Antigen tests don’t perform well as a mass testing solution

Womain being swabbed for COVID-19 test

There’s a time and place for antigen tests but they can’t give peace of mind to people without symptoms

The world needs rapid, scalable and accurate testing for SARS-CoV-2 given the resurgence of COVID-19 in many parts of the world, the fast-approaching northern hemisphere winter and the damaging economic and health impacts of coronavirus. Some are championing Antigen tests (which detect viral protein) as the answer. These tests are usually simple-looking tests (like pregnancy tests) that can be carried out quickly (in 10-20 minutes) at point-of-care, without the need for laboratory analysis. They can often be produced at scale and relatively cheaply. However, we need to be aware that whilst antigen tests will quickly help confirm primarily whether people with symptoms have SARS-CoV-2, they cannot reliably detect the virus in infected people who are not yet symptomatic.

Antigen tests are inherently less sensitive than the gold standard Nucleic Acid Amplification Tests (NAAT), of which the Polymerase Chain Reaction (PCR) test is the most well-known and widely-used example. Unlike antigen tests, NAAT amplify any viral genetic material present in a sample many millions, or even billions, of times. This means that the Limit of Detection (aka Analytical Sensitivity) of NAAT is orders of magnitude better than an Antigen test – one Harvard study* has shown that an approved Antigen test would have missed detecting 7 out of 10 people who were infected with SARS-CoV-2. But the accuracy of antigen tests is often only disclosed when detecting patients who have symptoms and remaining silent on their lower accuracy when testing people who are at an earlier stage of infection. Any one of these infected people, who test negative, might go on to unwittingly infect others, or even become a super-spreader seeding the next outbreak of virus.

NAAT are also very specific tests, as they rely on the detecting exact genetic code of the SARS-CoV-2 target gene sequence. A test’s Specificity is important to ensure there are minimal false positive results. This is particularly important when screening large numbers of people for a disease with a relatively low prevalence. If every passenger at an airport were tested using a test with a Specificity even as seemingly high as 97%, hundreds or even thousands of passengers a day might still be given false positive results, and consequently barred entry to their flight or destination, quarantined, and retested, all unnecessarily. The US state of Nevada recently suspended the use of two Antigen tests due to such high false positive rates.

In summary, antigen tests are very useful for confirming quickly whether someone who has symptoms has COVID-19, or if they have the flu. In countries with high numbers of symptomatic people, good antigen tests will be very helpful. However, antigen tests are less useful for testing infected people who are ‘presymptomatic’, where antigen tests may miss detecting SARS-CoV-2. An antigen test with 97% Specificity, when used in mass testing at pharmacies, will give false positive results to 3 in every 100 people tested who will either self-isolate unnecessarily for 10-14 days or need to get a more accurate test to be sure they are positive and really need to self-isolate.

Antigen tests should not be reported by newspapers, or marketed by pharmacists, as giving peace of mind to the majority of the public without symptoms (asymptomatics) as most of these people at any one time are not infected but some will receive false positive results. Of those recently infected people who are asymptomatic, up to half of them will wrongly test negative with an antigen test, which could lead them unknowingly infect loved ones or other members of the public. This is not a firm foundation for mass testing.

We need a test that delivers all three key ingredients: speed, scale and accuracy. The paying public will lose trust in tests where a significant proportion of the results are known to be false negatives or false positives. PCR is, unfortunately, relatively slow and not scalable due to its requirement for lab-based equipment and reagents that are in short supply. However, other NAAT options which deliver on all three requirements do exist. FRANKD is an isothermal NAAT (also known as a RT-LAMP test). It is rapid (30 mins), scalable (not subject to the current global shortage of PCR reagents), and, most crucially, has accuracy similar to the PCR gold standard.

* https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302192/

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