Pediatrician taking saliva test from children with face masks in a school

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As schools and businesses struggle to reopen in the midst of a global pandemic, institutions and test developers have been working on strategies to mass produce and deploy rapid tests, pool samples and step up contact tracing for COVID-19. These efforts wouldn’t necessarily replace standard polymerase chain reaction (PCR) diagnostic testing, but instead offer a way to repeat tests on a mass scale, enabling routine activities to take place safely.

Some in the clinical lab community worry that urgency is replacing accuracy in the national push to test large masses of people. As of now, the supply chains and tests to build a national testing strategy don’t exist, Alexander Greninger, MD, PhD, assistant director of the University of Washington’s Medicine Clinical Virology Laboratory and an assistant professor of laboratory medicine, told CLN Stat. No performance characteristics or clinical trials for these tests have been established, he continued. “All of a sudden we seem to care less about sensitivity or regulation.”

Others, such as Harvard epidemiologist William P. Hanage, PhD, contend that “requiring the perfect may be the enemy of the good.” Very sensitive and specific tests are important for guiding treatment in healthcare settings. However, when testing for the virus in communities, a test that is highly specific but not very sensitive, and cheap and fast enough to be taken daily, would be useful, he wrote. “This is obviously not ideal, but for screening purposes it may not be such a hindrance,” wrote Hanage. Speaking at the Next Generation Dx Summit on August 25, David Walt, PhD, professor of biologically inspired engineering at Harvard Medical School, voiced similar sentiments. "If you're trying to actually measure infectivity, the antigen tests are going to be more predictive... A rapid antigen test is probably more predictive than a PCR test that's stale." He added, "The antibody tests probably are less sensitive but nonetheless we know from models...showing that less accurate tests both in sensitivity and specificity if done frequently give you about equivalent if not a reduction in prevalence in a population,"

In the United States, the rolling daily average for tests peaked at approximately 822,000 on July 29, dropping down to 615,514 on August 23 and with ups and downs since, according to data from the COVID Tracking Project. “What we couldn’t anticipate back in April—and what is crippling our ability to get the virus under control—are the extraordinary delays in test results that we are seeing today. The honest truth is that millions of tests requiring waiting five-plus days for results are essentially worthless to contain the spread of the virus,” said Ashley Chang, head of media relations with the Rockefeller Foundation, which has called for a national strategy to ramp up millions of tests by the fall of 2020.

The Rockefeller Foundation and Duke-Margolis Center for Health Policy issued a report on September 9 estimating that the U.S. needs up to 193 million tests per month to mitigate COVID-19 to the point that the public could reasonably safely resume pre-pandemic activities. Expanded availability and use of less accurate but widely available rapid screening tests would be a key element of reaching this goal.

PCR testing is about 98% accurate and returns very few false positives, but in practice hasn't been returning results quickly enough. In one analysis, investigators reported that weekly screenings with a variety of less sensitive PCR tests could avoid outbreaks by delivering immediate results and having positive individuals self-isolate. Some jurisdictions have resorted to pooling PCR tests, which captures more test results and helps conserve supplies, according to one news report. Pooling, however, “is only a stopgap. It works best for diseases that are relatively rare, such as HIV and syphilis. If a disease is too common, then the work of pooling—the laborious mixing and remixing of samples—is more work than it’s worth,” according to another news report in the Atlantic.

Such dilemmas have spawned new innovations. Ginkgo Bioworks, for example, leveraged its Illumina gene-sequencing machines to create a rapid test that identifies 98 targets on SARS-CoV-2 through nasopharyngeal, oropharyngeal, and mid-turbinate nasal swabs. According to the Atlantic, Gingko, under a federal grant with its start-up partner Helix could be testing up to 1 to 3 million samples daily by the end of the year at several facilities.

As developers continue to release new assays, institutions and government entities have been fostering ambitious rapid testing strategies to help reopen America. Several contests in the spirit of Shark Tank have been underway. As CLN Stat has reported, the National Institutes of Health recently awarded $248.7 million in contracts to seven biomedical companies under its Rapid Acceleration of Diagnostic Technologies (RADx Tech) program, with a goal to deliver millions of rapid tests this fall. The technologies use a variety of platforms, from next-generation sequencing to CRISPR. The XPrize Foundation also is holding a $5 million 6-month competition to develop rapid, inexpensive COVID-19 tests. Winning teams are tasked with producing a minimum of 500 tests weekly at a live testing site within 2 months, eventually scaling up to thousands of tests per week.

The Rockefeller Foundation this past spring proposed ramping up tests from 1 million per week to 3 million by June, and 30 million by the fall. While it’s still recommending this goal, “we now know that the majority of these tests—at least 25 million—need to be antigen tests dedicated to asymptomatic screening, along with at least 5 million diagnostics tests per week,” said Chang. Rapid antigen tests have been making their mark, though some suffer from accuracy problems and face supply chain issues. A unique spike antigen test developed by a tiny Massachusetts company, e25 Bio, seeks to remove these barriers. Unlike other tests, it looks for the virus’ spike protein instead of trying to find nucleocapsid, which means it’s actually looking for live virus, the Atlantic reported. The test produces results in 15 minutes. Once this test is approved by the U.S. Food and Drug Administration (FDA), e25 Bio estimates the company could eventually produce 20 million to 40 million tests monthly.

Testing for America, a private-sector founded nonprofit, is on a mission to safely reopen U.S. schools, businesses and the economy through inexpensive, rapid tests. The organization recently announced a partnership between the Thurgood Marshall College Fund (TMCF) and The United Negro College Fund (UNCF) to support testing efforts at UNCF and TMCF colleges and universities. “TFA's ability to link us to high-quality providers, coupled with other safety guidance and financial support, will help bring necessary, continuous and reliable testing to entire campus communities,” said UNCF President and CEO Michael L. Lomax, PhD. This would impact nearly 300,000 students at more than 80 historically black colleges and universities. The Siemens Foundation and Siemens Healthineers today announced they are donating to TFA $500,000 in funding and an in-kind donation of COVID-19 testing technologies with a fair market value of $2,275,000 to support the safe reopening of historically black colleges and universities across the country.

A plan from the Johns Hopkins Center for Health Security hones in on at-home diagnostic tests to improve availability of testing options to consumers. FDA has issued emergency use authorizations (EUA) for a handful of home tests. Most recently the agency approved two saliva tests from the University of Illinois at Urbana-Champaign and Yale University. Yale’s SalivaDirect test is unique in that it doesn’t need a separate nucleic acid extraction step. The university plans to open source its testing protocol so that other laboratories around the country might use it. Developers of the University of Illinois’ I-COVID test have conducted more than 50,000 tests to date on the campus, with plans to test about 20,000 people daily this fall.

This is part of the university’s SHIELD strategy, a three-part approach to “target, test and tell” through data reporting, modeling and a smartphone app. The goal is to trace and isolate people who test positive. Another initiative, SHIELD T3, aims to broaden availability of testing and data technology.

The Forsyth Institute, which has been working with NIH’s RADx initiative to deploy rapid SARS-CoV-2 tests, has pointed out the effectiveness of saliva as a medium for detecting viruses. “Scientific data shows that COVID-19 not only exists in saliva, but attacks the ACE2 receptor in salivary glands. It actually replicates in saliva,” said Wenyuan Shi, PhD, chief executive officer and chief scientific officer of the Forsyth Institute. In some instances, saliva performs better than nasal swab tests.  “That is why this is the future,” added Shi.

Michael Mina, MD, PhD, a professor of epidemiology at the Harvard T.H. Chan School of Public Health, believes the widespread distribution of saliva tests could help reopen the country. His vision: test nearly everyone daily, making testing available at workplaces, airports and grocery stores. “Mina claims that his plan could bring the virus to heel in the U.S. within three weeks,” according to the Atlantic. Others in the field are more skeptical.

FDA’s recent EUA of Abbott’s rapid antigen test, which delivers results in 15 minutes and costs about $5, has attracted recent attention in advancing mass testing in the general population. Abbott said BinaxNOW COVID-19 Ag Card identified the virus with a sensitivity of 97.1% and specificity of 98.5% in a clinical study. This takes mass testing of the general population closer to reality, according to Alan Wu, PhD, director of clinical chemistry and toxicology at the University of California, San Francisco. People don’t like the PCR/nasopharyngeal swab tests because they’re painful and invasive. Antigen tests are much easier to administer, but they’re not as accurate as PCR. For this reason, Wu sees limited value in mass testing with antigen tests.

And yet, “I don’t think it can be stopped,” he said of the push to test more people.

As far back as April, Wu discussed the health consequences of conducting mass screenings in the general population for SARS-CoV-2, particularly with respect to antibody tests. “In the haste to produce a COVID-19 antibody test and the relaxing of FDA approval through the emergency use authorization, the quality and reliability of these assays may be substandard,” cautioned Wu in an editorial in The Journal of Applied Laboratory Medicine. Since then, his ideology hasn’t changed much.

“The precautions in my editorial still apply,” Wu told CLN Stat. Using an antigen test on people that may deliver false negative results, offers a false sense of security that could result in lax social distancing, and subsequently, more positive cases. “The intent is excellent, but the methodology is poor,” he said of mass testing with antigen and other rapid tests that are inferior. PCR is still the most reliable method, and yet, the supply is limited for PCR reagents. “I still think we should use PCR tests on nasal swabs and put the effort on having supplies available. This will require partnerships with the IVD industry and support from the federal government.”

Clinical labs need to be the adjudicators of false negative and false positive results, stressed Greninger. “If you see something, say something. Nobody likes a snitch, but we have to be more vocal about what we see from test performance, especially since we are oftentimes so much closer to the consequences than a device manufacturer.”