murthy.

One of the particles components is MPL (monophosphoryl lipid A), a component of bacterial cell walls, and the other is imiquimod, a chemical that mimics the effects of viral RNA. The particles are made of PLGA — poly(lactic acid)-co-(glycolic acid) — a synthetic polymer used for biodegradable grafts and sutures.

All three components are FDA-approved for human use individually. For several decades, the only FDA-approved vaccine additive was alum, until a cervical cancer vaccine containing MPL was approved in 2009. Because of immune system differences between mice and monkeys, the scientists replaced imiquimod with the related chemical resiquimod for monkey experiments.

In mice, the particles can stimulate production of antibodies to proteins from flu virus or anthrax bacteria several orders of magnitude more effectively than alum, the authors found. In addition, the immune cells persist in lymph nodes for at least 18 months, almost the lifetime of a mouse. In experiments with monkeys, nanoparticles with viral protein could induce robust responses greater than five times the response induced by a dose of the same viral protein given by itself, without the nanoparticles.

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Media Relations Contacts: Emory University — Holly Korschun (hkorsch@emory.edu; 404-727-3990); Georgia Tech — Abby Robinson (abby@innovate.gatech.edu; 404-385-3364)
Writer: Quinn Eastman/Emory University

 

Phillip Santangelo, assistant professor in the Coulter Department, has received an R01 NIH/National Institute for General Medicine Sciences award to develop single molecule sensitive probes for the study of virus replication, assembly and budding. The $1.48 million project will focus on the human respiratory syncytial (hRSV) virus. hRSV is recognized as the most important viral agent of serious pediatric respiratory tract disease. Worldwide, acute respiratory tract disease is the leading cause of mortality due to infectious disease, and hRSV remains one of the pathogens deemed most important for vaccine and antiviral development. He will collaborate with James E. Crowe, Jr., MD, The Departments of Microbiology and Immunology, and Pediatrics and The Vanderbilt Vaccine Center; Vanderbilt University Medical Center for the 5-year study.

Atlanta (September 24, 2010) — Assistant Professor Francesca Storici (Biology) has been awarded a research grant by the National Science Foundation (NSF) for a 3 year project focusing on “Mechanisms of RNA/DNA hybrid stability and of information flow from RNA to DNA in yeast cells". The goal of this research is to understand the mechanisms by which RNA can directly transfer information to the DNA of cells. The main objectives are: 1) to identify the main protein factors cleaving the RNA tract in an RNA/DNA hybrid during RNA-driven DNA repair and DNA modification and to characterize their in vivo functions, and 2) to reveal the role of DNA repair mechanisms in the removal of RNA embedded into DNA. This project addresses challenging questions in molecular biology: How likely is information flow from RNA to DNA in cells? How well is RNA tolerated in DNA? What are the consequences of RNA-driven modifications in cells? The study will be done using newly developed systems in the yeast Saccharomyces cerevisiae, which will be exploited to perform molecular and cellular biology experiments to identify and characterize the molecular mechanisms of RNA-driven DNA repair and editing.

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School of Biology

Francesca Storici

Georgia Tech's largest graduate student organization, Bioengineering and Bioscience Unified Graduate Students (BBUGS), with the support of the Parker H. Petit Institute for Bioengineering and Bioscience (IBB), hosted its annual Buzz on Biotechnology High School Open House.

Open to all Atlanta area high school students, parents and teachers, this year's event drew a record 400+ attendees from 56 different schools. Visitors came to engage in a wide variety of hands-on, innovative science and engineering demonstrations such as "Edible Cells," "Virtual Stomach Surgery," "Acids and Bases," "Electromyography Recordings of Muscles," "Protein Folding." They were able to tour the state-of-the-art laboratories of IBB such as neuroengineering, robotics, atomic force microscopy and biomedical engineering labs. Many guests also attended bioengineering and stem cell seminars and even had the opportunity to take Georgia Tech campus tours and talk with an admissions representative.

The day wrapped up with the always-popular "Egg Drop" contest to find the safest, and lightest, "egg helmet" by dropping all those constructed throughout the day from the atrium's third floor.

The open house event was created in 2003 by BBUGS to reach out to area high school students to indulge their curiosity by introducing them to the world of science and engineering in a fun and accessible way.

Essentially arrays of tiny test tubes, microplates have been used for decades to simultaneously test multiple samples for their responses to chemicals, living organisms or antibodies. Fluorescence or color changes in labels associated with compounds on the plates can signal the presence of particular proteins or gene sequences.

The researchers hope to replace these microplates with modern microelectronics technology, including disposable arrays containing thousands of electronic sensors connected to powerful signal processing circuitry. If they're successful, this new electronic biosensing platform could help realize the dream of personalized medicine by making possible real-time disease diagnosis - potentially in a physician's office - and by helping select individualized therapeutic approaches.

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Professor Greg Gibson (Biology) has received a 1 year pilot grant from the AFLAC Cancer Center for “Genomic profiling of late outcomes in survivors of childhood cancer". The study involves a collaboration with Drs. Ann Mertens and Karen Wasilewski in the Department of Hematology/Oncology at Emory University, and Dr. Ken Brigham, Director of the Center for Health Discovery and Well Being (CHDWB) at Emory. The objective of the project is to use a systems biology approach to try to understand why so many survivors of early childhood cancers begin to have a range of serious health problems as they reach adulthood, and to see if the CHDWB health care model might be an effective intervention. More information about the Emory childhood cancer survivor program can be found at http://www.choa.org/default.aspx?id=399

Professors Wendy Kelly and Jake Soper both received Defense Advanced Research Projects Agency (DARPA) Young Faculty Awards. This program selects rising research stars from around the country and exposes them to the needs of the Department of Defense. DARPA’s goal is to fund researchers who will focus a significant portion of their careers on Department of Defense and National Security issues. Only 33 awards were made nationally in 2009, with two awarded to faculty in Georgia Tech’s School of Chemistry and Biochemistry. DARPA is funding Dr. Kelly’s research on “Biosynthetic engineering of thiopeptide antibiotics” and Dr. Soper’s research on “Redox-Active Ligand-Mediated Radical Coupling at Terminal Metal Oxo Ligands: Reactions Relevant to Water Oxidation for Artificial Photosynthesis”.

Reproduction can be pressing business, fraught with challenges. But two University of Georgia scientists made a breakthrough discovery in reproduction and regeneration that has thrown open the doors to wide-ranging possibilities, including new therapies for devastating human diseases and the preservation of endangered animal species.

Steve Stice and Franklin West won what amounted to a hotly contested race to become the first scientists to produce induced pluripotent stem (iPS) cells from adult livestock

Scientists Make Breakthrough

Eva Lee Joins Interdisciplinary Team at Emory's New Center for Systems Vaccinology

Eva K. Lee, professor in the H. Milton Stewart School of Industrial and Systems Engineering at Georgia Tech and director of the Center for Operations Research in Medicine and HealthCare, joins a highly integrated and interdisciplinary team conducting research in the newly established Center for Systems Vaccinology at Emory University.

The National Institute of Allergy and Infectious Diseases of the National Institutes of Health awarded a five-year, $15.5 million grant to the Emory Vaccine Center at Yerkes National Primate Research Center in Atlanta. Scientists in the new Center will employ the modern analytic tools of systems biology to understand the immune responses vaccines stimulate in humans and will use this knowledge to guide design of vaccines against HIV, malaria and other global pandemics

Bali Pulendran, the Charles Howard Candler professor in the Department of Pathology and Laboratory Medicine at Emory University, the Emory Vaccine Center, and Yerkes Research Center, is principal investigator of the center. Rafi Ahmed, director of the Emory Vaccine Center and a Georgia Research Alliance Eminent Scholar, will serve as co-principal investigator.

Lee and other researchers at the center will address a major challenge thus far in the development of vaccines - that the effectiveness of vaccination can only be ascertained after vaccinated individuals have been exposed to infection. To study vaccine-induced immunity in humans, they will use a multidisciplinary approach Pulendran developed, which involves immunology, genomics and bioinformatics to predict the immunity of a vaccine without exposing individuals to infection.

Researchers working in the new Center for Systems Vaccinology will determine whether Pulendran's approach can be used to predict the effectiveness of other vaccines, including common vaccines against influenza, pneumococcal disease and shingles. The ability to successfully predict the immunity and efficacy of vaccines would facilitate the rapid evaluation of new and emerging vaccines and the identification of individuals who are unlikely to be protected by a vaccine.

The team's initial work will focus on two major projects on innate immunity and adaptive immunity that ultimately will facilitate vaccine development in several ways: (1) by enabling a strategy to prospectively predict the immunogenicity of vaccines; (2) by offering new and fundamental insights into the genes, cells and networks that orchestrate vaccine-induced immunity in the young and elderly; and (3) by facilitating the generation of an open access database of vaccine-induced molecular signatures.

The Center's interdisciplinary team comprises researchers and clinicians in areas as diverse as immunology, vaccinology, clinical medicine, computational modeling, and mathematics. In addition to Lee, the team includes Nick Haining (Dana Farber Cancer Institute, Boston), Shankar Subramaniam (University of California, San Diego), Alex Sette (La Jolla Institute for Allergy and Immunology, La Jolla), Mark Mulligan (Hope Clinic, Emory Vaccine Center,; and Myron Levine and Adriana Weinberg (University of Colorado, Denver).

Lee, along with Haining and Subramaniam, co-direct the "Genomics and Computational Biology" core of the initiative. The Core will provide expertise, analysis, and experimental platforms to systematically interrogate the immune response to the inactivated trivalent influenza vaccine, the pneumococcal polysaccharide vaccine, and the live attenuated varicella-zoster vaccine. Two major goals in this Core involve development of gene expression-based predictors of vaccine response in humans and use of genomic techniques as discovery tools to better understand the innate and adaptive immune response to vaccines.

Support for the first year of the Center initiative will come from the American Recovery and Reinvestment Act (ARRA).

Researchers have developed an improved coating technique that could strengthen the connection between titanium joint-replacement implants and a patient's own bone. The stronger connection - created by manipulating signals the body's own cells use to encourage growth - could allow the implants to last longer.

Implants coated with "flower bouquet" clusters of an engineered protein that mimics the body's own cell-adhesion material fibronectin made 50 percent more contact with the surrounding bone than implants coated with protein pairs or individual strands. The cluster-coated implants were fixed in place more than twice as securely as plugs made from bare titanium - which is how joints are currently attached.

Researchers believe the biologically-inspired material improves bone growth around the implant and strengthens the attachment and integration of the implant to the bone. This work also shows for the first time that biomaterials presenting biological sequences clustered together at the nanoscale enhance cell adhesion signals. These enhanced signals result in higher levels of bone cell differentiation in human stem cells and promote better integration of biomaterial implants into bone.

"By clustering the engineered fibronectin pieces together, we were able to create an amplified signal for attracting integrins, receptors that attached to the fibronectin and directed and enhanced bone formation around the implant," said Andres Garcia, professor in Georgia Tech's Woodruff School of Mechanical Engineering and the Petit Institute for Bioengineering and Bioscience.

Details of the new coating were reported in the August 18 issue of the journal Science Translational Medicine. The research was supported by the National Institutes of Health, the Arthritis Foundation, and the Atlanta Clinical and Translational Science Institute through the Georgia Tech/Emory Center for the Engineering of Living Tissues.

Total knee and hip replacements typically last about 15 years until the components wear down or loosen. For many younger patients, this means a second surgery to replace the first artificial joint. With approximately 40 percent of the 712,000 total hip and knee replacements in the United States in 2004 performed on younger patients 45-64 years old, improving the lifetime of the titanium joints and creating a better connection with the bone becomes extremely important.

In this study, Georgia Tech School of Chemistry and Biochemistry professor David Collard and his students coated clinical-grade titanium with a high density of polymer strands - akin to the bristles on a toothbrush. Then, Garcia and Tim Petrie - formerly a graduate student at Georgia Tech and currently a postdoctoral fellow at the University of Washington - modified the polymer to create three or five self-assembled tethered clusters of the engineered fibronectin, which contained the arginine-glycine-aspartic acid (RGD)sequence to which integrins binds.

To evaluate the in vivo performance of the coated titanium in bone healing, the researchers drilled two-millimeter circular holes into a rat's tibia bone and pressed tiny clinical-grade titanium cylinders into the holes. The research team tested coatings that included individual strands, pairs, three-strand clusters and five-strand clusters of the engineered fibronectin protein.

"To investigate the function of these surfaces in promoting bone growth, we quantified osseointegration, or the growth of bone around the implant and strength of the attachment of the implant to the bone," explained Garcia, who is also a Woodruff Faculty Fellow at Georgia Tech.

Analysis of the bone-implant interface four weeks later revealed a 50 percent enhancement in the amount of contact between the bone and implants coated with three- or five-strand tethered clusters compared to implants coated with single strands. The experiments also revealed a 75 percent increase in the contact of the three- and five-strand clusters compared to the current clinical standard for replacement-joint implants, which is uncoated titanium.

The researchers also tested the fixation of the implants by measuring the amount of force required to pull the implants out of the bone. Implants coated with three- and five-strand tethered clusters of the engineered fibronectin fragment displayed 250 percent higher mechanical fixation over the individual strand and pairs coatings and a 400 percent improvement compared to the unmodified polymer coating. The three- and five-cluster coatings also exhibited a twofold enhancement in pullout strength compared to uncoated titanium.

Georgia Tech bioengineering graduate students Ted Lee and David Dumbauld, chemistry graduate students Subodh Jagtap and Jenny Raynor, and research technician Kellie Templeman also contributed to this study.

This work was partly funded by Grant No. R01 EB004496-01 from the National Institutes of Health (NIH) and PHS Grant UL1 RR025008 from the Clinical and Translational Science Award program, NIH, National Center for Research Resources. The content is solely the responsibility of the principal investigator and does not necessarily represent the official view of the NIH.