Borrowing from several statistical science models, an interdisciplinary team of researchers from the University of Illinois at Urbana-Champaign has developed a novel computational approach for massively accelerating the search for a hepatitis C vaccine.
“Hepatitis C virus infects 170 million people and kills 350,000 annually,” explained Andrew L. Ferguson, an assistant professor of materials science and engineering and affiliate of chemical and biomolecular engineering at Illinois. “Effective drug treatments have recently become available, but their high cost makes them effectively unavailable in the developing world where most infections exist.”
“A vaccine offers the best hope for global control of the epidemic, but despite 20 years of study, none yet exists. A challenge to vaccine design is that we do not know what parts of the virus we should target to best protect the host. In other words, we do not know how to hit the virus where it hurts. In this work, we present an approach to systematically identify vulnerable targets and computationally design hepatitis C vaccine candidates predicted to cripple the virus.”
By applying so-called “spin glass” models from statistical physics commonly used to describe the behavior of magnets and fluids, the researchers translated clinical databases of hepatitis C virus sequences into “fitness landscapes” quantifying the replicative capacity of the virus as a function of its amino acid sequence. Charting the peaks and valleys of viral fitness, the fitness landscape reveals how best to attack the virus to force it from the high-fitness peaks down into the low-fitness valleys where it is least able to replicate and harm the host.
“We have computed the fitness landscape for the hepatitis C virus protein responsible for viral replication to identify parts of the virus most susceptible to immune attack,” said Gregory R. Hart, a graduate researcher in physics and first author of the paper, “Empirical fitness models for hepatitis C virus immunogen design,” appearing in the journal, Physical Biology. The research team used its model to computationally test 16.8 million candidate vaccines to identify 86 optimal formulations targeting viral vulnerabilities highly susceptible to vaccine-induced immune attack by the T-cells (white blood cells) of the host immune system.
“By identifying a small number of promising vaccine candidates within the vast search space of possible designs, our computational approach can guide experimental vaccine development and massively accelerate the search for a hepatitis C vaccine,” Ferguson added. “We anticipate that with increasing computational power and reducing sequencing costs, it will soon become feasible within the coming years to apply our technology to the complete HCV proteome and perform rational in silico design of a complete anti-HCV immunogen.”
By Rick Kubetz, College of Engineering Communications Office
Andrew Ferguson, assistant professor of Materials Science and Engineering and an affiliate with the Department of Chemical and Biomolecular Engineering, has received the Young Chemical Engineer of the Year Award-North America from the Institution of Chemical Engineers (IChemE).
The award is in recognition of his impressive work on thermodynamic modeling for the development of HIV vaccines.
HIV/AIDS is responsible for the death of nearly 30 million individuals, with another 34 million infected. In the developed world, HIV can be managed by expensive antiretroviral drugs, but a vaccine represents perhaps the only hope for the impoverished sub-Saharan nations most severely afflicted. Despite three decades of effort, an effective vaccine is unavailable.
“An impediment to the development of effective vaccines is the absence of ‘fitness landscapes’ describing the ability of the virus to replicate and damage a host as a function of its DNA sequence,” Ferguson explained. “Such landscapes could be used to rationally design vaccines to induce potent immune responses against vulnerable regions of the virus, and possibly abort infection altogether.”
Together with his co-workers, Ferguson confronted this challenge by pioneering a novel method to translate clinical databases of HIV sequences into viral fitness landscapes based on statistical mechanical models typically used to describe the physics of magnets and fluids.
“In an application to the structural HIV polyprotein Gag, the model predictions are in remarkable agreement with in vitro fitness measurements and clinical data tracking viral evolution in human hosts,” Ferguson said.
Heartened by these validations, the researchers have used their models to computationally design a candidate HIV vaccine formulation predicted to have high efficacy that is currently being tested in mice. A research article describing the work was published in the highly regarded journal Immunity (Immunity 38 606-617 (2013)) and highlighted in two commentary articles.
The Ferguson Lab continues to refine and apply this methodology to Hepatitis C, another devastating virus for which no vaccine exists.
“It is our hope that the innovative application of thermodynamic models to computational immunology will enable a powerful in silico approach to accelerate trial and error experimental vaccine design, and ultimately help alleviate the global suffering caused by infectious disease,” said Ferguson.
Ferguson joined the faculty of the University of Illinois at Urbana-Champaign in 2012. He received his Ph.D. in chemical and biological engineering from Princeton University in 2010 and worked as a postdoctoral fellow at MIT before coming to Illinois.
The awards ceremony in San Francisco was one of a series of events organized by IChemE to celebrate excellence, innovation and achievement in the chemical and process industries across the world.
“The IChemE awards program has been running for 20 years, and this year attracted a record number of entries from all over the world,” said Andy Furlong, IChemE director of policy and communication. “North America is responsible for producing some of the world’s best chemical engineers and all of this year’s winners fully deserve their accolades.”
IChemE awards were also presented to a team from the Fraser Stoddart lab at Northwestern University and to Quentin Baker from BakerRisk.