NEW YORK – While initial studies have indicated the SARS-CoV-2 Omicron variant may present sensitivity challenges to existing rapid antigen tests, the data remains inconclusive.
However, even if sensitivity is not an issue, the variant's seemingly quicker course of infection could undermine the effectiveness of rapid testing, especially single-timepoint testing done by individuals in advance of events or other activities.
According to a notice published by the US Food and Drug Administration at the end of December, early research led by the National Institutes of Health's RADx program suggested that rapid antigen tests may have reduced sensitivity to the Omicron variant.
However, that finding was based on an analysis of a very small number of samples and should not be taken as the last word on the subject, cautioned Bruce Tromberg, leader of the RADx program. He added that further work done after the FDA notice somewhat countered those initial results.
The data underlying the FDA announcement came from nine Omicron samples the RADx researchers and their colleagues at Emory University obtained from a partner lab at the University of Washington, Tromberg said. They used those samples to create serial dilutions, which they then ran on various rapid antigen tests as well as on PCR tests. They also created and tested equivalent serial dilutions for the Delta variant and the wild-type virus.
"Basically what they are saying in that FDA guidance is that in these three pools that they made, they could go to a greater dilution in the Delta pool as compared to the Omicron pool," Tromberg said, adding that the rapid antigen tests could detect the virus at higher PCR cycle threshold counts in the case of the Delta variant compared to Omicron, further indicating that the tests were more sensitive for picking up the former.
Tromberg said that while this sort of dilution experiment is a first step toward evaluating if and how Omicron impacts rapid test performance, the gold standard "is to go into the clinic and measure actual patients and pay attention to when the samples were acquired after the onset of symptoms" as well as "whether the person had been vaccinated and boosted prior to infection, because all of those things matter."
"Is the benchtop reduction in sensitivity that we are seeing going to translate into reduced sensitivity in the clinic?" he asked. "That is still an open question."
This work is ongoing, Tromberg said, but he noted that the clinical data he and his colleagues have collected so far has found that rapid tests actually show better performance in real clinical samples than they did in the pooled serial dilutions.
He acknowledged that this was a counterintuitive result, but suggested it could reflect differences in the time points during infection at which the different samples were taken. Previous studies have observed that the ratio of N protein to nucleic acid picked up by swab samples change over the course of an infection. That means that the relationship between N protein concentration and PCR CT count will vary depending on when during their infection a person is sampled. Differences between when in the course of infection the benchtop and clinical samples were taken could be driving the apparent sensitivity data, he said.
Tromberg suggested that the apparently greater speed and efficiency with which Omicron infects individuals might mean people should test sooner after an exposure than they might for previous strains.
He referred to a RADx-funded study out of the University of Illinois that looked at the effectiveness of rapid antigen testing compared to PCR in the pre-Omicron environment. He noted that the study demonstrated a window of around three to six days where rapid antigen tests would pick up infection.
"That was a fairly wide window, and what we are thinking is that [with Omicron] the window is kind of compressed," he said. "The attack rate of this virus is super high, and that sweet spot moment could be narrowed down. So I'm recommending that people test within one to two days of a known or suspected exposure."
In a medRxiv preprint published last week, researchers from the COVID-19 Sports and Society Working Group identified discrepancies between rapid antigen testing and PCR in a group of 30 individuals tested regularly throughout December 2021 as part of a workplace testing program. Looking at those 30 individuals (29 of whom exhibited the S-gene dropout associated with the Omicron variant), the study found that in all cases, rapid antigen tests produced a false negative result on the day of and day after their first positive PCR test. During that period, 28 of those individuals had PCR CT counts of below 29, indicating a viral load above the threshold for infectiousness, the authors wrote. At the second day following the initial positive PCR test, 75 percent of the individuals were still negative by rapid antigen test, while rapid antigen testing was positive for more than 80 percent of subjects by day three and for 100 percent of subjects on day four. The researchers also identified four instances of transmission that occurred while an individual was testing negative for the virus by rapid antigen assay. The study used Abbott's BinaxNow and Quidel's QuickVue tests.
Tromberg, who was not involved in the medRxiv study, noted that this finding did not necessarily represent a break from the performance of rapid antigen tests in previous variants. The U of Illinois study likewise observed that rapid antigen tests did not pick up early infections as well as PCR.
"If you line up the sensitivity of the antigen assay and the saliva RT-PCR in the days before your first infectiousness positivity, the saliva PCR right out of the gate has a very high sensitivity, like 80 percent, and the antigen sensitivity is like 30 percent," he said. "So it's no surprise. You're seeing the difference in the limit of detection between those two assays. My impression is that that is what the [medRxiv] paper is seeing as well."
A paper published last week in the New England Journal of Medicine likewise highlighted the fact that rapid antigen tests will miss many patients in the first days of infection regardless of the SARS-CoV-2 variant involved.
Blythe Adamson, first author of the medRxiv study said that in her work she has seen a decline in effectiveness of both PCR and rapid antigen testing. That decline, she noted, isn't necessarily due to a drop in the performance of the tests themselves, but rather to the fact that the speed with which Omicron infects individuals has made testing less effective for flagging individuals before they transmit the virus.
An affiliate assistant professor at the University of Washington School of Pharmacy, Adamson also runs a New York-based firm, Infectious Economics, that has helped businesses develop plans and protocols for safely reopening throughout the pandemic. A number of her clients have used daily PCR testing throughout the pandemic with, Adamson said, good results.
"I could almost always pick up that someone was positive before they became infectious," she said. "For keeping Broadway shows open, for instance, daily PCR testing was working really well to prevent any exposures inside a theater."
Omicron has changed that, Adamson said. "With Omicron, someone would test negative and we would notice infections [transmitted by that seemingly negative individual] 12 to 24 hours later, which was so much shorter than we have seen with any other variant."
"Because of this, I became concerned that the rigorous testing and safety protocols that we had been using may not be sufficient any more for Omicron," she said. "So, for a period of time in these workplaces, not for research purposes, but for safety purposes, we added daily antigen testing on top of daily PCR testing."
Adamson said that the emergence of Omicron raised questions about how useful rapid antigen tests were for determining whether individuals could safely participate in activities without fear of catching or transmitting the virus.
"We have to be really cautious when we are trying to screen people into a high-risk activity," she said. "If they are asymptomatic, a rapid antigen test probably isn't going to be a very good tool to be confident someone is negative and not infectious before participating."
Tromberg said he believed the tests were still useful but recommended they be used regularly in serial fashion as opposed to spot checking prior to, for instance, a meeting or event.
"It can still be very effective in helping to guide decisions," he said. "Just don't make a super important decision based on one negative antigen test."
Whether this message will be heeded by the public is another question, Tromberg acknowledged. By and large, rapid antigen testing has proved only marginally effective at stopping the spread of SARS-CoV-2 at the population level, a result some observers have attributed to the lack of well-structured approaches to using such tests.