US government documents have shed light on why early COVID-19 testing proved faulty. In early 2020, the Centers for Disease Control and Prevention (CDC) were rushing to design and manufacture test kits that could detect coronavirus. In February 2020, public health facilities reported errors with PCR tests designed by the CDC, leaving the United States blind to the increasing number of COVID-19 cases. Although other countries were producing effective test kits, these were not adopted in the US, as reported by TrialSite. The early failure of the CDC’s test kits was due to contamination and an overburdened laboratory, according to a BuzzFeed investigation. Buzzfeed News has gained access to interview notes and investigative documents from the US Department of Health and Human Services (HHS), the department responsible for investigating the test’s failure, which shed light on what went wrong with the tests. Of course, fast forward to today, and yet another testing crisis occurs—there aren’t nearly enough available to respond to the massive Omicron wave. It would appear for a second time now a shortage in SARS-CoV-2 tests materially impacts response in America. What can we learn from recent history?
Why was the CDC making COVID-19 tests?
When news about a novel coronavirus started circulating globally in December 2019, the responsibility for developing a new test to detect the virus in the US fell to the Respiratory Virus Diagnostic (RVD) Lab of the CDC. The RVD Lab was staffed by 9 people, only three of whom were full-time employees.
In January 2020, the World Health Organization (WHO) published instructions from the German Center for Infection Research for a successful COVID-19 test. Countries across the world started manufacturing the tests and distributing them using these instructions, yet the CDC continued to develop their own test. According to interview notes acquired by Buzzfeed News, scientists from the CDC believed they could produce a better test, as in 2012 the CDC’s MERS test performed better than the WHO test, according to a CDC employee.
A CDC employee told BuzzFeed News that the CDC believed it would be better if there were both US and German tests distributed worldwide, and that simply copying instructions for the WHO test would not have been possible, politically. The employee went on record to say, “Imagine the backlash we would have had if CDC had said, ‘Hey, let’s use a German test’.”
How do the tests work?
The test to detect SARS-CoV-2, the virus responsible for COVID-19, was developed by Xiaoyan Lu, a microbiologist at the RVD Lab, in January 2020. Three key regions of the virus genome were used for the test: N1, N2, and N3. N1 and N2 were new and specific to SARS-CoV-2, whereas N3 was found in all SARS-like coronaviruses.
The RVD lab ordered large batches of chemicals, called reagents, to detect the three viral regions. These reagents were developed off-site in a “core lab” at the CDC. A fourth part of the test, called the positive controls, was also needed. These positive controls are copies of the part of the virus’ genes keyed to each of the three reagents. Every lab that acquires a new test needs to mix the reagents and positive controls to prove that the test is working and can detect the virus.
To prove the test does not deliver false positives, the reagents should also be mixed with distilled water to cause a negative result. To prevent contamination resulting in false positives, manufacturers do not add positive controls until the final step before shipping. In most situations, positive controls are mostly manufactured at a separate site to ensure there is no contamination.
Due to time pressures, the RVD lab requested that the core lab that was responsible for the reagents also make the positive controls. “We couldn’t get it anywhere else,” said Lu.
By January 18, 2020, the RVD lab had a diagnostic test ready for manufacturing. The RVD lab required assistance to produce the tests, and the CDC responded by “activating” the Emergency Operations Center, establishing a task force of senior officials to oversee the manufacturing of the tests.
What went wrong?
Despite preparedness for pandemics and health outbreaks by the US government, the CDC kept coronavirus research contained to the small RVD lab, which was underfunded.
The RVD lab required the FDA‘s emergency use authorization (EUA) to distribute the new tests to public health facilities. Receiving the EUA was a challenge that required the core lab to send over reagents for 600 test kits, while the RVD team had to check that each test was working. The RVD lab also took over making the positive controls using templates from the core lab, according to the interview notes.
The initial goal for the CDC test was to detect outbreaks, not to diagnose sick people. However, in the early days of the pandemic in 2020, the CDC test was the only legal test to be used in the US once FDA EUA was granted on February 4, 2020.
Due to the small number of tests available, testing was limited to symptomatic travelers returning from China. These criteria were determined before there were any cases in the US and it was still believed that only symptomatic people were contagious. This meant that the new emergency authorized CDC test was aimed at a group too small to spot an outbreak.
Once EUA was received, the RVD lab released 400 kits for distribution. Each of these kits contained enough tests for 800 people and they were sent to 48 public health labs across the US. Before tests could be used, the labs had to verify that the tests worked by testing reagents against positive controls and distilled water.
By the end of the first week, the RVD lab received the results of the test verifications. The water test produced false positives 75% of the time, specifically for N3, however, the N1 reagents also failed in some labs in New York. The only COVID-19 test available in the US for spotting a coronavirus outbreak didn’t work.
The hypothesis for the failed tests was that the core lab was contaminated when manufacturing the reagents and the positive controls. Although the core lab was thoroughly cleaned and decontaminated, an FDA microbiologist, Timothy Stenzel, was sent to the CDC’s headquarters in February 2020 to determine why tests were failing. Stenzel discovered that the core lab and distribution lab were clean, however, the respiratory virus lab appeared “messy.”
Stenzel realized that the RVD lab had handled both virus samples and positive controls in its main room, possibly resulting in contamination of the N1 and N3 reagents in the rooms nearby, as scientists were allowed to move freely between the rooms. Stenzel urged CDC leaders to move manufacturing of the test kits out of their labs and to a private manufacturer, a move that happened a week after his visit.
Aftermath of the test failures
As case numbers in the US rose and the situation evolved to a global pandemic, the CDC’s unreliable and faulty tests were scrapped. By the end of February 2020, the CDC permitted public health labs to get rid of the N3 component from tests they had received. The CDC started sending out kits with only the N1 and N2 reagents.
By this time, medical centers and academic labs across the US had started developing their own tests using the N1 and N2 components. The FDA permitted these tests to be used on February 29, 2020.
The CDC is yet to announce its own explanation of what went wrong with the initial test kits. The fact that the responsibility to manufacture tests was placed solely on the CDC is a problem that needs to be addressed prior to future pandemics. The issues encountered point to the lack of a national strategy for dealing with the pandemic. Not only were there not enough tests at the start of the pandemic, but there was also a lack of ventilators, masks, personal protective equipment, and swabs.
Looking forward
The current Biden administration has a plan to create a central pandemic office, and a proposal for a $65 billion (although it has been scaled down to $10 billion) “mission control” office to deal with any future pandemics. Whether or not this will be based at the CDC is still unclear. TrialSite will continue to report on the situation and any further explanation from the CDC about the 2020 tests. Hopefully, similar mistakes aren’t again underway.