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Clinical Investigators Validating Mouth Swab PCR Test for TB

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NEW YORK – Clinical investigators are testing an approach being developed by Longhorn Vaccines and Diagnostics to diagnose tuberculosis using mouth swabs, which could become an alternate approach to sample collection methods currently used to do TB testing.

Partly because of the convenience of the collection method, the technique is helping increase access to testing and finding people with TB that have been undetected by traditional testing methods, said Bernard Fourie, a professor and TB research specialist at the University of Pretoria, South Africa, who is also one of the clinical investigators.

Using Longhorn's nucleic acid stabilization method and qPCR assay in an ongoing study, Fourie and his colleagues detected Mycobacterium tuberculosis DNA in the mouths of one-third of the people in a high risk infectious disease population that would not have been identified using smear microscopy or rapid molecular testing, Fourie said.

The study participants tested positive for incipient or subclinical tuberculosis, a point in the evolution of the condition when patients are not showing symptoms but are likely to progress to active disease and transmit infections to others.

The investigators presented the results of their study in April 2019 at the 29th European Congress of Clinical Microbiology & Infectious Diseases in Amsterdam, Netherlands, but the work is ongoing, and the researchers are continuing to track the progress and clinical outcomes of the study participants.

In their study, the group combined use of Longhorn's qPCR assay with the firm's PrimeStore Molecular Transport Medium (MTM), which stabilizes microbial nucleic acids and enables safe transportation of mouth swab samples at ambient temperatures, preserving their integrity for nucleic acid testing. The group collected and tested samples from people during house visits in an urban setting in South Africa with a high prevalence of TB and HIV. The researchers used flocked swabs to collect oral salivary specimens from 73 adults. Each person had a cough and one or more risk factors for TB, including previous TB, or was asymptomatic but residing with someone diagnosed with TB.

The investigators combined the swab samples that they had collected with PrimeStore MTM to enable microbial inactivation, DNA stabilization, and transportation of the specimens at ambient temperature to a nearby lab. The group detected M. tuberculosis DNA in 24, or 32.9 percent, of the 73 samples using Longhorn's PCR diagnostic assay running on a Roche LightCycler platform.

Fourie said that he believes the approach holds promise as an easy to perform, safe, and patient-friendly procedure for triaging people who are presumed to have TB at the household level, and it provides a basis for targeted patient follow-up. Fellow investigators in Pretoria are planning to implement the technique, he said.

The approach has been instrumental in convincing subjects to attend clinics for follow-up treatment or medical counselling, which is by itself an important outcome, Fourie said.

In their work, the investigators are seeing sensitivity levels that are at least equivalent to Cepheid's advanced assay for TB testing, the Xpert MTB/RIF Ultra, but with a comparatively minimal specimen, Fourie said.

Longhorn received the go-ahead to market PrimeStore MTM in 2018 through the US Food and Drug Administration's de novo pathway.

The classification cleared PrimeStore MTM for the stabilization, transportation, and inactivation of infectious unprocessed nasal washes suspected of containing Influenza A virus RNA, and for the stabilization, transportation, and inactivation of infectious unprocessed samples suspected of containing M. tuberculosis DNA.

Because the clearance involved samples suspected of containing influenza A virus RNA and M. tuberculosis DNA, clinicians can use PrimeStore to test for multiple pathogens associated with both conditions, said Jeff Fischer, president of Longhorn. The clearance was an important milestone for closely held Longhorn, which has been in business since 2006, he said.

The company is focused on further proving the clinical utility of the TB diagnostic testing approach with a view to achieving adoption in low resource, high prevalence countries, he said.

Use of a swab to collect saliva in the mouth may lead to a suitable complementary approach to other TB testing methods, and in the long run become a "more cost-effective way" of doing this kind of testing, according to Fischer.

A number of companies are either providing or looking to develop diagnostic tests that have a variety of sampling methods.

Blood-based laboratory assays developed by Qiagen and Oxford Immunotec, that leverage interferon gamma release assay (IGRA) technology, have already found acceptance in the market for detecting latent TB infection, and Cepheid's sputum-based Xpert molecular diagnostic platform and tests have found broad adoption to detect active TB disease.

ProteinLogic, a new entrant developing a test based on an immune system biomarker signature and predictive models, uses blood samples as a basis for detecting active TB disease as opposed to latent infection, and Rapid Diagnostics is looking to establish manufacturing and assembly facilities in China for components of a molecular multi-drug resistant TB (MDR-TB) point-of-care test that uses either swab or liquid samples.  

Proponents of near-patient testing argue that doing laboratory testing can slow down receipt of clinical results because patients and their doctors have to wait while samples are shipped to laboratories that run the tests and then provide results. Cartridge-based molecular tests, such as Cepheid's TB assays running on its GeneXpert platform, provide a rapid time to result, but how quickly test results can be achieved ultimately depends on clinical workflows.

Fischer noted that using PCR, mouth swabs, and PrimeStore MTM, laboratory directors can conduct a high volume of tests using a laboratory PCR platform. They also can choose from a range of available compatible PCR platforms, freeing them from having to purchase a single machine, he said.

Being able to conduct a larger volume of tests in a single run should contribute to driving down overall costs, and tests may then be done in the future at affordable price points, possibly as low as $5 per test, Fischer said.

PrimeStore enables testing with multiple pathogens and sample types and can be used with a number of real-time PCR platforms, Longhorn said. Its system is compatible with next-generation sequencers including Thermo Fisher's Ion Torrent and Illumina's MiSeq.

The company is developing a next-generation sequencing assay for the diagnosis of drug-resistant tuberculosis, which it anticipates will soon undergo evaluation as part of a program run by the Foundation for Innovative New Diagnostics (FIND) and Unitaid to evaluate the use of such technology in low- and middle-income countries.

The Bethesda, Maryland-based firm is currently marketing PrimeStore MTM to government entities and infectious disease surveillance groups, and it is looking to expand into animal testing by developing a molecular diagnostic test for African swine fever.

It anticipates eventually submitting applications to obtain US regulatory clearance and IVDR approval in Europe for its TB assay, though the firm did not disclose anticipated timing. 

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