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DARPA Programs Leveraging Host-Response Testing, CRISPR for Future Pandemic Preparedness

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NEW YORK ─ The Defense Advanced Research Projects Agency (DARPA), an agency of the US Department of Defense, is supporting the development of testing platforms to enable a rapid response for diagnosis and treatment during a pandemic.

An initiative with a product closest to market, called the Epigenetic Characterization and Observation (ECHO) Program, was launched in 2018 to support the development of a point-of-care diagnostic platform that analyzes epigenetic fingerprints to provide a detailed map of a person's exposure to infectious diseases, weapons of mass destruction, and the precursors of weapons of mass destruction, DARPA said.

The agency launched a second program, called DIGET for Detect It with Gene Editing Technologies, last October to enable the development and commercialization of a laboratory test that uses gene-editing technology to monitor, detect, and differentiate among 1,000 disease-causing pathogens at once from a single patient sample.

A panel that can be deployed at the point of need to detect pathogens that are likely to be the most contagious and cause the most severe illnesses is also under development as part of the DIGET program. The results of testing using the broad lab-based pathogen panel would inform the addition of critical targets to the point-of-care panel, DARPA said.

Both programs employ testing modalities that differ from each other, but they are crucially linked in their objective to facilitate more comprehensive and faster approaches to testing than are available through current PCR- and antigen-based tests, according to managers of both DARPA programs.

Both the ECHO and DIGET programs are taking aim at the diagnosis of SARS-CoV-2 and its emerging contagious variants, as well as other infectious diseases of potentially high prevalence or severity during pandemics, epidemics, or routine clinical practice.

According to DIGET Program Manager Jean-Paul Chretien, they are the two main DARPA programs for pandemic-related point-of-care diagnostic platform and test development.

In addition to facilitating the development of platforms for pandemic preparedness, Chretien said, the ECHO and DIGET programs also support the development of tests to detect other medical conditions of interest to the military and civilians.

Many types of respiratory infections, for example, have the potential to disrupt military operations and cause illnesses during training. Other conditions of concern for the DoD include gastrointestinal infections and vector- or mosquito-borne diseases that sometimes arise in remote settings.

"With DIGET, we're taking advantage of the high specificity and sensitivity of CRISPR to develop a platform as accurate as gold standard PCR," Chretien said. "But the goal is to also provide test results quickly at the point of need and be able to multiplex and detect many targets at the same time."

As part of the program, DARPA is collaborating with Kansas City, Missouri-based MRIGlobal to develop and commercialize both the laboratory and point-of-care platforms.

DARPA has awarded MRIGlobal a contract of up to $36.7 million over four years. MRIGlobal is currently developing the core assay chemistries for both the lab and point-of-care platforms, Chretien noted.

The collaborators are developing the point-of-care diagnostic test to be disposable and have approximately 10 targets that are deemed most important. The laboratory platform would monitor and detect 1,000, or more, targets at a time.

Though both platforms are in early development, the collaborators "can already see their potential in the context of the current pandemic," Chretien said.

If it were available, the massively multiplexed laboratory platform would detect multiple strains at the same time and be rapidly reconfigured with new targets as new strains come to light, while the point-of-care system could be deployed in doctors' offices and other such settings or be used in the home, Chretien said.

Such an approach is expected to be even more effective when it is paired with broad host-response testing and surveillance, Eric Van Gieson, DARPA's ECHO program manager, said in an interview.

"Right now, you have to wait about four or five days until you have enough virus that it can be detected by the most sensitive RT-PCR test," Van Gieson said. "You have to wait even longer for an antigen test because it is less sensitive. By detecting the host response, we are seeing people testing positive within 36 hours."

The diagnostic platform leverages epigenome-based host-response biomarkers, including chromatid and methylation markers that reflect how the immune system is responding to threats, he said.

According to DARPA, technology being developed as part of ECHO could enable rapid diagnostic testing for troops who may have been exposed to threat agents or who may be suffering from infections, and provide timely information to enable effective medical countermeasures. 

As part of the ECHO program, Fluidigm is a subcontractor to the Icahn School of Medicine at Mount Sinai, which received an award of $46.8 million.

Last August, the San Francisco-based firm obtained US Food and Drug Administration Emergency Use Authorization for its Advanta Dx SARS-CoV-2 RT-PCR assay, an extraction-free saliva-based test to detect nucleic acid from the SARS-CoV-2 virus. Its next test leverages the host response for SARS-CoV-2 diagnosis, Van Gieson said.

The platform uses real-time PCR for host detection assays that target the epigenome and viral RNA for early-stage monitoring of potentially infected people. A single integrated fluidic circuit can screen 192 samples across 24 different parallel processed assays. Labs will be able to generate more than 6,000 individual test results per day with just one hour of hands-on time, Fluidigm said.

A company spokesperson said the firm believes the application of its "microfluidics technologies to epigenetic testing has significant potential to increase the speed and capacity of critical screening efforts." The partnership with DARPA will enable it to accelerate the development of its microfluidics technologies "in support of new applications and systems that extend beyond epigenetics," the spokesperson added.

The first host-response point-of-care test being develop by DARPA with Fluidigm and Mount Sinai is expected to consist of RNA biomarkers, but the developers have a focus for future versions of the test on incorporating longer-lasting methylation and chromatin remodeling biomarkers, Van Gieson said.

Further, the collaborators are developing the platform to be diagnostic and prognostic so that it can be used to predict disease outcomes, he said. Healthcare personnel would use it to determine whether people are going to be asymptomatic or whether the illness is going to be mild or severe, or possibly lead to death.

"Even if you have a platform that you think allows you to test for every possible pathogen, there can always be an infection that you haven't seen yet, or you hadn't thought to put in a panel," Van Gieson said, adding that a host-response test is "fairly generic and allows you to distinguish at least a category of pathogens," enabling early medical intervention.

Having the ability to evaluate the host response and detect a broad range of specific pathogens with high-throughput and at the point of care would be ideal, he added.

As well as facilitating the development of future diagnostic testing systems, the DoD is supporting the use of current technology and announced this month that Abbott Rapid DX has been awarded a $255 million contract to provide 50 million SARS-CoV-2 rapid point-of-care antigen tests.

Further, the US Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA) is supporting the development of current diagnostic testing technology for SARS-CoV-2, including host-response testing. Under a contract valued at up to $72 million funded by BARDA, Burlingame, California-based Inflammatix is developing a sample-to-answer, point-of-care system that analyzes RNA expression using machine learning and produces results in less than 30 minutes.

According to Matt Hepburn, an infectious diseases physician and DoD's Operation Warp Speed vaccine development lead, the current pandemic triggered advances in point-of-care diagnostic testing that can be leveraged in the future for more effective infectious disease testing.

Hepburn is not involved in the ECHO of DIGET programs but is familiar with the technologies and worked previously for DARPA and as the director of medical preparedness with a focus on pandemic preparedness on the National Security Council for former US President Barack Obama.

"COVID taught the diagnostic industry how to test somebody, isolate them, and hopefully control the spread of disease," he said. "This is important not only for COVID but also for many other infectious diseases such as HIV, hepatitis C infections, sexually transmitted infections, influenza, and many other conditions. If we can make testing accessible, affordable, commonplace, and easy to use, and we can figure out a way to do effecting reporting and tracking, we can have a tremendous impact on infectious diseases."