Three weeks into a virus-induced shutdown, as downtown streets remain silent and the economy finds itself teetering on the brink of a steep and sudden recession, a research boom is sweeping through local universities, hospitals and commercial labs. For scientists working nonstop behind the scenes, the race is on to defeat a deadly virus that has brought the whole world to its knees.
Their war has many fronts, but chief among them are testing and treatment, which are seeing a flurry of activity. Stanford University and University of California, San Francisco (UCSF) have ramped up their testing capacity and launched clinical trials at a furious pace. Since the coronavirus pandemic took off, Stanford's epidemiologists have been working with Santa Clara County health officials to model the pandemic's trajectory; its virologists have developed various ways to test for virus; and its medical researchers are now launching clinical trials for promising drugs that have proved effective for fighting Ebola, the flu and Hepatitis D.
Researchers also are collaborating with counterparts in other universities as well as public agencies and private labs to share — and scale — their breakthroughs.
Private companies also have stepped up, with commercial labs developing tests and distributing drugs that they believe may become critical weapons in the war against COVID-19 and with manufacturers joining the effort to create personal protective equipment, such as masks and face shields, for health care workers.
Thus far in the battle, public health strategies have led the charge, deploying the tactic of social distancing. On Tuesday, Santa Clara County residents received a glimmer of hope: Staying home to help "flatten the curve" appears to be working, even though the number of COVID-19 cases is still expected to climb between now and May 1, Dr. Sara Cody, the county's health official, told the county Board of Supervisors during her April 7 update.
Yet the hopeful news came with another message: Numerous conditions have to be met before officials can relax their social-distancing orders.
The county will need to get to a point where widespread testing for COVID-19 is available and hospitals can safely and effectively treat everyone living in the county.
"We have to at least be able to test everyone who has symptoms," Cody said. "And we also have to have enough testing capacity so that we can test where we think there is some risk of accelerated transmission or there is risk in a particular community. So we've got to have testing capacity."
Testing as defense
While Cody said she is optimistic about the latest data on COVID-19 cases, county, state and federal officials have consistently pointed to testing as a glaring weakness in the collective response to coronavirus. As of Thursday, only 13,360 people in Santa Clara County have been tested for COVID-19, county data show, with 1,442 testing positive — a rate of 10.79%. It takes an average of 2.27 days to get a test result, a problem that Dr. Karen Smith of Santa Clara Public Health Department attributed Tuesday to delays at just about every step of the testing process.
Testing, she said, is limited by a shortage of swabs that are used to take samples and by the worldwide shortage of reagent, a key chemical for sample analysis.
That said, where the government has lagged, Stanford has been able to rev up its testing capacity. One of the nation's first coronavirus tests came from Benjamin Pinsky, associate professor of pathology and of infectious diseases at Stanford School of Medicine who has been developing a COVID-19 test since late January and whose team was validating and confirming results throughout February, according to Stanford.
In early March, Stanford's Clinical Virology Laboratory, of which Pinsky is medical director, was capable of conducting 1,000 daily tests, with a turnaround time for results between 36 and 48 hours, according to the university. Now, the lab can now perform 2,000 tests daily, Pinsky told this news organization in an email, and the turnaround time has been cut down to 24 hours.
Pinsky said the team has been able to optimize its workflow and boost production over the past month by validating multiple additional extraction instruments and thermal cyclers — machines that amplify DNA segments using a copying process called polymerase chain reaction.
UCSF also has boosted its testing capacity by opening a new lab that can process more than 2,000 samples per day and return results in 24 hours. In early March, when UCSF began testing for COVID-19, it had a capacity to test only 60 to 100 tests daily, according to the university.
On Tuesday, UCSF Health President and CEO Mark R. Laret and UCSF Chancellor Sam Hawgood co-wrote in a letter that it will allow public health officials from the nine Bay Area counties, including San Mateo and Santa Clara, to submit their samples to UCSF for free analysis.
While virology labs at Stanford and UCSF are using the polymerase chain reaction (PCR) technique to zoom in on the virus' DNA segments, a research team headed by Eran Bendavid, associate professor of medicine at Stanford, is looking at blood samples for evidence. On April 3 and 4, the team took 2,500 blood samples from volunteers at drive-thru sites in Mountain View, Los Gatos and San Jose. The team used targeted Facebook surveys in an attempt to get a population-representative sample of the county for its experiment.
The goal of the study is to examine the antibodies in the blood sample, a technique known as serology, to gauge the percentage of county residents who are — or have been — infected with COVID-19. A similar study was concurrently conducted in the Los Angeles area by researchers from University of Southern California.
"We need to understand how widespread the disease actually is," Jay Bhattacharya, a professor of medicine at Stanford University who is involved with the project, said on Saturday morning, as the second day trial was kicking off. "To do that, we need to understand how many people are infected. The current test people use to check whether they have the condition — the PCR test — it just checks whether you currently have the virus in you. It doesn't check whether you had it and recovered. An antibody test does both."
Stanford Health is also using blood samples to test its employees for COVID-19. On April 6, the serologic test that was developed by Stanford Medicine was launched at the university's medical facilities. While the university is currently only testing health care workers, Stanford Health spokesperson Lisa Kim said Stanford hopes to deploy these tests more broadly within the next two months.
"The test will enable us to determine which health care workers might be at low risk for working with COVID-19 patients, as well as understanding disease prevalence in our communities," Kim said.
Going on the offensive
Just as testing has accelerated, so have medical trials of potentially life-saving drugs. At an April 2 virtual town hall put on by medical leaders at Stanford, Dr. Yvonne Maldonado and Dean of Stanford Medicine Dr. Lloyd Minor, both said that the university's early development of the PCR test has increased the university's capacity to stage trials.
"Because we are one of the first to launch our own PCR test — and we hope we'll have serologic testing available in the near future as well — it gives us the capacity to monitor patients for not only immediate medical care but clinical trials," Maldonado said.
Two of Stanford's trials involve remdesivir, a drug produced by the Foster City-based company Gilead Sciences, Inc. Scientists from various institutions across the globe, including a team at Stanford Hospital, are examining whether remdesivir can prevent the coronavirus from replicating.
"The RNA virus gets into the cells and uses them as little hotels (to replicate)," said Kari Nadeau, co-investigator and professor of pediatric food allergy, immunology and asthma at the School of Medicine.
With the virus proliferating, some COVID-19 patients' immune systems overreact, causing severe symptoms that lead to death. Researchers hope that limiting the virus' replication will prevent the immune system from becoming overly active.
Gilead announced on April 4 that it has produced 1.5 million doses of remdesivir, enough to treat 140,000 patients. It plans to supply the drug at no charge.
Nadeau's trial began enrolling patients on March 30. Stanford is collaborating with 65 other sites worldwide; the aim is to study the drug's effects on 600 patients.
For the trial, Stanford patients will receive an intravenous dose of the medication daily for 10 days. The researchers will see how the patients do over a 15-day period. Nadeau said they expect to see a difference between the control group and those who receive the drug. They hope the drug will result in fewer people needing ventilators and fewer deaths.
Neera Ahuja, the study's principal investigator and division chief of hospital medicine at Stanford University School of Medicine, said if the evidence is convincing of the drug's effectiveness, and the side effects and adverse reactions pass federal scrutiny, the FDA approval could come within a month.
"That's unheard of in the non-pandemic world," she said.
Stanford is one of many institutions now looking at remdesivir. Among the National Institutes of Health trials of the drug is one involving patients who are on ventilators; another is studying patients with moderate COVID-19 symptoms. A third will compare the results for moderately ill patients who will be given the drug and for people who only receive standard care.
The studies involve dozens of hospitals throughout California, including the VA Palo Alto Health Care System, Stanford Health Care, Kaiser Permanente and the Regional Medical Center in San Jose. Gilead also is involved in studies using remdesivir in China and France.
Stanford is also looking at other drugs, including those that have in the past proved effective in treating other infections. Maldonado said at the April 2 town hall that in addition to its work on remdesivir, Stanford is preparing to move ahead with trials for Lambda, an immunomodulator, and the viral inhibitors Camostat and favipiravir.
"They have been studied in other infections, so we think we can obtain rapid FDA INDs so that we can start doing primarily outpatient trials for these drugs," Maldonado said, referring to "investigational new drug" authorization.
"So if they work in reducing symptoms and perhaps prevent spread by reducing viral shedding from an infected person, then these could be scaled up in the not too distant future. We're hoping those will enroll (patients) pretty quickly."
Prassana Jagganathan, a Stanford infectious disease specialist who is heading the trial on Lambda, said the drug may be able to strengthen the human immune system to better fight COVID-19. Lambda, he said, appears to target cells that are located on the epithelium (outer tissue layer) of respiratory tracts, including areas such as lungs and pharynx. As such it can be particularly suitable for treating patients with COVID-19, which can trigger respiratory failure.
"It's a molecule that we think can actually stimulate and aid antiviral defenses against a multitude of different viruses," Jagganathan said.
While Lambda had not been used to treat respiratory illnesses, another interferon called Alfa had proven effective, he said. The problem with using Alfa to treat COVID-19, Jagganathan said, is that the receptors for Alfa are far more distributed throughout the human body, including in immune cells. Thus, side effects of Alfa include fever or the flu, symptoms that resemble those of COVID-19.
The primary outcome of the randomized clinical trial, which will include 120 participants, is to see how long people are shedding the virus, Jagganathan said.
"We are hypothesizing that the folks who get Lambda will have a shorter duration of virus that we can detect," Jagganathan said.
In addition to drugs, Stanford is experimenting with another promising remedy: the antibodies from patients who have already contracted — and recovered from — COVID-19. The new experimental therapy program, which Stanford Blood Center announced on April 7, takes blood from the recovered patients, removes the plasma containing the antibodies, and returns the remaining blood components such as red blood cells back to the donor. The antibodies are then given to critically ill COVID-19 patients through a transfusion, the center stated.
The blood center is working with Stanford Medicine in hopes that the antibodies, which are immune proteins that attack pathogens such as viruses, might help lessen the severity of the COVID-19.
Though the use of antibodies to treat COVID-19 patients is in the investigational phase, the technique, also known as passive antibody therapy, dates back as far as the 1890s. And prior outbreaks with other coronaviruses, including the one that caused SARS, showed that neutralizing antibodies were helpful in reducing the effects of the disease.
Likewise, the technique was used in the 2009-2010 H1N1 influenza virus pandemic to reduce patients' respiratory viral load, inflammatory reactions and death, researchers Arturo Casadevall and Liise-anne Pirofski wrote in an article published in The Journal of Clinical Investigation on March 13. It also was used in the 2013 West African Ebola epidemic.
Stanford Blood Center will begin collecting the plasma this week and plans to increase collections in the following weeks as it identifies more donors. The donors must be fully recovered and symptom-free for at least 14 days. If they are only symptom-free for 14 to 28 days, they will be asked to retake a COVID-19 test at no cost. The repeat test must be negative to be eligible to donate.
The process takes about one to two hours using standard blood- and plasma-removal methods. The collections take place at the center's Palo Alto headquarters at 3373 Hillview Ave. in Palo Alto, where special care will be taken by a small team in a dedicated room, according to Dr. Suchi Pandey, the blood center's chief medical officer. (Interested donors can visit stanfordbloodcenter.org/covid19plasma and fill out an intake form.)
Getting enough of the antibodies to treat many patients could take time. Pandey said in an email that there's also no known way to cultivate or increase the amount of plasma in a laboratory, so blood centers and hospitals rely on donors.
"The volume of plasma collected from a donor is based on specific donor parameters such as weight. Depending on the volume of plasma collected, the unit may be divided into separate plasma components, which can be used to treat up to three patients," she said.
The U.S. Food and Drug Administration recently approved use of the antibody treatment by hospitals, initially only for critically ill patients.
It will later be used in clinical trials on patients in different stages of the disease, according to the blood center.
Find comprehensive coverage on the Midpeninsula's response to the new coronavirus by Palo Alto Online, the Mountain View Voice and the Almanac here.