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Harnessing Changes in Light, WUSTL, U of Michigan Researchers Developing Ebola Test


NEW YORK – Harnessing information that can come from subtle shifts in light, researchers led by a team from Washington University in St. Louis and the University of Michigan have optimized a test for the detection of the Ebola virus.

The technology the test is based on was originally codeveloped by the laboratory of Ryan Bailey, now at the University of Michigan, with diagnostic firm Genalyte, which has commercialized the technology as the Maverick instrument. The new assay, though, adapts the original tech to fill "critical gaps within the diagnostic space" by shortening the window between infection and diagnosis to allow for earlier treatment, according to Abraham Qavi, a postdoctoral researcher in clinical pathology at WUSTL and one of the authors of a study published earlier this month in Cell Reports Methods describing the test.

While the tech has been used for other kinds of biochemical targets and assays, Qavi and his collaborators have a particular interest in viral infections, such as Ebola. For Ebola and other filoviruses that cause hemorrhagic fevers, there's a "critical window period" where detecting the disease is essential to treatment, Qavi said, "but current assays, like RT-PCR and antigen-based testing, just simply cannot detect it early."

The Ebola market is not a new market opportunity for diagnostics, however. In 2019, Orasure Technologies received de novo premarket review from the US Food and Drug Administration for its rapid lateral flow Ebola test, and in 2020 Mologic announced it was working with the Institut Pasteur de Dakar to develop a rapid diagnostic test for the virus. Meantime, Becton Dickinson and a team at Boston University School of Medicine developed a point-of-care test for Ebola in 2018, although BD said at the time it had no plans to commercialize the test.

The test from WUSTL is still relatively early-stage — so far, the test Qavi and his colleagues developed has been validated only in nonhuman primates, but the researchers are currently in the process of planning human trials as a next step. Gaya Amarasinghe, one of the study's authors and a professor of pathology and immunology at WUSTL, said that he doesn't anticipate major issues when validating the test in human samples, but that it's "hard to predict until we actually do it."

In most optical sensors, "light goes in and light goes out, and you look at the difference with the before and after," Qavi said. But this test is different. With a silicon photonic microring resonator platform, light goes in but is "trapped" within a structure and thus has "more opportunity to interact with anything on the surface."

"Instead of a one-hit deal, you now have … hundreds of thousands of interactions with that light with any type of analyte" that is placed on a sensor chip within the device, he said. Those interactions result in shifts in wavelengths, which are then measured and correlated, producing a result in about 40 minutes.

The Ebola test itself detects the soluble glycoprotein (sGP) biomarker in Ebola utilizing the microring resonator and a microfluidic device with a built-in sensor chip. Krista Meserve, another author on the paper and a graduate student in chemistry at the University of Michigan, said that the sensor chip has capture agents — antibodies in this case — that interact with the biomarker of interest as a serum sample moves across the sensor chip's surface via the microfluidic device. The biomarker becomes stuck on the microrings as it binds with the capture antibodies and that binding changes the refractive index within the sensor, which shifts the resonant wavelengths, Meserve said. That shift is measured, with the measurement proportional to the concentration of sGP in the sample.

"Over the course of the assay, we can watch this wavelength change, and then using that overall change is how we correlate that [wavelength shift] to [biomarker] concentration," Meserve said.

Qavi noted that the team relied on previous data from coauthors that had determined the levels of sGP that correlate to infection and compared the results from their test to that data to provide a diagnosis.

The difference between this test and other rapid antigen tests for Ebola, such as Orasure's lateral flow test, is that it targets a different antigen that is "thought to be an early marker of Ebola infection," Qavi said, although he noted that the researchers have not done a side-by-side comparison of sGP and Orasure's VP40. Because sGP potentially shows up in a patient infected with Ebola sooner than other biomarkers, the test would be able to get into the window between infection and diagnosis "earlier than conventional diagnostic tests," he said.

"The earlier patients can be diagnosed, the faster we can initiate treatment, contact tracing, and isolation measures."

In addition, the Orasure test is qualitative, which makes it "great in the context of screening and a yes/no answer," Qavi said. The WUSTL test, however, is quantitative and can provide a numerical readout of the concentration of virus in a sample, he said. 

Although this test was primarily focused on Ebola, Meserve said that her colleagues in Michigan are also working on using the technology with other infectious diseases, including latent tuberculosis, where they measure 14 different cytokine and chemokine targets simultaneously "to create unique signatures for the different disease states involved with tuberculosis infection."

Each chip has 128 individual sensors spaced across the chip surface and putting different capture agents onto different rings would allow for multiplexing, since you would know which rings correspond to each target and can track how the capture agents bind to the targets, Meserve said.

The multiplexing ability would play a key role in the development of a future infectious disease panel, Qavi said, and further differentiates the test from rapid lateral flow Ebola assays.

"One of the issues that you see commonly with viral infections is that the symptoms are nonspecific," he said. The researchers aim to develop a much broader panel to determine whether a patient's symptoms of viral infection are resulting from "something that needs to be triaged immediately" or something benign like a cold. Qavi said that the panel would possibly "include other infections that may be endemic in areas which Ebola virus pandemics occur," such as respiratory viruses, influenza, and malaria.

The assay could be adapted to other diseases relatively easily, Meserve added. Once a target has been decided on, the capture antibodies, analyte of interest, and tracer antibodies would be selected, and the appropriate reagents would be chosen. It can also be adapted for other sample types, such as plasma, cerebrospinal fluid, and whole blood, she said.

Qavi emphasized the flexibility of the platform, saying that "anything you can theoretically do with ELISA, you can also do with the platform, just much more sensitively, much more multiplexed, and much more streamlined."

Right now, the most straightforward commercialization pathway for the Ebola test would likely be to roll it out in centralized labs on Genalyte's existing Maverick instrument, said Ryan Bailey, a professor of chemistry at the University of Michigan and another study author who codeveloped the technology. Genalyte has commercial rights to the technology platform and multiple assays using the technology, although it does not have commercial rights to the Ebola test, he noted. Genalyte's focus is on clinical spaces in the developed world, rather than low- and middle-income countries, said Bailey, who has a minor financial interest in the company, as noted in the Cell Reports Methods paper.

Bailey declined to go into specifics but said that it would not be difficult to miniaturize the technology so it can be used in point-of-care settings and taken out of the lab. The existing full-size instrument is double the size of a desktop computer, but the key portions for this test — the chip and microfluidic setup — are half the size of a credit card, so there are opportunities to make the instrument smaller, he said.

Because many LMICs where Ebola is prevalent lack significant central laboratory infrastructure, miniaturizing the instrument would let users perform the test and get results in places with less access, Bailey said. However, more work would need to be done with local health authorities in these countries to ensure the integrity of reagents is maintained and samples are processed appropriately, he said.