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Implementation Strategies for Rapid Antigen Testing Crucial to Keeping COVID-19 Cases Down


NEW YORK – While regulatory differences between the US and Europe have impacted the price and accessibility of rapid antigen tests for COVID-19, the relative strictness or laxness of a country's authorization process may be secondary to its implementation of rapid testing in terms of stemming the virus's spread.

The US and Europe have taken divergent paths on SARS-CoV-2 rapid antigen testing, with a looser regulatory regime and more government support for rapid and home testing leading to more accessible and less expensive tests in many EU territories.

The UK and Germany, for instance, provide rapid antigen testing free of charge. In the UK, tests can be ordered for free online or picked up from local testing centers. In Germany, the government began in March of this year providing asymptomatic individuals with one free rapid test per week to be conducted at a range of healthcare facilities including doctor's offices, public test centers, and pharmacies.

In Germany, home SARS-CoV-2 tests from dozens of manufacturers are available for purchase from retailers including many pharmacies and grocery stores, typically in packs containing multiple tests and at a price of around €1 per test.

This contrasts with the US where just eight rapid SARS-CoV-2 tests have received US Food and Drug Administration Emergency Use Authorization for over-the-counter sales, and prices typically range from $20 to $30 for a two-pack of tests. Availability of these tests has also been an issue in the US, especially in the face of the Delta variant's spread this summer throughout much of the country.

The Biden administration announced this week it would put $1 billion toward rapid antigen tests with the aim of expanding availability fourfold by December.

Many US proponents of rapid antigen testing have claimed that the FDA's more stringent requirements around test production and performance have proved counterproductive, limiting the public's access to these tests and making them too expensive to use as tools for regular screening. They argue that while some tests sold in EU markets may have relatively low sensitivity or specificity, the greater accessibility to these tests means people can buy them easily and use them frequently, making them useful for picking up cases and breaking chains of infections despite their sometimes middling performance.

The FDA, meanwhile, has maintained that availability is important but that access to testing and high regulatory standards remain compatible goals. While this may be true in theory, the agency has in effect limited the number of vendors selling SARS-CoV-2 rapid antigen tests in the US, both directly, by rejecting tests accepted for use in other countries, and indirectly, by discouraging — intentionally or not — vendors from even applying for EUA.

Less clear is how these different approaches to rapid antigen testing have influenced the course of the pandemic in these countries. Had laxer regulation from the FDA led to an influx of less expensive, lower performing tests, would this have improved or compromised the COVID-19 response in the US?

The raw case and fatality figures don't point to an obvious answer. Germany has significantly outperformed the US, with, according to numbers from the New York Times' COVID Tracker, total cases of 5,140 per 100,000 people and 113 deaths per 100,000 people, compared to 13,238 cases per 100,000 people and 213 deaths per 100,000 people in the US. However, the UK, which also has an extensive rapid antigen testing program (which relies heavily on a test from vendor Innova that the FDA has rejected for use in the US) has fared roughly the same as the US, posting total cases of 12,113 per 100,000 and 214 deaths per 1000,000.

A number of studies have shown that rapid antigen testing, particularly when done frequently, is an effective screening tool and can match the sensitivity of less regular molecular testing.

For instance, a June study of 43 individuals at the University of Illinois — where on-campus students and staff are required to undergo regular saliva-based SARS-CoV-2 molecular testing — found that testing every three days with Quidel's Sofia SARS Antigen FIA test and the Sofia 2 device detected SARS-CoV-2 with a sensitivity of 98 percent, the equivalent of weekly testing using molecular assays.

The Quidel test has received FDA EUA, which means the study did not directly address the question of how effective rapid antigen tests that did not meet the FDA's requirements might be when used for serial screening.

In August, a team led by researchers from Cambridge, Massachusetts-based test developer E25Bio and lab co-working company BioLabs published a study in JAMA Network Open looking at the effectiveness of E25Bio's home antigen test (which is not currently on the market in the US and has not received FDA EUA) for SARS-CoV-2 as a screening tool.

The study followed 257 individuals at three BioLabs facilities (where E25Bio is a resident company) in Cambridge and Boston over the course of six months. Participants were tested twice weekly using the E25Bio test and by PCR. Over the course of the study, 15 individuals had COVID-19, with all of these cases picked up by twice-weekly rapid antigen testing. Looking at the performance of the E25Bio test at single time points, the assay was 79 percent sensitive within zero to 12 days of symptoms emerging and 96 percent sensitive within zero to three days of symptom onset.

"The results I think are pretty compelling in that they show that, albeit with a very low frequency of COVID infection among our members, [the test] detected 15 out of 15 infections, pretty much performing as well as PCR," said Laura Holberger, VP, strategic partnerships at BioLabs and senior author on the study.

College campuses and workplaces, however, are relatively controlled environments where regular testing regimens can be implemented more easily than within the broader community. Results from the few large-scale studies exploring the effectiveness of rapid antigen testing in larger populations are more mixed.

From November 2020 through April 2021, the UK government ran a trial studying the impact of widespread testing with the Innova SARS-CoV-2 rapid antigen test in Liverpool. Over that time period, 283,338 residents (57 percent of the total city population) took an Innova test, with 47 percent taking more than one test. The study investigators estimated that use of the rapid test increased case detection by 18 percent compared to similar UK areas without a rapid testing regime and prevented between 850 and 6,600 infections. The study saw only an insignificant reduction in hospital admissions, however.

A Slovakian study published in Science in March found widespread rapid antigen testing to be more effective. Conducted in October and November 2020, the campaign ran 5,276,832 SD-Biosensor Standard Q rapid antigen assays testing more than 80 percent of the country's population between 10 and 65 years old along with older adults who were still a part of the workforce. Testing was conducted in three rounds. The first round, a pilot, tested four of Slovakia's counties most affected by the virus. That was followed a week later with a round that tested the full population, which was followed a week later by a third round of testing targeting high prevalence counties. The rounds tested, respectively, 87 percent, 83 percent, and 84 percent of the eligible populations and identified a total of 50,466 positive individuals.

The researchers estimated that cases declined by 70 percent over this time period compared to a scenario where no steps were taken to mitigate spread and added that while the observational nature of the study made it difficult to tease out the effects of the testing campaign from other interventions introduced during this time period, modeling indicated the decrease in prevalence could not be explained solely by these other interventions.

In March of this year, the German city of Tübingen experimented with reopening nonessential businesses while implementing widespread rapid testing. Residents could undergo rapid antigen testing at multiple stations around the city, and upon testing negative they were given a "day ticket" that allowed them to participate in activities like shopping in nonessential stores or go to an outdoor bar or restaurant or to a movie theater. Individuals who tested positive were passed on for PCR testing.

Comparing COVID-19 case numbers in Tübingen to rates in a defined control region still under lockdown over a period of four weeks, the researchers found that rates increased but only temporarily and that roughly half of the increase was due to infections that would not have been detected without the testing program.

The study demonstrated that rapid antigen testing done on a large scale and in a structured manner can be useful, suggested Ulf Dittmer, director of the Institute of Virology at Germany's Essen University Hospital.

"If you actually remove people from infection chains by large-scale screens and they go into quarantine and are not infecting other people, then I think it has a quite good effect," said Dittmer, who was not involved in the Tübingen work.

Germany requires non-vaccinated individuals to provide proof of a recent negative SARS-CoV-2 test to engage in many social and economic activities. Asked whether the German experience and its relative success in managing COVID-19 compared to the US speaks to the effectiveness of the country's looser approach to regulating rapid antigen testing, an FDA official highlighted the other differences in US and German policy.

"You have to also look at everything they do around the pandemic. Testing by itself isn't quite the panacea. What other steps are being taken?" the official said, noting, for instance, that Germany has been paying individuals to quarantine following a positive test result (though the government is ending that program this month).

BioLabs' Holberger said that while she believed the FDA has "set the bar too high" for rapid antigen and home tests, such tests will be most effective used within some sort of structured system.

"I don't think that they are as effective if just used randomly," she said. "The antigen tests give you a moderately sensitive snapshot in time, but without being used in the context of a high-frequency testing protocol, I don't think they are as useful."

In the UK, implementing rapid antigen testing in a sufficiently structured way has proved challenging, said Alex Crozier, a researcher in the division of biosciences at University College London. He noted that there was hope that the tests would be used in a more formal way to clear individuals for event-going, "but that hasn't really materialized in reality."

"Challenges arise when individuals, well-meaning members of the public, are given these tests and they have mild symptoms but test negative and then still go out," Crozier said. "They don't understand that these tests are really risk mitigation tools, rather than a sort of definitive yes or no answer."

Broadly speaking, analyses demonstrating the usefulness of population-scale rapid antigen testing have been "quite limited," he added.

That said, it does not appear that Germany's laxer rapid antigen test regulations have undermined its COVID-19 response compared to the US. And the UK's COVID-19 stats are essentially equivalent to the US' stats, despite its heavy reliance on the Innova test.

"I haven't seen any evidence that shows that at a population level [rapid antigen tests] are having a negative effect," Crozier said. "It's very hard to interpret [data] from such a complex social system. But all of the evidence at the moment points in favor" of these tests' usefulness.