The viral diseases like Zika. Ebola. Dengue. Influenza. Chikungunya pose serious health threats to U.S. troops, as well as to civilian populations in the United States and around the world, says DARPA. Vaccines exist for but a few of these infectious diseases. And since these viruses have an uncanny ability to mutate and morph as they reproduce inside their hosts, those few vaccines that do exist are quickly outdated, providing little protection against the latest viral strains. That’s why flu vaccine manufacturers, for example, must produce new versions annually, at enormous expense and with variable year-to-year efficacy. The goal of the INTERCEPT program is to develop viral therapies that are effective against a broad spectrum of viral strains, and that can co-evolve and outpace new strains.
Besides vaccination strategies, this threat is handled by the use of antivirals which inhibit virus replication and spread. However, protection against IAV is compromised by rapid resistance development, and by vaccines that need to be reformulated on an annual basis and do not protect against pandemic strains.
Current preventive and therapeutic approaches, including vaccines and anti-viral drugs, are designed to target the virus in its original state at the time of discovery or diagnosis. This paradigm of “static” therapeutics and preventives requires repeated and time-consuming development, manufacturing, and testing, resulting in major health response gaps, economic burden, and limited capability to address newly emerging biothreats.
INTERCEPT uses viral evolution as the basis for its protective effect. Because TIPs are harmless, virus-derived particles with defective genomes that can only replicate in the presence of virus, they interfere with viral infection by competing for essential viral components. And, just like their parent virus, TIPs are susceptible to mutation over time and co-evolve with the mutating virus, thus diminishing the virus’ ability to evade the therapeutic.
DARPA’s INTERfering and Co-Evolving Prevention and Therapy (INTERCEPT) program
Viral pathogens pose a continuous and shifting biological threat to military readiness and national security overall in the form of infectious disease with pandemic potential. Today’s limited vaccines and other antivirals are often circumvented by quickly mutating viruses that evolve to develop resistance to treatments that are carefully formulated to act only specific strains of a virus.
Whereas current preventive and therapeutic approaches are designed to target viruses in their original state at the time of discovery or diagnosis, INTERCEPT program aims to harness viral evolution to create a novel, adaptive form of medical countermeasure—therapeutic interfering particles (TIPs)—that outcompetes viruses in the body to prevent or treat infection.
Viruses are among the simplest infectious entities known. All consist of two main parts: genetic material (DNA or RNA) surrounded by a protein shell. To reproduce, the virus attaches itself to, and then enters, a cell within a host organism and releases its genetic material into that cell. The viral genes then hijack the host cell’s biological machinery, forcing the cell to generate new copies of the viral genome and shell proteins. While still inside the host cell, those freshly minted viral genomes and protein shells assemble into new viruses, which eventually burst from the cell and disperse to infect others.
The observation that defective IAV particles, a natural byproduct of their replication, interfere with the spread of influenza viruses and other respiratory agents by competing for cellular resources and by inducing antiviral responses, opens an exciting possibility for new therapeutic and preventive approaches.
INTERCEPT aims to harness the potential of Therapeutic Interfering Particles, or TIPs—tiny virus-like entities made of laboratory-grown snippets of genetic material packaged inside protein shells. Like viruses, TIPs can enter host cells, but they have no impact on their host because TIPs lack the genes required to independently hijack a host cell’s genetic machinery. “You can think of these TIP-filled envelopes as tiny Trojan horses, but instead of containing warriors they contain pretenders that ultimately outnumber real disease-causing viruses and interfere with their ability to replicate,” said Jim Gimlett, DARPA program manager. And because TIPs are made of genetic material, he added, they will be subject to mutation and diversification over time just as the genomes of real viruses are.
“We want to get ahead of any pathogen that may hit our shores and be as ambitious as we can to take pandemics off the table. We have pioneered new work in DNA and RNA approaches to immunization. Specifically, we are thinking about nucleic acid approaches to immunization. The idea is that you can tell your cells that produce antibodies what the right code is for producing the antibodies that would be effective against a pathogen. So you would get a shot, but that shot would have a code in it to tell your cells how to respond to that pathogen—and what that would lead to is a near-instantaneous immunity against that pathogen and an ability to really fight against it,” said director of its BTO, neuroprosthetic researcher Justin Sanchez.
Over the course of this countermeasure-development effort, INTERCEPT performer teams will use novel molecular and genetic design tools, high throughput genomic technologies, and advanced computational methods to address TIP safety, efficacy, long-term co-evolution, and generalizability. If successful, INTERCEPT will deliver new treatments for fast-evolving viruses such as Ebola, SARS, Dengue, Zika, and Chikungunya—providing broad coverage against multiple strains—and make available a platform technology that could be readily adapted to confront even engineered viral threats.
To explore the TIP concept as a potential therapeutic and/or preventive platform that can keep pace with fast-evolving pathogens, INTERCEPT will address four fundamental questions:
- Safety & efficacy: Can TIPs be built that are safe and out-compete the pathogen to control infections short-term?
- Co-evolution: Can TIPs evolve and keep pace with evolving pathogens to control an infection long-term?
- Population-scale efficacy: Can TIPs co-transmit alongside pathogen to help control the spread of infectious disease across populations?
- Generalizability: Can the TIP concept be extended across multiple viruses and for multiple acute and chronic infectious diseases?
Nevertheless, important roadblocks need to be removed before defective interfering particles (DIP) for therapeutic use (TIP) can be used for treatment of humans. In particular,
i) save and efficient production systems for TIP need to be established,
ii) the full antiviral potential of TIPs needs to be explored by generating and testing TIPs other than the prototype particles such as DI244 established by Dimmock’s group [Dimmock and Easton, 2014],
iii) antiviral activity and safety of optimized TIPs need to be assessed in state-of-the-art cell culture [Frensing, Heldt et al., 2013 and Frensing et al., 2014] and animal models and
iv) mathematical models for TIP/IAV co-infection [Laske, Heldt, et al., 2016] need to be further developed which will pave the way for rational design and optimization of TIPs. The interdisciplinary joint research project DIA_TIP funded by the DARPA will use a systems biology approach to meet these challenges.
The INTERCEPT program is expected to encompass a four-year effort organized in two phases of two years duration each. During the Phase I period, performer teams such as Dstl will establish proof-of-concept of TIPs safety, broad range efficacy, and initial TIP-pathogen coevolution using in vitro and in vivo models of viral infection, as well as mathematical models of TIP-pathogen-host dynamics. The Phase II period will focus on the validation of long-term TIP safety and efficacy, long-term co-evolution studies, and TIP co-transmission dynamics for population-scale disease control.
The Defence Science and Technology Laboratory (Dstl) at Porton Down will support the INTERfering and Co-Evolving Prevention and Therapy (INTERCEPT) program under a contract valued at $997,726 plus options totaling $448,317.
VirionHealth Receives up to $4.2m from DARPA
VirionHealth Ltd, a new biotechnology company developing novel therapeutics for respiratory viral infections, announced that it has won non-dilutive funding worth up to $4.2 million from the US Defense Advanced Research Projects Agency (DARPA). The award will support development of VirionHealth’s new class of biological antivirals, in particular both preclinical and Phase 1 clinical studies for its lead programme.
This effort is funded under DARPA’s INTERfering and Co-Evolving Prevention and Therapy (INTERCEPT) program. Whereas other anti-infective strategies typically take aim at a static target, and become obsolete if the target mutates, INTERCEPT seeks to develop a novel approach that uses evolution to defeat rapidly mutating pathogens and thus keep pace with fast-evolving targets.
VirionHealth’s new class of biological antivirals acts by outcompeting replication of infectious viruses to both prevent and treat viral infections. The company is exploiting this technology to develop the first broad-spectrum therapy, potentially simplifying and accelerating treatment by removing the need for differential diagnosis. In addition, the technology is far less susceptible to resistance than other approaches due to its unique viral out-competition abilities and innate immune system stimulation. Resistance has become one of the most significant concerns for public health globally.
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