Rapid Antigen Tests: Could they Curb the Pandemic?

As reviewed in the Testing Explainer and explored in a question last June, rapid antigen tests are viral tests for active infection that check for the presence of specific viral proteins called antigens. The simplest antigen tests use a paper strip and work like home pregnancy tests. The person taking the test lightly swabs the inside of their nose and then puts the swab in a small vial filled with a buffer solution. The solution is then poured onto a testing strip that contains specific sites that bind or sequester SARS-CoV-2 antigens. If antigens are present in the sample, a line or spot clearly marks this on the testing strip. Results are usually ready within 5 to 15 minutes.

What is the best use for antigen tests?

For diagnosis and treatment, where doctors need to know if a patient has the virus, PCR tests shine due to their high accuracy. Antigen tests are advantageous for many other public health applications due to their scalability, simplicity, and ability to provide on-the-spot results.

Antigen tests are easy to manufacture in bulk and don’t require additional reagents, so they are more scalable than PCR tests. This means they can be administered to more people and more often. Dr. Fauci has mentioned that antigen tests could be used to gather data by using “a less sensitive test more often” or on a larger group of people. In essence, although each individual test might carry less weight than a PCR test, the overall data about the community can be extremely valuable.

Antigen tests also provide extremely quick results compared to PCR tests, meaning that, in some cases, transmission might be stopped sooner — especially because the tests excel at detecting infection during the peak of infectiousness (there is a distinction between infection and infectiousness, explained here). Fifty leading scientists, led by Dr. Michael Mina, have called for using antigen tests to quickly identify individuals with contagious levels of virus so they can isolate, preventing further transmission and possibly curbing outbreaks. Dr. Mina argues that adding a program of rapid antigen testing to existing public health measures (masks, physical distancing, ventilation) might break the back of the pandemic in weeks, rather than the months needed to vaccinate enough people to restore normalcy.

The idea is simple: rapid antigen paper-strip tests can detect the virus during the peak of contagious infection, letting people isolate so they don’t infect others. Their speed and ease of use make them ideal for public health screening at home, school, work, etc. By reducing onward transmission, ubiquitous testing could yield vaccine-like herd effects. Let’s explore this approach.

Are they good enough to cut transmission?

Yes! To stop outbreaks, one must check for contagiousness. Contagiousness sensitivity is the probability that a test will detect the virus in someone who is capable of spreading it.  Rapid tests have excellent contagiousness sensitivity, comparable even to PCR tests. This means that they can catch nearly everyone currently transmitting appreciable amounts of virus.

Some laboratory clinicians, however, say that antigen tests aren’t sensitive enough to rely on. That’s because when treating patients, diagnostic sensitivity (the probability of detecting any evidence of viral infection) is crucial. PCR tests maximize diagnostic sensitivity by amplifying viral RNA debris. They can detect RNA before a patient becomes contagious and even weeks after a patient stops being contagious (and is no longer of interest to efforts to contain the pandemic)!

Concerns have also been raised about antigen tests that report virus that’s not really there (false positives). The false positive rate in the most recent BinaxNOW rapid test studies was ~1/400. False positive rates can be further reduced by including confirmatory test strips in each pack that test against a different antigen to allow any positive result to be quickly double-checked. Dr. Mina believes that requiring both to be positive could drive the false positive rate below 0.1%.

Why isn’t PCR practical for ubiquitous public health screening?

In order to curb the spread of COVID-19 on a public health level, we need frequent testing and quick results. While PCR tests are extremely useful for clinical testing due to their high diagnostic sensitivity, the cost and speed of antigen tests outperform PCR tests. Oftentimes, individuals taking PCR tests learn that they’re infected — and likely contagious — well after they should have isolated. And while PCR-based clinical labs are great resources for diagnostic testing and even small surveillance programs, they are not designed to perform tens of millions of tests per day as required for large-scale public health screening. PCR tests are expensive in resources (high cost) and time (labs flooded with work); results are slow because samples must be shipped to certified labs; and backlogs increase when infection rates and demand for testing rise.

If not used thoughtfully, high-sensitivity PCR tests can also cause people to be quarantined unnecessarily, after they are no longer contagious.

When will widespread antigen testing be adopted as a public health screening tool?

The idea of using rapid antigen testing to help stop the spread of COVID-19 is still relatively new, but it is gaining more awareness and support. Unfortunately, there are still regulatory hurdles within the FDA for public health screening tools. The FDA regulates tests, and their charter prioritizes diagnostic sensitivity. They want non-lab tests to achieve diagnostic sensitivity at least 90% as good as PCR tests. However, for public health screening purposes, we’re more interested in sensitivity of tests among infectious people. This means that antigen tests that may be useful for identifying infectiousness and public health data are denied approval due to their inability to match PCR test results.

Advocates for widespread rapid antigen testing are lobbying the federal government to create a public health pathway to regulate these tests. The other challenge has been funding and test supply.

One way to expand the availability of rapid testing using existing legal avenues is to perform non-clinical surveillance-based testing. For surveillance testing, test results are not reported directly back to the individual. Instead, for a positive rapid test result, the individual should be told that “In the event of the test indicating a potential presence of COVID-19, you will be notified of ‘findings of potential clinical significance’ and be encouraged to contact your doctor for additional testing. This test alone may not be sufficient to detect or rule out the possibility that you have been exposed to or are infected with COVID-19. You should carefully monitor your symptoms and, notwithstanding the results of any testing, you must stay home and consult with your physician if you experience symptoms of COVID-19.” To give one example using this approach, the National Scientist Volunteer Database has developed a platform for on-site, rapid and affordable COVID-19 surveillance in schools and other community organizations.

Bottom Line:

Obstacles remain, but scalability, simplicity, and public support could help disseminate rapid antigen testing much faster than vaccination, avoiding untold loss of life and economic damage. A serious effort to apply these tests to curb outbreaks deserves consideration. More info is available at rapidtests.org.