Covid Update: Negative or Not?

In an accompanying article, I report that my wife and I both tested negative before our return trip from Europe and for 5-7 days after returning to Del Mar. These tests were all variants of the rapid COVID antigen tests that report results after 10-15 minutes. I concluded (or hoped) that we had not been infected with the COVID virus or its several variants during our trip. With recent reports that these antigen tests may report false negatives for many days after infection, it is important to review how reliable these tests are for fully vaccinated, asymptomatic individuals at this time in the pandemic. Could these negative tests have misled us?

A recent study (Sensitivity of rapid COVID antigen tests during PCR-confirmed COVID infection by Chu VT, Schwartz NG, Donnelly MAP, et al. JAMA Intern Med. Published online April 29, 2022. doi:10.1001/jamainternmed.2022.1827) conducted in San Diego and the Denver area, recently published by JAMA Internal Medicine, compared the sensitivity… of the Quidel QuickVue SARS Antigen test that detects the presence of the COVID virus nucleocapsid (NC) protein to the gold standard viral nucleic acid RT-PCR test. The antigen test strip has a positive control (a blue line appears within 10 minutes of sample loading) and a separate red line appears if the test is positive, meaning that NC protein was present in the nasal swab sample.

The antigen test was 80% effective in detecting PCR-confirmed infection 3-4 days after symptoms of infection appeared in unvaccinated individuals, but only 50% effective in vaccinated subjects. These studies were conducted in 2021 before the Omicron variant was present in the study population, so it is highly unlikely that variation in the NC protein (which is much less variable than the spike protein) explains these results.

What is going on to explain the lower sensitivity in vaccinated subjects? The most likely explanation, although not the only one, is that the viral load is reduced after vaccination, resulting in less NC protein for the antigen test to detect. This would imply that individuals with asymptomatic infection might have false negative antigen tests because their viral load is likely to be low. 

The immune system should be activated after vaccination much earlier than in unvaccinated individuals, leading both to a lower viral load and a delay in symptoms of infection. There are more complicated related explanations. Fully vaccinated older individuals may have less effective immune responses that initially control the virus at low and undetectable levels, but then fail and allow the virus and symptoms to emerge later than expected. 

We still have a lot to learn about COVID infection and its consequences, how variable they are between individuals, and how virus variation contributes to disease severity. More studies like the one cited are needed to understand how virus detection assays work in the current disease context. But for now, negative rapid antigen test results should be considered inconclusive if COVID-like symptoms are present (50% sensitivity is not reassuring), and the much more sensitive nucleic acid test (RT-PCR) should be considered. After our trip to Europe, I am happy to report that we were antigen test and PCR test negative.