By Matthew Bauer and Nicole Welch
Diagnostic tests have changed in the eyes of many Americans across the COVID-19 pandemic.
The traditional site of diagnostic testing, the doctor’s office, has taken a back seat during the COVID-19 pandemic. We can now receive at-home antigen tests in the mail, drive through PCR tests at local sports stadiums, and our workplace cafeteria may serve as a de facto COVID-19 testing site.
The new paradigm of fast, easily accessible, and user-based diagnostics helps to reduce barriers for people to test for COVID-19.
However, nearly all these tests give binary results of yes or no for detecting a specific piece of the SARS-CoV-2 virus. As we look ahead, both the ongoing COVID-19 pandemic and future pandemics will require binary tests, but also tests that give us more granular information about the disease. These changes should be integrated into future diagnostic paradigms, empowering clinical diagnostics to meet both the needs of patients and the broader public health community.
What do current COVID-19 diagnostic tests look like?
The vast majority of COVID-19 diagnostics are molecular (PCR) tests. These are considered the gold standard of many diagnostic tests by using specific probes to amplify and detect the presence of a piece of viral RNA. Because of the test’s high sensitivity, specificity, and speed, it is a ubiquitous tool in diagnosing COVID-19. However, because this test only can detect a single virus in a single sample, diagnostic centers such as at the Broad Institute of MIT and Harvard, they are required to have hundreds of expensive PCR machines to keep up with testing needs.
At-home tests or rapid COVID-19 tests (antigen tests) have also emerged as an essential tool for the average consumer to test themselves with very little resources and even faster turnaround time. These tests can be self-administered, and results visually read out within 15-20 minutes. This test is most compared to at-home pregnancy tests which function in a very similar way in terms of recognizing a specific protein. The advantages to these tests are the rapid turnaround time and no specialized equipment is needed to perform the test. However, they are less sensitive compared to PCR, and require user interpretation of a colorimetric change, which can be very difficult to judge for some samples. Lastly, these tests are expensive for the end consumer when not freely provided by the U.S. government, and still only provide the binary (Yes, No) results of detecting a specific protein piece of a virus.
Both current antigen and molecular-based diagnostic tests have been instrumental in detecting SARS-CoV-2 virus. The availability of these tests allows for quick response to infections and helps inform public health measures based on the number of positive case counts within different geographic regions. But these tests fail to provide information about virus subtype, which is critical to understanding the underlying biology and spread of the virus.
What might the ideal diagnostic test look like?
An ideal diagnostic test would need to be fast, sensitive, comprehensive, highly specific, and provide genetic information about the pathogen being tested. It should also move away from testing for a single pathogen, by multiplexing the diagnostic for many different viruses or common infections. This would help determine if a person has multiple infections at once, for example, the influenza infection and SARS-CoV-2 virus.
Some diagnostic companies have attempted to solve this problem. For example, BioFire Diagnostics has developed a multiplexed diagnostic that can identify 22 different pathogens (viruses and bacteria) in roughly 1 hour. This type of diagnostic test is closer to the kinds of tests ordered by a physician when infection status is unknown or inconclusive per standard tests. Though BioFire offers the advantage of testing for multiple pathogens, it falls short on sample throughput (the ability to process many samples at the same time) and sensitivity. To meet the high sample volume demands of a pandemic, a comprehensive test with higher throughput is needed.
Researchers at the Broad Institute of MIT and Harvard have developed a diagnostic platform with the potential to meet these current and future public health needs. This test, called mCARMEN, is a different type of molecular diagnostic that relies on CRISPR-based detection of viruses. This CRISPR-based assay boosts sensitivity and specificity over the gold standard, PCR tests. By combining the test with microfluidics, which facilitate the analysis of liquids at a micro-scale, the researchers have been able to develop highly-multiplexed panels for respiratory virus and SARS-CoV-2 variant of concern detection with only a nasal swab as input.
mCARMEN, like PCR, has similar sample-to-result turnaround times, requirements for specialized equipment, and high throughput capabilities. Yet, mCARMEN can detect multiple infections at once, unlike PCR. This test came at a critical time when treatment using monoclonal antibodies worked differently for those infected with Omicron versus Delta variants of the SARS-CoV-2 virus. By knowing the vast majority of individuals testing positive in late December had Omicron, physicians could tailor the treatment accordingly.
The holistic results offered by mCARMEN highlight the assay’s utility in light of current and future variants. However, this test remains relegated to the lab, and is not available over-the-counter, like antigen tests.
A forward-looking view of diagnostics
The pandemic has spurred many changes in health care infrastructure, but the future of diagnostics and the speed of diagnostic innovation may be one of the greatest takeaways.
Clinical diagnostic tests in the future should be multiplexed assays that can detect dozens of different pathogens from a single test, and with a higher sample processing throughput than current technologies. We can expect the continued clinical development of diagnostics like mCARMEN, which incorporate not only binary (Yes, No) results, but also qualitative information about the type of pathogen to directly inform clinical decisions. Outside of the context of viral diagnostics, this type of diagnostic could also counter the growing problem of bacterial resistance spurred by overprescribing antibiotics for non-bacterial infections.
Lastly, given the increased consumer confidence in administering at-home COVID-19 tests, we will likely see over the counter at-home tests for influenza or other respiratory diseases in the not-too-distant future. These changes will hopefully empower patients to have more agency to test and diagnose illnesses themselves.