A short seven weeks after the World Health Organization declared Omicron a SARS-CoV-2 variant of concern, this new form of the virus has driven exponential surges in case numbers around the world. Spreading at its current rate, the variant will have infected more than half the population of Europe and Central Asia within the next six to eight weeks, the WHO predicted on Tuesday (January 11); according to the Centers for Disease Control and Prevention, Omicron now accounts for more than 95 percent of the hundreds of thousands of new cases being reported every day in the US.
As scientists race to understand this new variant and how mutations in its genome may contribute to its transmissibility and pathogenicity, questions have arisen regarding the tests that have come to play a critical role in identifying infections.
Rapid antigen tests, also called lateral flow tests, detect viral proteins from SARS-CoV-2 in mucus from a person’s nose or throat. Fast and simple to carry out, the tests have been widely used not only to monitor population-wide infection rates, but to help people make decisions about whether to travel on public transport, go to work, gather with friends and family, or send their child to school. In recognition of their value, US President Joe Biden’s administration has committed to shipping as many as a billion free at-home test kits to households around the country, and announced that private insurers will be required to reimburse people for the tests.
Yet reports in the last couple of weeks have prompted a conversation among scientists and public health experts about whether currently available forms of these tests are quite as effective at picking up cases of Omicron as they have been at detecting previous variants—and thus whether there should be any modifications to how they’re used or interpreted.
A small study by researchers in the US this month, for example, reported that two widely used rapid antigen tests (Abbott BinaxNOW and Quidel QuickVue) seemed to lag by several days in the detection of Omicron cases, with many infected people continuing to test negative despite receiving positive results from more-accurate but slower PCR tests of saliva samples; some of the participants unwittingly transmitted the virus to other people between testing negative on rapid antigen tests. Writing in their paper, which was posted as a preprint on medRxiv on January 5 and was widely covered in the media, the study authors speculated that rapid tests are likely to be less effective in workplace screening for Omicron than they have been for other variants.
An earlier study, posted as a preprint by researchers in Switzerland, compared the performance of seven SARS-CoV-2 rapid antigen tests on cultured virus, rather than on samples provided by people. The authors of that paper concluded that the diagnostics might be inherently less sensitive to Omicron. The US Food and Drug Administration (FDA) subsequently included the idea in one of its Omicron updates, noting in late December that “early data suggests that antigen tests do detect the omicron variant but may have reduced sensitivity.”
There is no test, PCR or otherwise, that can prove that you are not infectious.—Al Edwards, University of Reading School of Pharmacy
Other groups have drawn slightly different conclusions; one team that posted findings as a medRxiv preprint on Monday (January 10) determined that while the rapid tests it examined were less sensitive than PCR tests at picking up Omicron, they identified 95 percent of people with high levels of the virus, and more when only considering people with symptoms.
The findings, which pertain specifically to Abbott BinaxNOW, are in line with what has been reported for tests of other variants, and indicate that “there does not seem to be any performance deficit with Omicron,” study coauthor Joseph DeRisi of the University of California, San Francisco, and the Chan Zuckerberg Biohub tells The New York Times.
Several national organizations have now announced their own plans to investigate. On Sunday (January 9), for example, Germany’s health minister, physician Karl Lauterbach, told the local broadcast channel ARD that one of the government’s health agencies was running an assessment of various tests’ performance, and would be recommending those that most accurately detect Omicron infections. “We do not know exactly how well these tests work for Omicron,” he said, according to Reuters, while emphasizing that COVID-19 testing was still important.
The UK Health Security Agency, which has tentatively concluded that lateral flow devices currently in use by the National Health Service show comparable sensitivity to Omicron as to other variants, is also continuing to monitor the their performance.
For now, it’s unclear whether rapid antigen tests really are less effective at picking up Omicron cases, or what might be causing such a difference, say researchers who spoke with The Scientist. But while it’s an important topic to study from the perspective of understanding Omicron better, any differences in accuracy are likely to be small and do not represent a cause for public health concern provided people keep using the devices sensibly, says Al Edwards, who researches and develops clinical and microbiological tests at the University of Reading School of Pharmacy.
“If you use them with the knowledge that they’re not perfect,” like any diagnostic test, Edwards says, “then if they’re slightly less perfect or more perfect, it’s not a big problem.”
Why might a test perform less well for Omicron?
Despite the preliminary nature of the data, scientists and public health experts have presented a number of hypotheses to explain why certain rapid antigen tests might appear to perform slightly less well for this variant.
One possibility, highlighted by the FDA, is that the devices are less sensitive to this particular form of SARS-CoV-2. This could occur if the antibodies contained in a rapid test are worse at binding to a particular viral antigen in the sample, perhaps because of a change in the structure of that antigen. The UK company Avacta recently cited such lowered sensitivity as the reason it was pausing sales of its own rapid antigen test, after in-house lab assays showed that the device identified fewer Omicron cases than it did infections with other variants in clinical samples where levels of the virus were low, Reuters reported this week.
Edwards says that while some tests may well be less sensitive to particular variants for this reason, it’s unlikely to be a problem across the board. “It’s possible one product would stop working with one variant,” he says. “But most products will use different antibodies to detect the virus, so you would never expect all lateral flow tests to simultaneously fail.” Some researchers, as well as test-maker Abbott, have also noted that while Omicron contains genetic mutations compared to its predecessors, many of those mutations are in what’s known as the spike (S) protein, not in the nucleocapsid (N) protein targeted by many rapid antigen tests.
I think the headlines have already outpaced what we know, as far as the throat goes.—Gigi Kwik Gronvall, Johns Hopkins Center for Health Security
A separate reason that tests could appear to be less sensitive to Omicron than to other variants is if the amount of virus making it into a sample is consistently lower than normal—in this case, fewer samples from people infected with Omicron would contain enough viral antigen to hit the device’s detection threshold.
This could happen, for example, if Omicron is replicating in different parts of the body from previous variants, and so “perhaps people are not sampling in the right place to be able to detect the virus,” says immunologist Gigi Kwik Gronvall, a senior scholar at the Johns Hopkins Center for Health Security and an associate professor at the Johns Hopkins Bloomberg School of Public Health. According to this hypothesis, someone might be “able to get more virus from a saliva or a throat swab” than a nasal swab.
A couple of studies have lent support to this idea. Some researchers have interpreted this month’s US study comparing rapid antigen tests and PCR saliva tests as suggesting throat swabbing picks up more cases, for example. A separate preprint from researchers in South Africa found that PCR tests were better at detecting positive cases in throat swabs than they were with nasal swabs. But Edwards cautions that these kinds of comparisons are challenging to carry out, and that he’s waiting for more data before he draws conclusions about whether the location of swabbing is likely to contribute to substantial differences in test performance for Omicron.
Another possibility, notes Gronvall, relates to Omicron’s apparent ability to replicate much faster, at least in certain tissues, than previous variants, meaning that a negative result is informative for less time. In other words, “people go from being under the threshold of detection for the test to being positive much more quickly than for Delta,” she says. This might explain some studies reporting “that people were transmitting before they tested positive.”
Scientists studying the biology of Omicron’s spread have additionally discussed whether reports of reduced test efficacy could in fact be related to underlying differences in how infectious Omicron is compared to previous versions of SARS-CoV-2. A variant that is infectious at lower doses, for example, could be associated with a higher false negative rate in people who are contagious.
Molecular and virological studies looking into Omicron transmission are still early-stage, but a number of preprints posted in the last few weeks suggest there may be relevant differences in how and where Omicron infects human tissue. For example, Ravindra Gupta, a professor of clinical microbiology at the University of Cambridge, and colleagues have found that Omicron appears to have shifted away from infecting the cells targeted by previous versions of SARS-CoV-2—those with both the ACE2 and TMPRSS2 proteins on their surfaces. While Omicron still requires ACE2, it’s now much better at getting into cells that have little or no TMPRSS2.
This change, which the team reported in a preprint a few weeks ago, could explain observations that Omicron tends to be found in greater quantities in the upper airways, such as the nose and throat, rather than deep in the lungs—a move that may also make the virus more transmissible by increasing how much is released when someone speaks or coughs, Gupta notes. He adds that some preliminary data also suggest that Omicron has increased binding affinity for the ACE2 protein (although that finding isn’t consistent across research groups), something that could confer higher infectivity and may mean that a smaller amount of virus is needed to infect another person.
Molecular virologist Joe Grove of the MRC University of Glasgow Centre for Virus Research and colleagues have also studied how Omicron infection differs from previous variants at the cellular level. They reported in a recent preprint that the reduced dependence on TMPRSS2 seems to be related to a switch in cell-entry mechanism: while earlier versions of SARS-CoV-2 used TMPRSS2 to fuse with the cell membrane and inject their contents, Omicron favors a TMPRSS2-independent, endocytic route whereby the virus is swallowed up by the cell.
This switch, which has been implied by other groups’ work as well, could make Omicron a more stable and therefore potentially more transmissible virus compared to previous variants, Grove speculates. For viruses in general, “cell surface fusion typically requires the virus to have like a hair trigger, so it triggers fusion more readily,” he says. “This is good for entering a cell, but not good for stability,” although it’s too early to say if this general tendency affects SARS-CoV-2’s spread.
When it comes to explaining possible differences in Omicron testing, researchers have yet to tease these and other hypotheses apart from one another, and from confounding factors that complicate comparisons of Omicron to previous variants—such as the fact that, while previous variants spread through largely susceptible populations, many people now being infected with Omicron have already been vaccinated and/or infected with a previous variant.
“Ideas are plentiful and potential hypotheses are plentiful,” Gronvall says, “but the reality is that we need to do these studies to be able to figure it out.”
Should people change their behavior?
Even without a clear explanation for what’s going on with Omicron testing, some countries have responded to recent studies by recommending changes in the way people use rapid antigen tests.
Israel’s health ministry, for example, has advised people to swab both the nose and throat, Reuters reports this week. Several researchers in the US have discussed the same as a way to potentially boost a test’s chance of picking up enough virus to detect. (Some countries, such as the UK, had already approved devices designed to work with throat-and-nasal samples.)
Researchers who spoke to The Scientist say that there’s a lack of evidence that this practice is beneficial. “I think the headlines have already outpaced what we know, as far as the throat goes,” Gronvall says, adding that using this approach on tests that are designed to work only with nasal swabs is clearly not an FDA-approved way to go. While “it would be surprising if [a rapid antigen test] didn’t work” with a combined throat-and-nasal swab, she says, more studies will be needed to show if it makes a difference to test performance.
Some countries have responded to recent studies by recommending changes in the way people use rapid antigen tests.
The FDA itself has advised against the practice, stating in a tweet last week: “The home antigen tests available today are only authorized using nasal swabs. We don’t have any data yet suggesting throat swabs are an accurate or appropriate method for at-home tests.”
Edwards, who has collaborated with other researchers on efforts to make instructions on at-home diagnostics as clear as possible, echoes this point, noting that it’s already hard enough to ensure people follow instructions on these devices. Changing the nature of a test or its instructions “sort of undermines anyone’s understanding of how a test works,” he says, adding that scientists often struggle to assess diagnostics’ efficacy at lessening disease transmission “in the wild.”
One easy way that people could improve their use of at-home kits, particularly in the context of reducing risk at a group event or gathering, is by using the devices as close as possible to the event they’re needed for, says Gronvall. That has always been good practice, she adds, but “if it turns out that the reason why the tests aren’t as a sensitive is because [Omicron] is replicating faster [and] people are going from negative to positive more quickly,” then it becomes especially important not to use a test too far in advance.
Above all, people should remember that no test is perfect, researchers who spoke with The Scientist emphasize; a negative result is never a guarantee that a person doesn’t have SARS-CoV-2 or that they are unable to infect other people. COVID-19 cases vary a great deal among individuals, with different people producing and spreading different amounts of virus at different times after infection, Edwards says. Despite some suggestions to the contrary, he argues, “lateral flow tests are not a good test for infectiousness” at an individual level: “There is no test, PCR or otherwise, that can prove that you are not infectious.”
Gronvall says she advises people “to think about when you were potentially exposed—if you are having symptoms but are not yet testing positive, you probably have it [and] you need to retest in a couple of days.” People should remember too that testing needs to be combined with immunization and other health measures to help stop COVID-19 from spreading, she adds.
Edwards agrees that testing is just one part of the fight against COVID-19, saying that he is not concerned about small changes in test performance for different variants. “The only thing I’m worried about is if people are led to believe that [rapid antigen tests are] perfect when they’re not, or if people believe that because they’re not perfect they shouldn’t bother,” he says. “The two extremes are very harmful—one extreme of saying ‘Well I’ve done my test, I know I’m negative, I can go and do anything I like,’ and the other extreme of saying, ‘Well I’m not going to bother with these tests because they’re not accurate.’”