More on False Positive and False Negative Serological Tests for COVID-19

An earlier posting looked at sensitivity and specificity of the first FDA-allowed emergency serological test for antibodies to SARS-CoV-2. It then identified some implications for getting people back to work through what a recent article in Nature called an "immunity passport." \1/

The news article cautions that "[k]its have flooded the market, but most aren’t accurate enough to confirm whether an individual has been exposed to the virus." The kits use components of the virus that the antibodies latch onto (the antigens) to detect the antibodies in the blood. Blood samples can be sent to a qualified laboratory for testing. In addition, "[s]everal companies ... offer point-of-care kits, which are designed to be used by health professionals to check if an individual has had the virus." In fact, "some companies market them for people to use at home." But

most kits have not undergone rigorous testing to ensure they’re reliable, says Michael Busch, director of the Vitalant Research Institute in San Francisco]. During a meeting at the UK Parliament’s House of Commons Science and Technology Select Committee on 8 April, Kathy Hall, the director of the testing strategy for COVID-19, said that no country appeared to have a validated antibody test that can accurately determine whether an individual has had COVID-19. ... [S]o far, most test assessments have involved only some tens of individuals because they have been developed quickly. ... [S]ome commercial antibody tests have recorded specificities as low as 40% early in the infection. In an analysis of 9 commercial tests available in Denmark, 3 lab-based tests had sensitivities ranging 67–93% and specificities of 93–100%. In the same study, five out of six point-of-care tests had sensitivities ranging 80–93%, and 80-100% specificity, but some kits were tested on fewer than 30 people. Testing was suspended for one kit.

Point-of-care tests are even less reliable than tests being used in labs, adds [David Smith, a clinical virologist at the University of Western Australia in Perth]. This is because they use a smaller sample of blood — typically from a finger prick — and are conducted in a less controlled environment than a lab .... The WHO recommends that point-of-care tests only be used for research.

False positives arise when a test uses an antigen that reacts with antibodies for pathogens other than SARS-CoV-2. In other words, the test is not 100% specific to the one type of virus. "An analysis of EUROIMMUN’s antibody test found that although it detected SARS-CoV-2 antibodies in three people with COVID-19, it returned a positive result for two people with another coronavirus." It is notable that "[i]t took several years to develop antibody tests for HIV with more than 99% specificity."

A further problem with issuing an "immunity passport" on the basis of a serologcal test is that the test may not detect the kind of antibodies that confer immunity to subsequent infection. It is not clear whether all people who have had COVID-19 develop the necessary "neutralizing" antibodies. An unpublished analysis of 175 people in China who had recovered from COVID-19 and had mild symptoms reported that 10 individuals produced no detectable neutralizing antibodies — even though some had high levels of binding antibodies. These people may lack protective immunity. Moreover, one study showed that viral RNA load declines slowly after antibodies are detected in the blood. Consequently, there could be a period in which a recovered patient is still shedding infectious virus.

A news article in this week's Science magazine also contains information on using serologic test data to estimate the proportion of people who have been infected (prevalence). \2/ It described a German study in which "Streeck and his colleagues claimed the commercial antibody test they used has “more than 99% specificity,” but a Danish group found the test produced three false positives in a sample of 82 controls, for a specificity of only 96%."

The article also mentions a survey in which "Massachusetts General Hospital pathologists John Iafrate and Vivek Naranbhai ... collected blood samples from 200 passersby on a street corner [and] used a test whose maker, BioMedomics, says it has a specificity of only about 90%, though Iafrate says MGH’s own validation tests found a specificity of higher than 99.5%."

NOTES

1. Smriti Mallapaty, Will Antibody Tests for the Coronavirus Really Change Everything?, Nature, Apr. 18, 2020, doi:10.1038/d41586-020-01115-z
2. Gretchen Vogel, Antibody Surveys Suggesting Vast Undercount of Coronavirus Infections May Be Unreliable, Science, 368:350-351, Apr. 24, 2020, DOI:10.1126/science.368.6489.350, doi:10.1126/science.abc3831