Diagnostics Companies Responding to Ebola Crisis

Could a rapid diagnostic test to identify Ebola have prevented the first cases of Ebola transmission in the United States? While it is too late to know for sure, diagnostics manufacturers, federal U.S. defense and health agencies, and regulatory bodies are aggressively working to leverage their current assets to help contain the global epidemic. While Thomas Eric Duncan’s travel history was a missed opportunity to provide earlier isolation and care, administrators at Texas Health Presbyterian Hospital in Dallas say that the lack of an accurate, rapid diagnostic hampered efforts to detect and diagnose the virus. The current gold standard for Ebola diagnosis relies upon polymerase chain reaction (PCR) testing. There are currently no U.S. Food and Drug Administration-approved or -cleared tests for Ebola, but the FDA, as of Nov. 1, has given emergency authorization for use of five Ebola tests. The most recent emergency approvals were two assays developed by BioFire Defense (Salt Lake City; a BioMérieux company). The company’s one-hour FilmArray Biothreat-E test is now cleared for emergency commercial use, as is a second assay (FilmArray NGDS BT-E Assay) that can be used only by laboratories designated by the Department of Defense (DOD). “It would have taken years to get this product approved through the traditional process,” said Kirk Ririe, BioFire’s CEO, in a statement. The assay is run on the FDA-approved BioFire FilmArray system. The company says there are approximately 300 of the $39,000 machines in commercial use in high- and moderate-complexity clinical laboratories. The company flew one out to Bellevue Hospital (New York City) where a U.S. doctor returning from West Africa is being treated for the virus. The other assays approved for emergency use were developed by government agencies—the U.S. Centers for Disease Control and Prevention’s (CDC’s) Ebola Virus NP Real-time RT-PCR Assay and the Ebola Virus VP40 Real-time RT-PCR Assay, as well as the DOD’s EZ1 Real-time RT-PCR Assay. The DOD’s Ebola Zaire Target 1 real-time PCR assay—developed using Life Technologies’ TaqMan series of assays, can be run on several analyzers, including Roche Diagnostics’ LightCycler, the JBAIDS system by BioFire Diagnostics, and the Applied Biosystems 7500 (under the Life Technologies brand of Thermo Fisher Scientific). While the DOD’s assay is based on a single ribonucleic-based target, it is reported that the department is working on a rapid diagnostic using the xMAP Technology and instrument (Luminex; Austin, Texas). Some analysts believe the DOD has an interest in developing a high-capacity multiplexing system, likely with the ability to simultaneously test for Ebola as well as other endemic conditions in West Africa, like malaria and other hemorrhagic viruses. Luminex had previously announced that it was supporting the U.S. Army Medical Research Institute of Infectious Diseases’ (USAMRIID) diagnostics division to develop rapid diagnostics for the Ebola virus. USAMRIID is using the Luminex xMAP technology and MAGPIX instrument. Unlike the DOD’s ribonucleic acid assay, this work focuses on testing serum samples for the presence of viral antigens as well as antibodies directed at these antigens. Luminex says its MAGPIX instrument has been deployed to Africa to support research efforts. Separately, with the support of a four-year National Institutes of Health (NIH) grant, Luminex, along with academic partners, is nearing the completion of development of a multiplex immunoassay Ebola test. The company is assessing whether to seek emergency clearance status but cautions that the test has only been used in simian models to date. “One reason I see that the country is not further along in Ebola diagnostic efforts is inadequate government funding,” Amy Altman, vice president for biodefense at Luminex, tells DTET. She notes that given decreases to infectious disease research funding over the past 10 years and the “miniscule” size of the Ebola diagnostic market before the present outbreak, there was not a business case to justify development. “Companies involved in biothreat work were primed to respond to this Ebola outbreak because Ebola has been listed as a potential biothreat for years, but in a larger way if we are to be prepared for the next emergence of a neglected tropical infectious disease that may not necessarily be a biothreat, we will need greater federal sustainment funding.” POC Tests Also Needed While PCR is the dominant technology for Ebola testing in laboratories, PCR-based tests are not practical in settings requiring point-of-care (POC) testing, such as in airports. Additionally, in resource-constrained areas such as in Africa, cutting the time to run a PCR test by hours does not address greater infrastructure and capacity issues such as getting the sample to the lab, which can take hours, if not days. The Foundation for Innovative New Diagnostics (FIND) says that key to stopping virus transmission are improvements in diagnostic capabilities. The group says that most of the testing done to date in Africa is carried out in a small number of mobile laboratories or in centralized facilities. The turnaround time for testing is close to six hours for patients located in the same town as the laboratory but can be three days for patients living in neighboring towns or districts. Given the cost and difficulty of testing (including the need for personal protective gear to collect samples), diagnostics are largely used to confirm disease in a smaller group of patients with more advanced disease. Current rates of case confirmation, FIND says, are relatively high in Guinea and Sierra Leone (75 percent to 90 percent) but are substantially lower in the hardest hit country of Liberia (30 percent), where laboratory services can’t keep pace with the caseload. In addressing these unique needs, researchers are balancing the need for rapid, POC results with the need for sensitivity. Typically, rapid POC tests have not been able to achieve the sensitivity of PCR-based tests. But in this case, accuracy is of paramount importance to stopping the spread, and false positives or false negatives could further transmit the virus with deadly impact. Takeaway: While the combination of a lack of urgency and financial incentives may have hampered full development efforts of Ebola diagnostics in the past, U.S. diagnostics manufacturers are now scrambling with governmental partners to leverage their core technologies to develop rapid PCR tests and POC diagnostics to combat the Ebola epidemic. Side Box: PCR-Based Ebola Diagnostic Efforts Diagnostics companies both big and small are looking to apply their existing technologic capabilities to tackle the Ebola diagnostics challenge. Below is sampling of companies that have reported working on other PCR-based solutions:

• »Alere (Waltham, Mass.) has begun working to add an Ebola assay for its fully automated nucleic acid Alere q testing platform, which has been launched in multiple developing countries.

• »Cepheid (Sunnyvale, Calif.) had previously conducted work on in-field nucleic acid assays for the Ebola, Marburg, and Lassa fever viruses for the Canadian government utilizing their automated GeneXpert platform. Although the assay was never fully developed or commercialized, the company is seeking funding to revitalize this program and move toward rapid emergency regulatory clearance. The company’s previous experience and the safety component of the closed GeneXpert system put the company in an advantageous position, Cepheid’s CEO John Bishop said on an October earnings call. He added that with the additional funding for incremental development, the company could have a prototype available for evaluation within eight weeks.

• »Roche (Basal, Switzerland) has a PCR-based Ebola test currently labeled for research use only. Roland Diggelman, the company’s chief operating officer for the diagnostics division, said on an October earnings call that the company is in negotiations for submission for emergency use authorization by the FDA and also with the World Health Organization (WHO) for prequalification of the test. Test results take two hours and it is possible to run around 480 samples per day on a single Roche LightCycler machine.

• »PositiveID (Delray Beach, Fla.) believes its handheld Firefly Dx real-time PCR system can deliver results in under 20 minutes at the POC. The company, in early November, signed a research and development agreement with the DOD’s Special Operations Research, Development, & Acquisition Center, Science & Technology Directorate, to further develop the Firefly Dx system for use across the its mission space.

Side Box: POC Ebola Test Development Several American companies are working on applying their technology to POC Ebola testing. Corgenix (Denver) has a longstanding relationship with the hemorrhagic fever group from Tulane University (under Robert Garry, Ph.D.) and the Viral Hemorrhagic Fever Consortium. The group was recently awarded a three-year, $2.9 million NIH grant to continue work on the development of a rapid, recombinant diagnostic test for Ebola. The dipstick-type test is based on lateral-flow technology. OraSure Technologies (Bethlehem, Pa.) confirmed to analysts in mid-October that the company had initiated conversations with the FDA, WHO, and the CDC regarding applying their POC oral-fluid-based platform to the detection of Ebola. On an October earnings call, CEO Douglas Michels said the company is well positioned to extend its technology and hopes to reach key research milestones regarding adaptation of the technology to Ebola by the end of the year.