Why the U.S. coronavirus testing failures were inevitable

Leah Craig stepped out of her car and into a nightmare. Days after developing a sore throat, the 29-year-old started coughing uncontrollably, something her asthma only made worse. By the evening of March 18, Craig was struggling to breathe when she opened an email from her synagogue in Los Angeles that said a member who’d attended the previous week’s Purim celebration had tested positive for COVID-19.

She and her fiancé, Soren, promptly drove to the hospital at the University of California, Los Angeles (UCLA), where a nurse in the emergency room grabbed a plastic swab akin to a long Q-Tip and inserted it deep into Craig’s nasal cavity.

Whereas South Korea, Taiwan, and Germany have been able to return results in under 24 hours, Craig was told to wait three to five days. Well over a week later, she hadn’t received her diagnosis. “I know I’m really lucky to have even been tested,” Craig says, acknowledging the nation’s difficulties with making tests for the novel coronavirus widely available.

So far, more than 831,000 Americans have been tested for COVID-19—but 98 percent of those tests were conducted after March 14, the day the White House coronavirus task force announced a major push, according to the volunteer-driven COVID Tracking Project. The delays in part result from design flaws with the early diagnostic tests developed by the Centers for Disease Control and Prevention (CDC).

At the same time, those CDC errors have exposed other shortcomings in the nation's capacity for diagnostic testing that existed years before the novel coronavirus emerged in China, according to Catharina Boehme, the CEO of Foundation for Innovative New Diagnostics (FIND), a medical nonprofit based in Geneva, Switzerland.

Since 2006, the Biomedical Advanced Research and Development Authority, which is a branch of the U.S. Department of Health and Human Services, has provided hundreds of millions of dollars in grants for so-called rapid-response platforms—initiatives intended to develop technology at a fast pace when an outbreak emerges. These funds were directed primarily toward the development of therapeutic treatments and vaccines rather than creating diagnostic methods for new threats or increasing the volume of tests the system could perform. As a result, Boehme says, test development has lagged behind efforts to bring new vaccines to clinical trials.

Testing has also been hampered by shortages of vital components, including the chemical solution used to extract genetic material from clinical samples, the machines needed to run the test, and the swabs used to collect the samples, according to a statement released by the American Society for Microbiology.

Commercial and university laboratories rushed to fill the gap. Many of them, especially larger companies such as LabCorp and Roche, now use a similar but improved version of the CDC’s testing technique. Smaller labs such as Mammoth Biosciences and Sherlock Biosciences have gotten more creative, developing tests using CRISPR, a promising gene-editing technology. Multiple startups have also developed a collection of at-home tests, but doctors and the U.S. Food and Drug Administration (FDA) have warned against their use, in part because self-administering a nasal swab is difficult and could cause injury. Also, a poorly-executed swab could lead to a negative result when a person is actually infected.

The frenetic rollout of testing during the past two weeks explains why the U.S. now leads the world in the number of reported COVID-19 cases, and it gives a truer emerging picture of the magnitude of the country’s pandemic. On March 29, Anthony Fauci, the head of the National Institute of Allergy and Infectious Diseases, told CNN that the U.S. could experience 100,000 deaths and millions of cases despite the recent surge in testing.

“Diagnostics are the forgotten small brother of pandemic response. When it all goes right, they’re almost invisible,” Boehme says. “COVID-19 has shown the world the importance of diagnostics.”

The problem with primers

After Chinese officials published the genetic sequence of the new coronavirus, officially called SARS-CoV-2, on January 10, laboratories around the world hurried to develop a strategy for diagnosing the disease. A team from Germany was among the first, and its test was adopted by the World Health Organization on January 17, becoming the de facto gold standard. The U.S., though, continued to forge its own test at the CDC, as it has done in the past, such as with the West African Ebola outbreak in 2014, when a rapid diagnostic test was prepared for use in the region and for U.S. personnel who might have been exposed.

Nearly all COVID-19 tests use similar approaches to spot the presence of the virus’s genetic material in clinical samples of sputum, saliva, or a swab from deep in the nasal passages. Once a lab has the sample, scientists extract all the genetic material, but detecting coronavirus among the cells and the multitude of microbes in the nose and mouth is challenging.

To make it easier, molecular pathologists use a technique called a polymerase chain reaction to amplify the genetic signal from a particular virus. This method relies on custom-designed “primers” to make copies of the coronavirus’s genetic code. Scientists then use a chemical probe that glows only when it interacts with these copies. If a sample reaches a certain level of brightness, the patient has tested positive.

On March 4, the CDC sent test kits using four sets of primers to state health labs. Three were designed to detect the coronavirus, while the other was supposed to hone in on unrelated genetic material to act as a negative control. But that’s not what happened.

Within days, some labs reported back that they were getting false positive results in their negative controls. The CDC recalled the problem batches but didn’t explain what was wrong, according to Tomer Altman, a Silicon Valley bioinformatics consultant.

Altman, who designs primers for these kinds of tests, thinks he has identified one of the flaws. He analyzed the CDC’s testing components on widely used software, and the program flagged major problems, including one known as primer dimer. That’s when a pair of the primers generate a false signal by binding to each other rather than to the coronavirus’s genetic code. “It’s like running a race with a 10-pound weight tied to your foot,” Altman says—although he cautions that his analysis wasn’t comprehensive and doesn’t definitively show what the problem was.

Normally, state labs would receive, administer, and analyze results from tests developed by the CDC. But with the recall of the faulty batches and commercial tests under production, testing for COVID-19 has lagged dangerously nationwide—and has yet to fully recover.

“We’re failing on so many levels,” says Benjamin tenOever, a microbiologist at the Icahn School of Medicine at Mt. Sinai in New York City who’s an authority on viruses.

Requests for comment from the CDC have not been answered.

Rigid rules

Aside from failing to allocate sufficient funds for the design of diagnostic tests, the U.S. has lacked the administrative flexibility to react effectively, says Luciana Borio, vice president at In-Q-Tel, a nonprofit venture capital firm, and former director of medical and biodefense preparedness at the National Security Council. As a result, the nationwide system couldn’t rapidly coordinate the COVID-19 response among all the different agencies, clinics, hospitals, and corporations. “We need to bring in the private sector to be a part of our planning and ask them what they need to be a part of this [response],” Borio says.

By developing a test loosely based on the CDC version during the 2009 H1N1 influenza pandemic, Karen Kaul, a molecular pathologist at NorthShore Hospital outside Chicago, ramped up testing capacity for thousands of people in mere days. At the time, groups such as hers could make such “laboratory-developed tests” without approval by the FDA, provided they met the safety requirements described in the Clinical Laboratory Improvement Act.

During the past decade, there’s been an explosion of laboratory-developed tests (especially for genetics), aggressively marketed to physicians and consumers, leading the FDA, in 2014, to propose a more stringent approval process to better ensure patient safety. That guidance was never finalized and was withdrawn in January 2017 as President Barack Obama left office, but the FDA’s cautionary impulse did have a chilling effect on laboratory-developed tests, such as when the agency attempted to block the creation of some tests for the mosquito-borne sickness Zika in 2016. Since Obama left office, the policy has been under Congressional deliberation.

Laboratories still needed to seek FDA approval before using their own tests during an emergency situation, which slowed the ability of clinical labs such as Kaul’s in Chicago and larger commercial operations to bring to bear safe and reliable alternatives for COVID-19. So on February 29, the FDA loosened some of the paperwork requirements, allowing groups to make and use laboratory-developed tests prior to official approval.

The lack of alacrity can be attributed in part to the absence of emerging disease outbreaks in the U.S. in recent years, says Catharina Boehme, of the Foundation for Innovative New Diagnostics. East Asian countries, scarred by the SARS outbreak in 2002 and 2003, invested heavily in testing infrastructure. But the U.S. largely escaped SARS, and because the country had been flexible enough to manage the H1N1 outbreak a decade earlier, agencies and systems weren’t ready for the novel coronavirus.

“There’s a lot of panic in outbreak situations, but we very rapidly forget,” Boehme says. “There has been very little investment in preparedness, and all the investment flows to response.” Preparedness means taking steps to respond as soon as agencies hear of a potential threat, having the mechanisms in place to develop diagnostic tests safely and fast, and the system capacity to meet testing demands.

Even now, with wider testing available, only people with overt symptoms are getting tested. Since many cases of COVID-19 are mild or asymptomatic, it’s not known how many people have been infected, and we may never know how many new cases will arise as a result of the lag.

Even after a second trip to the emergency room because of her difficulty breathing, Leah Craig didn’t receive her test results until March 28. UCLA told her she’d tested negative but also said that her result was likely false, adding to her confusion and worry. Now Craig and Soren are isolating themselves in one half of the small, two-bedroom apartment they share with Craig’s mother. Although UCLA told Craig she could be re-tested, Craig said it wouldn’t be worth the additional burden on the system.

“We could have tested more people sooner,” says Kelly Wroblewski, director of infectious disease at the Association for Public Health Laboratories. “It’s a cascade of unfortunate events.”