How the Department of Pathology and Laboratory Medicine created a test that didn’t exist in just 19 days
Tran is a professor of clinical pathology at the School of Medicine. He was following reports out of China about a mysterious new respiratory virus, SARS-CoV-2. Not much was known at the time about how the novel coronavirus spread or what the mortality rate was.
Tran was mindful of how fast viruses can spread globally. He led the laboratory’s response to the 2014 Ebola epidemic and had experience with the 2009 novel H1N1 “Swine Flu” pandemic. Like many, he thought the outbreak might follow a similar course to the Severe Acute Respiratory Syndrome outbreak in 2003, which resulted in 774 deaths worldwide.
By late January, it was clear the new coronavirus, which causes COVID-19, was no longer contained in China. The Centers for Disease Control (CDC) announced the first person-to-person case within the United States, and on January 31, the World Health Organization declared a global health emergency.
Tran began talking to infectious disease colleagues about whether UC Davis Health would need an in-house COVID-19 test.
At the time, tests for Covid-19 were authorized for emergency use by the Food and Drug Administration and had to meet CDC guidelines. The only tests available were at the CDC in Atlanta, which meant samples had to be sent to Georgia. This process could take several days.
During the second week of February, the CDC began releasing COVID-19 test kits that would allow public health laboratories to provide results in several hours. But almost immediately, there were problems with the kits, possibly due to a contaminated reagent.
All the while, the novel coronavirus was silently spreading. Its presence in the Sacramento region became known on February 26, when UC Davis Health announced it had treated the nation’s first known case of community-transmitted COVID-19.
Then, on February 29, everything changed. The FDA announced it would allow diagnostic laboratories to create something that did not exist yet: their own COVID-19 tests. The race was on.
— Marcelo Prado
Race against the virus
“March 1 was madness,” said Marcelo Prado, supervisor for the Molecular Pathology Laboratory at UC Davis. “We felt as though we were in a race against this virus. It was impressive to see the mobilization of resources and the number of people coming together to bring up COVID-19 diagnostic testing. It involved our entire lab section,” said Prado.
The Specialty Testing Center where Prado works usually keeps regular business hours. It was not designed to run 24 hours a day. But in the weeks that followed the FDA announcement, staff in the lab worked upwards of 16 hours a day, sometimes until the lights would literally go out. “All the lights are programmed to go off at 2 a.m.,” explained Prado. “We would have to turn them back on and go back to work.”
The team felt incredible pressure to create the test. “The sooner we could provide diagnostic testing, the sooner medical staff would be able to identify the patients with the virus and quarantine them. But we were essentially starting from scratch,” said Prado.
Virus’ genomic material detected with PCR test
The Molecular Pathology Lab specializes in detecting genomic material — RNA and DNA — to identify pathogens like bacteria or viruses. The lab can also detect inherited disorders. “RNA is what we are looking for with the SARs-CoV-2 Virus,” said Prado.
The COVID-19 test they were creating is known as a reverse-transcription polymerase chain reaction or RT-PCR test.
PCR tests can detect genetic material. Because SARS-CoV-2 has an RNA genome, the first step is to synthesize complementary DNA, known as cDNA. The genetic material is then identified and multiplied through a series of amplification steps.
Sometimes called “molecular photocopying,” the amplification in PCR tests can be repeated dozens of times, leading to millions of copies of the original genetic material. The method is used to test for bacteria and viruses and allows for an accurate diagnosis even if only a small amount of DNA is collected.
Swab collects RNA of respiratory illness
Scott Bainbridge, a supervisor in the Department of Pathology and Laboratory Medicine, explained that the method of sample collection for a PCR test depends on the type of illness or pathogen.
“For example, Zika virus is a blood-borne illness from a mosquito so we would use a blood sample for that PCR test. But for a respiratory illness like COVID-19, you will find the virus in the nasal cavities or the back of the throat. So, we use a swab,” said Bainbridge. “The test goes after the RNA of the virus. It has very high specificity. So, if you are positive, chances are extremely high you have the virus,” he said.
Last March, Bainbridge was the busiest he had ever been in his life. "Friends and family were saying they had nothing to do, but I was working long days."
But the long days were not the biggest challenge. “The hardest part of all of this was procuring the necessary reagents,” said Bainbridge.
Reagents are an essential component for PCR testing. Laboratories around the world were competing to get the reagents needed to scale up COVID-19 testing. “The supply chain was broken,” said Bainbridge.
Any time a new reagent is used, the test has to be revalidated. “No sooner did we bring up a test, we found we couldn’t get enough supplies and reagents to sustain it,” said Prado.
They had to repeat the effort time and time again to hedge against the shortages. “We couldn’t afford to cease operation. When the whole world is going after the same material, it quickly dries up,” said Prado.
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The data behind the testing
A dedicated IT team made sure all the new testing data flowed smoothly to where it needed to go and provided actionable information to healthcare providers.
Bob Hamilton is a supervisor for the Epic Beaker laboratory and Bugsy infection control information systems. In addition to other functions, the team manages lab orders, test results, specimen handling, and identify patients at risk for infections like COVID-19.
“I work with a talented team of folks that integrate lab instruments with Beaker and Bugsy. We build orders and tests inside of Beaker and send the results to physicians and elsewhere,” said Hamilton. “In the case of COVID-19, we also had to send the results to the California Department of Public Health and other health agencies.”
As COVID-19 tests were gearing up last March, the IT team was working from 7 a.m. until 10 p.m., or sometimes in the middle of the night, if that was when a test was validated on a particular machine.
“Our team was incredible. We had a sense that what we were doing was crucial,” said Hamilton. “The most important thing for us was to ensure that physicians received accurate and timely results so they could treat their patients.”
Teamwork across the university
— Lydia Howell
Scientists at the California National Primate Research Center and the Center for Immunology and Infectious Diseases also joined the effort, isolating, characterizing and culturing coronavirus from a patient treated at UC Davis in order to validate the tests.
At one point, with supply chains stretched, Tran needed transport media tubes and swabs. He reached out to Gerhard Bauer, the director of the Good Manufacturing Practice (GMP) laboratory at the UC Davis Institute for Regenerative Cures.
Bauer was able to manufacture the tubes and swabs at the GMP lab, around 1,200 per week. The UC Davis Microbiology Lab tested the containers for sterility.
Simultaneously, the Pathology Clinical Trials team worked to get samples from volunteers to validate these new tubes as required by the FDA to confirm they worked with the COVID-19 tests.
“This was full mobilization of the clinical laboratory, spanning at least four laboratory specialty sections – it would not be possible without our amazing clinical lab scientists,” said Tran. “We were validating two tests at the same time and planning to validate a third platform based on our Roche Diagnostics cobas® 6800 System platform,” said Tran.
First in-house COVID-19 test
All the hard work came together on March 19 when UC Davis Health offered its first in-house COVID-19 test to a patient. The monumental achievement was just 19 days after the first FDA announcement.
But there was no time for a break. The first test would only be able to test 20 patients a day, and it was clear that would not be adequate for the growing pandemic.
“It was a huge relief to get that first one done, but we knew we would need to move it to a faster and more automated system,” said Tran.
On March 28, they went live with the Roche system. On April 3, UC Davis announced the speed-up of testing capacity, with the Roche 6800 being able to run up to 400 tests per day with a later capacity to perform more than 1,000 tests per day.
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Resources in place before the pandemic
“Labs are often behind the scenes, and we are sometimes taken for granted because our tests are always quick and available,” said Lydia Pleotis Howell. Howell is a professor and the chair of the Department of Pathology and Laboratory Medicine and medical director of UC Davis Health’s clinical laboratories. “Suddenly, we were thrust into the spotlight because there was a lab test that was urgently needed but did not exist yet,” said Howell.
Howell said her department received tremendous support to help them get the resources they needed. She also credits the department’s support before the pandemic as part of the reason for their success. “As a research university, we had great equipment in place, like the Roche Diagnostics Cobas® 6800, before COVID-19.”
She is incredibly proud of the pathology staff. “Patient care is often on hold until providers get that pivotal test result. And it is critical that our results are right. Even though we may not see their faces, these are our patients,” said Howell.
Between March of 2020 and the end of March 2021, UC Davis Health ran more than 100,000 COVID-19 clinical tests.
During that time, there were more than 31 million infections in the United States and more than 500,000 deaths.
But other medical needs didn’t stop. Between March 1, 2020 and February 28, 2021, UC Davis Health also processed more than 2.8 million non-COVID-19 tests.
The future of COVID-19 testing
— Nam Tran
Although the pandemic is not over, more than 200 million doses of the vaccine have been administered. There is a sense that life will gradually begin to return to normal.
But the impact of the virus will likely be felt for years, which is why Tran and his colleagues are trying to anticipate current pandemic and post-pandemic needs.
For example, the department is building a repository of samples from COVID-19 patients for potential clues as to why “long-haul” patients continue to experience symptoms.
“We are validating our existing routine tests to see how well they perform in these long-haul patients. Biomarkers normally used for evaluating patients with heart attacks, heart failure, inflammatory diseases and coagulation disorders are being evaluated across the laboratory services,” said Tran.
He also thinks it may be necessary to monitor antibody levels and perhaps T-cell activity in the future. COVID-19-specific antibodies and T-cells are created in response to either an infection or to a vaccine. But it is unknown how long those antibodies and T-cells will stay around in the body to fight off future infections.
"We may need antibody testing that provides more than a simple 'yes' or 'no' answer. We might need to test for how many antibodies someone has in order to allow them to go back to work or school. Or a certain level of antibody may mean they need to be revaccinated. This remains up in the air right now and is reliant on additional studies and guidance from the CDC.”
But much about the novel virus that spread worldwide in 2020 is still unknown, and new variants will continue to add new chapters to the story.
Which is why he and other members of the pathology team are ready to adapt and respond, as they have done repeatedly this past year. "We are living scientific discovery in real time,” said Tran.