Antibodies in blood soon after COVID-19 onset may predict severity

A look at antibodies in patients soon after they were infected with the virus that causes COVID-19 showed key differences between those whose cases remained mild and those who later developed severe symptoms.

January 18, 2022 - By Bruce Goldman

Blood drawn from patients shortly after they were infected with SARS-CoV-2, the virus that causes COVID-19, may indicate who is most likely to land in the hospital, a study led by Stanford Medicine investigators has found.

“We’ve identified an early biomarker of risk for progression to severe symptoms,” said Taia Wang, MD, PhD, assistant professor of infectious diseases and of microbiology and immunology. “And we found that antibodies elicited by an mRNA vaccine — in this case, Pfizer’s — differ in important, beneficial ways from those in people infected with SARS-CoV-2 who later progress to severe symptoms.” The upshot could eventually be a test that, given soon after a positive COVID-19 result, would help clinicians focus attention on those likely to need it most.

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A paper describing the study’s findings was published Jan. 18 in Science Translational Medicine. Wang shares senior authorship with Gene Tan, PhD, assistant professor at the J. Craig Venter Institute in La Jolla, California. Lead co-authors of the study are Stanford postdoctoral scholar Saborni Chakraborty, PhD, and graduate student Joseph Gonzalez.

“Severe COVID-19 is largely a hyperinflammatory disease, particularly in the lungs,” Wang said. “We wondered why a minority of people develop this excessive inflammatory response, when most people don’t.”

To find out, Wang and her colleagues collected blood samples from 178 adults who had tested positive for COVID-19 upon visiting a Stanford Health Care hospital or clinic. At the time of testing, these individuals’ symptoms were universally mild. As time passed, 15 participants developed symptoms bad enough to land them in the emergency department.

Taia Wang

Antibodies show distinctions

Analyzing the antibodies in blood samples taken from study participants on the day of their coronavirus test and 28 days later, the researchers ferreted out some notable differences between those who developed severe symptoms and those who didn’t.

Antibodies are proteins shaped, roughly speaking, like two-branched trees. They’re produced by immune cells and secreted in response to things the body perceives as foreign, such as microbial pathogens. An amazing feature of antibodies is that their branches can assume a multitude of shapes. The resulting spatial and electrochemical diversity of the areas defined by antibodies’ branches and their intersection is so great that, in the aggregate, antibodies take on all comers.

When an antibody’s shape and electrochemistry is complementary to a feature of a pathogen, it gloms on tightly. Sometimes the adherence isn’t in the right spot to prevent the pathogen from doing its nefarious business. Antibodies that bind pathogens in just the right places, preventing infection, are called neutralizing antibodies.

In either case, the resulting adhesion generates what’s called an immune complex, drawing immune cells to the site.

The researchers found that while many participants whose symptoms remained mild had healthy levels of neutralizing antibodies to SARS-CoV-2 from the get-go, participants who wound up hospitalized had initially minimal or undetectable levels of neutralizing antibodies, although their immune cells started pumping them out later in the infection’s course.

A second finding involved an often-neglected structural aspect of antibodies’ “trunks”: They are decorated with chains of various kinds of sugar molecules linked together. The makeup of these sugar chains has an effect on how inflammatory an immune complex will be.

We wondered why a minority of people develop this excessive inflammatory response, when most people don’t.

Many types of immune cells have receptors for this sugar-coated antibody trunk. These receptors distinguish among antibodies’ sugar molecules, helping to determine how fiercely the immune cells respond. A key finding of the new study was that in participants who progressed to severe COVID-19, sugar chains on certain antibodies targeting SARS-CoV2 were deficient in a variety of sugar called fucose. This deficiency was evident on the day these “progressors” first tested positive. So, it wasn’t a result of severe infection but preceded it.

Furthermore, immune cells in these patients featured inordinately high levels of receptors for these fucose-lacking types of antibodies. Such receptors, called CD16a, are known to boost immune cells’ inflammatory activity.

“Some inflammation is absolutely necessary to an effective immune response,” Wang said. “But too much can cause trouble, as in the massive inflammation we see in the lungs of people whose immune systems have failed to block SARS-CoV-2 quickly upon getting infected” — for example, because their early immune response didn’t generate enough neutralizing antibodies to the virus.

A look at vaccine response

The scientists also studied the antibodies elicited in 29 adults after they received the first and second doses of the Pfizer mRNA vaccine. They compared these antibodies with those of adults who didn’t progress to severe disease about a month after either being vaccinated or infected; they also compared them with antibodies from individuals hospitalized with COVID-19. Two vaccine doses led to overall high neutralizing-antibody levels. In addition, antibody fucose content was high in the vaccinated and mildly symptomatic groups but low in the hospitalized individuals.

Wang and her associates tested their findings in mice that had been bioengineered so their immune cells featured human receptors for antibodies on their surfaces. They applied immune complexes — extracted, variously, from patients with high levels of fucose-deficient antibodies, patients with normal levels or vaccinated adults — to the mice’s windpipes. The investigators observed four hours later that the fucose-deficient immune-complex extracts generated a massive inflammatory reaction in the mice’s lungs. Neither normal-fucose extracts nor extracts from vaccinated individuals had this effect.

When the experiment was repeated in similar mice that had been bioengineered to lack CD16a, there was no such hyperinflammatory response in their lungs.

Wang said the immunological factors the researchers have identified — a sluggish neutralizing-antibody response, deficient fucose levels on antibody-attached sugar chains, and hyperabundant receptors for fucose-deficient antibodies — were each, on their own, modestly predictive of COVID-19 severity. But taken together, they allowed the scientists to guess the disease’s course with an accuracy of about 80%.

Wang speculates that the abundance of CD16a on immune cells and the relative absence of fucose on antibodies’ sugar chains may not be entirely unrelated phenomena in some people, and that while neither alone is enough to consistently induce severe inflammatory symptoms following SARS-CoV-2 infection, the combination leads to a devastating inflammatory overdrive.

Other Stanford co-authors of the study are postdoctoral scholars Vamsee Mallajosyula, PhD, Megha Dubey, PhD, Usama Ashraf, PhD, Bowie Cheng, PhD, Nimish Kathale, PhD, Fei Gao, PhD, and Prabhu Arunachalam, PhD; life science research professionals Kim Tran and Courtney Scallan; genomics manager Xuhuai Ji, MD, PhD; Scott Boyd, MD, PhD, associate professor of pathology; Mark Davis, PhD, director of the Stanford Institute for Immunity, Transplantation and Infection and professor of microbiology and immunology; Marisa Holubar, MD, clinical associate professor of infectious diseases; Chaitan Khosla, PhD, professor of chemical engineering and of chemistry; Holden Maecker, PhD, professor of microbiology and immunology; Yvonne Maldonado, MD, professor of pediatric infectious diseases and of epidemiology and population health; Elizabeth Mellins, MD, professor of pediatric human gene therapy; Kari Nadeau, MD, PhD, professor of medicine and of pediatrics; Bali Pulendran, PhD, professor of pathology and of microbiology and immunology; Upinder Singh, MD, professor of infectious diseases and geographic medicine and of microbiology and immunology; Aruna Subramanian, MD, clinical professor of infectious diseases; PJ Utz, MD, professor of immunology and rheumatology; and Prasanna Jagannathan, MD, assistant professor of infectious diseases and of microbiology and immunology.

Researchers from San Jose State University; the University of California, San Francisco; the Icahn School of Medicine; and Cornell University contributed to the work.

The research was funded by the National Institutes of Health (grants U19AI111825, U54CA260517, R01AI139119, U01AI150741-02S1, 5T32AI007290, U24CA224319 and U01DK124165), Fast Grants, CEND COVID Catalyst Fund, the Crown Foundation, the Sunshine Foundation and the Marino Family Foundation. 

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Surgical masks reduce COVID-19 spread, large-scale study shows

Researchers found that surgical masks impede the spread of COVID-19 and that just a few, low-cost interventions increase mask-wearing compliance.

September 1, 2021 - By Krista Conger

Providing free masks to people in rural Bangladesh was one measure researchers tested to limit the spread of COVID-19. Courtesy of Innovations for Poverty Action

A large, randomized trial led by researchers at Stanford Medicine and Yale University has found that wearing a surgical face mask over the mouth and nose is an effective way to reduce the occurrence of COVID-19 in community settings.

It also showed that relatively low-cost, targeted interventions to promote mask-wearing can significantly increase the use of face coverings in rural, low-income countries. Based on the results, the interventional model is being scaled up to reach tens of millions of people in Southeast Asia and Latin America over the next few months.

The findings were released Sept. 1 on the Innovations for Poverty Action website, prior to their publication in a scientific journal, because the information is considered of pressing importance for public health as the pandemic worsens in many parts of the world.

“We now have evidence from a randomized, controlled trial that mask promotion increases the use of face coverings and prevents the spread of COVID-19,” said Stephen Luby, MD, professor of medicine at Stanford. “This is the gold standard for evaluating public health interventions. Importantly, this approach was designed be scalable in lower- and middle-income countries struggling to get or distribute vaccines against the virus.”

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Luby shares senior authorship with Ahmed Mushfiq Mobarak, PhD, professor of economics at Yale, of a paper describing the research. The lead authors are Ashley Styczynski, MD, MPH, an infectious disease fellow at Stanford; Jason Abaluck, PhD, professor of economics at Yale; and Laura Kwong, PhD, a former postdoctoral scholar at Stanford who is now an assistant professor of environmental health sciences at the University of California-Berkeley.

The researchers also partnered with Innovations for Poverty Action, a global research and policy nonprofit organization.

Increasing mask use in rural Bangladesh

The researchers enrolled nearly 350,000 people from 600 villages in rural Bangladesh. Those living in villages randomly assigned to a series of interventions promoting the use of surgical masks were about 11% less likely than those living in control villages to develop COVID-19, which is caused by infection with the SARS-CoV-2 virus, during the eight-week study period. The protective effect increased to nearly 35% for people over 60 years old.

Providing free masks, informing people about the importance of covering both the mouth and nose, reminding people in-person when they were unmasked in public, and role-modeling by community leaders tripled regular mask usage compared with control villages that received no interventions, the researchers found.

In the intervention villages, they also saw a slight increase in physical distancing in public spaces, such as marketplaces. This finding indicates that mask-wearing doesn’t give a false sense of security that leads to risk-taking behaviors — a concern cited by the World Health Organization during the early days of the pandemic when its officials were considering whether to recommend universal masking.

“Our study is the first randomized controlled trial exploring whether facial masking prevents COVID-19 transmission at the community level,” Styczynski said. “It’s notable that even though fewer than 50% of the people in the intervention villages wore masks in public places, we still saw a significant risk reduction in symptomatic COVID-19 in these communities, particularly in elderly, more vulnerable people.”

Cloth vs. surgical masks

There were significantly fewer COVID-19 cases in villages with surgical masks compared with the control villages. (Although there were also fewer COVID-19 cases in villages with cloth masks as compared to control villages, the difference was not statistically significant.) This aligns with lab tests showing that surgical masks have better filtration than cloth masks. However, cloth masks did reduce the overall likelihood of experiencing symptoms of respiratory illness during the study period.

Bangladesh is a densely populated country in South Asia. It was chosen as the site of the trial for several reasons: One, mask promotion is considered vital in countries where physical distancing can be difficult; two, Innovations for Poverty Action Bangladesh had already established a research framework in the country; and three, many local partners were eager to support a randomized, controlled trial of masking.

“We saw an opportunity to better understand the effect of masks, which can be a very important way for people in low-resource areas to protect themselves while they wait for vaccines,” Kwong said. “So we collaborated with behavioral scientists, economists, public health experts and religious figures to design ways to promote mask use at a community level.”

Despite a growing body of scientific evidence that masks reduce the spread of the virus that causes COVID-19, it has been difficult to increase mask-wearing, particularly in low-resource countries and among people living in remote or rural areas. In June of 2020, only one-fifth of Bangladeshis in public areas were wearing a mask that properly covered the mouth and nose despite a nationwide mask mandate that was in effect at the time.

Educational and behavioral interventions

The researchers wanted to explore whether it was possible to increase mask-wearing in Bangladeshi villages through a variety of educational and behavioral interventions over an eight-week study period: Free cloth or washable, reusable surgical masks were given to people at home and in marketplaces, mosques and other public spaces; notable Bangladeshi figures, including the prime minister, a star cricket player and a leading imam, provided information about why wearing a mask is important; people appearing in public places without masks were reminded to wear masks; and community leaders modeled mask-wearing.

The villages were selected by researchers at Innovations for Poverty Action Bangladesh. The researchers paired 600 villages countrywide based on population size and density, geographic location, and any available COVID-19 case data. For each of the 300 pairs of villages, one was randomly assigned to receive the interventions while the other served as a control and received no interventions. Two-thirds of the intervention villages received surgical masks, while the other one-third received cloth masks. In total, 178,288 people were in the intervention group, and 163,838 people were in the control group.

The interventions were rolled out in waves from mid-November to early January. For eight weeks after the interventions, observers stationed at various public places in both the control and intervention villages recorded whether a person was wearing a mask over both their mouth and nose and whether they appeared to be practicing physical distancing — that is, staying at least an arm’s length away from all other people.

At week 5 and week 9, villagers were asked if they had experienced any COVID-19 symptoms — including fever, cough, nasal congestion and sore throat — during the previous month and, if so, whether they would provide a blood sample to test for the presence of SARS-CoV-2. About 40% of symptomatic people consented to subsequent blood collection.

We saw the largest impact on older people who are at greater risk of death from COVID-19.

The observers found that just over 13% of people in the villages that received no interventions wore a mask properly, compared with more than 42% of people in the villages where each household received free masks and in-person reminders to wear them. Physical distancing was observed 24.1% of the time in control villages and 29.2% of the time in intervention villages.

About 7.6% of people in the intervention villages reported COVID-19 symptoms compared with about 8.6% of those in the control villages during the eight-week study period — a statistically significant difference that indicates a roughly 12% reduction in the risk of experiencing respiratory symptoms.

The researchers found that among the more than 350,000 people studied, the rate of people who reported symptoms of COVID-19, consented to blood collection and tested positive for the virus was 0.76% in the control villages and 0.68% in the intervention villages, showing an overall reduction in risk for symptomatic, confirmed infection of 9.3% in the intervention villages regardless of mask type.

When the researchers considered only those villages that received surgical masks (omitting villages that received cloth masks), the reduction in risk increased to 11%. Furthermore, the protective effect of surgical masks was greater for older people: As a group, those ages 50 to 60 were 23% less likely to develop COVID-19 if they wore a surgical mask, and those over 60 were 35% less likely if they did.

“This is statistically significant and, we believe, probably a low estimate of the effectiveness of surgical masks in community settings,” Styczynski said. The fact that the study was conducted at a time when the rate of transmission of COVID-19 in Bangladesh was relatively low, that a minority of symptomatic people consented to blood collection to confirm their disease status, and that fewer than half of the people in the intervention villages used facial coverings means the true impact of near-universal masking could be much more significant — particularly in areas with more indoor gatherings and events, she noted.

“If mask-wearing rates were higher, we would expect to see an even bigger impact on transmission,” Luby said. “But even at this level, we saw the largest impact on older people who are at greater risk of death from COVID-19.”

The interventions are now being rolled out in other parts of Bangladesh and in Pakistan, India, Nepal and parts of Latin America. But the researchers also hope there are lessons in the study for Americans.

“Unfortunately, much of the conversation around masking in the United States is not evidence-based,” Luby said. “Our study provides strong evidence that mask wearing can interrupt the transmission of SARS-CoV-2. It also suggests that filtration efficiency is important. This includes the fit of the mask as well as the materials from which it is made. A cloth mask is certainly better than nothing. But now might be a good time to consider upgrading to a surgical mask.”

The study was supported by a grant from GiveWell.org to Innovations for Poverty Action.

Researchers from Innovation for Poverty Action; the University of California-Berkeley; Johns Hopkins Bloomberg School of Public Health; the NGRI North South University in Dhaka, Bangladesh; and Deakin University in Melbourne also contributed to the study.

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Stanford Medicine opens clinic for patients struggling with long COVID

With research showing up to 30% of COVID-19 patients experiencing lingering symptoms, Stanford Health Care treats such “long haulers” with multidisciplinary teams.

July 30, 2021 - By Tracie White

Hector Bonilla examines Rosie Flores at  Stanford's Post-Acute COVID-19 Syndrome Clinic. Flores's health has improved since she started visiting the clinic, but some symptoms remain.

For about five months after contracting COVID-19, Rosie Flores lay on the couch at her home in Mountain View, California, feeling so fatigued that standing up was a struggle.

“I remember walking to my bed from the couch to grab a comforter and being out of breath,” said Flores, 47, who tested positive for the coronavirus in July 2020. “My arms felt like noodles. A phone conversation would exhaust me. My life was just living on the couch.”

Almost a year out, that fatigue has finally improved some. She went back to work part time in December as a project coordinator at Stanford Health Care, returning full time in March, but a day’s work still zaps her energy, and she continues to struggle with other symptoms, such as impaired memory, hair loss and balance problems.

In the fall, Flores was diagnosed at Stanford Health Care with symptoms of post-viral COVID-19 or, as it’s better known, long COVID. Unfortunately, she is not alone. As coronavirus cases have ebbed nationwide since the peak last winter, this newly described illness, estimated to affect up to 30% of recovering coronavirus patients, has caught the attention of the media, the federal government and the medical community, raising concerns that the long-term public health impact could be overwhelming.

At Stanford, some physicians who have been treating COVID-19 patients and researching long COVID realized they needed a clinic specifically for patients like Flores. Stanford Health Care’s Post-Acute COVID-19 Syndrome Clinic, or PACS, opened in May.

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“As the pandemic progressed, we started seeing patients with all kinds of lingering symptoms after their initial COVID infection, including fatigue, dizziness, cognitive dysfunction, mood symptoms, chest pain, shortness of breath, insomnia, loss of taste and smell, hair loss and sleep disturbance,” said Linda Geng, MD, PhD, clinical assistant professor of medicine, who co-directs the clinic at Stanford. “It was clear this was a huge problem, and we needed to serve these patients.”

Lingering symptoms

Stories in the media about large numbers of patients who recovered from COVID-19, only to develop new and lingering symptoms, first appeared last summer. Some of the patients started calling themselves long-haulers, and the name stuck. Often, they said, they were dismissed by doctors who didn’t believe them.

The cause of long COVID remains unclear, and the number of people who suffer from it is unknown. It can persist for months and range from mild to incapacitating. There is no definitive lab test to diagnose it, and there are no standardized treatments. In many cases, patients are left wondering if they will ever get better.

Clinicians are taking cues from what is known about other chronic illnesses, such as myalgic encephalomyelitis/chronic fatigue syndrome, a condition that often manifests after a viral infection and also has no known cause or standardized treatment, said Aruna Subramanian, MD, clinical professor of infectious disease at Stanford, who co-directs the ME/CFS Clinic. Long-COVID and ME/CFS symptoms are often similar and can include headaches and brain fog, as well as profound fatigue and something called post-exertional malaise — the worsening of symptoms after even minor physical or mental exertion.

Hector Bonilla and Linda Geng
Steve Fisch

“There seems to be a lot of overlap,” Subramanian said. “Working in the ME/CFS clinic, we see people who may have had other viral triggers, got sick … and their lives changed.”

Geng added that more research is needed to determine whether patients with long COVID fall into separate categories.

“This is a very heterogenous condition,” she said. “We may find different subgroups. There are patients who have multiple symptoms — dizziness, shortness of breath, insomnia all coming together — and then there are those with more isolated and defined COVID-specific symptoms like loss of smell and taste. The important thing to remember is to validate our patients; just because the condition is poorly understood doesn’t mean it’s not real.”

Whatever the case, enough scientific evidence has piled up to confirm that the problem is not only real but worrisome, according to the federal government. In December, Congress provided the National Institutes of Health with $1.15 billion to study the long-term symptoms of COVID-19. The NIH named the illness post-acute sequelae of SARS-CoV-2 infection and launched an initiative to find treatments.

“We do not know yet the magnitude of the problem, but given the number of individuals of all ages who have been or will be infected with SARS-CoV-2, the coronavirus that causes COVID-19, the public health impact could be profound,” Francis Collins, MD, PhD, director of the NIH, said in a press release announcing the initiative.

Studies providing evidence of the disorder first appeared in fall of 2020. In February, a study published in JAMA Open Network that followed COVID-19 patients up to nine months found about 30% reported persistent symptoms. A Nature Medicine article published in March, based on reports from 3,700 self-described long-haulers from 56 countries, showed nearly half couldn’t work full time for six months after first getting sick.

In May, a study by Stanford Medicine epidemiologists found that 70% of hospitalized COVID-19 patients had at least one symptom months later; another Stanford study found that even those with less severe cases of the virus, who were never hospitalized, were experiencing long COVID.

Physicians and scientists at Stanford continue to track symptoms and conduct imaging; they’re also searching for causes and treatments.

“There’s evidence the virus is triggering inflammation,” Subramanian said. “We know there is gastrointestinal involvement, but we don’t know much about these long-term symptoms in general — nausea, diarrhea, headaches. There seems to be some immune dysregulation. … We are wondering whether COVID is a trigger for ME/CFS.”

“We need new ideas so we can move treatment forward,” she added.

Just because the condition is poorly understood doesn't mean it's not real.

The PACS Clinic is designed to be a portal connecting long-COVID patients with a multidisciplinary team of post-COVID experts, including pulmonologists, cardiologists and neurologists, depending on symptoms. Some patients may have racing heartbeats and need to see a cardiologist. Many complain of shortness of breath and are referred to a pulmonologist. If a patient was hospitalized with COVID-19 and on a ventilator for a long period, the problem could be something called post-intensive care syndrome, and treatment could involve heart and lung and other rehabilitation.

Some patients have also been referred to the ME/CFS clinic, which can provide experimental medications, pain management techniques and activity-management training to help control the severe fatigue.

The co-directors of the PACS Clinic, Geng and Hector Bonilla, MD, clinical associate professor of infectious diseases, are experts in complex chronic diseases and post-viral illnesses. Geng’s expertise is in the diagnostic evaluation of patients with a wide variety of unexplained symptoms and mystery medical conditions, which is why long COVID caught her attention. She thought she could help by joining forces with other faculty members from various disciplines to tackle this complex condition, she said.

“When this condition came to light, it seemed very similar to many cases we had seen in our diagnotic clinic prior to COVID,” Geng said, referring to Stanford Health Care’s Consultative Care Clinic, which provides diagnostic services for patients with unexplained illnesses and symptoms. “We have seen patients with mysterious, puzzling symptoms after viral and other infectious illnesses. Long COVID can manifest in multiple systems of the body, including cardiopulmonary, endocrine, gastrointestinal, rheumatologic, neurologic, musculoskeletal, and so on.”

“We need to take a whole-body approach to patient care,” she added.

The long haul

Flores, who’s participating in a Stanford study of long COVID patients, has seen an array of specialists, including an audiologist, hematologist, cardiologist and pulmonologist. She’s been referred to a movement-disorders clinic. She’s discovered that she’s lost 10% to 15% of her hearing and that her balance is off. She has difficulty walking a straight line. No one knows why her hair keeps falling out.

“I feel like my memory has improved but not anywhere close to where it once was,” she said. There were times, especially in the early phase of her illness, when she would look at a word in print that she knew but couldn’t remember what it meant or how to pronounce it. A few times, she had difficulty speaking, and that scared her.

Most recently, she was given an off-label drug called aripiprazole that Bonilla studied in an earlier trial as an experimental treatment for ME/CFS. It gave her more energy and allowed her to work full time. Without it, she said, she wasn’t sure she could continue in her job.

“I was ready to give up, but those pills really helped,” she said. Still, her life is far from what it was before she got sick. She no longer volunteers at her church. A phone call to a friend can exhaust her. She can’t do a six-minute walk, and her balance remains unsteady. As each day passes, she grows more impatient for new research to provide better answers.

“You think it’s going to get better, but it doesn’t,” she said. “Everyone thinks you are doing well, but you’re not. My hair is still coming out in handfuls. If I close my eyes, I start swaying. That’s where I am right now.”

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Dean Winslow leads national COVID-19 Testing and Diagnostics Working Group

A professor of medicine and former Air Force colonel, Winslow temporarily relocated to Washington to head an interagency group responding to this pandemic and preparing for the next one.

JUL 20 2021 | JODY BERGER

In 2008, Dean Winslow holds an injured Iraqi child he was able to send to Shriners Burn Center in Boston.

Last fall, Dean Winslow, MD, saw the numbers everyone else saw: COVID-19 was killing nearly 2,000 Americans and infecting as many as 180,000 more each day. But he responded like few people could.

Winslow worked with state, federal and military leaders to get himself to Washington, D.C., where he now directs the COVID-19 Testing and Diagnostics Working Group, an 82-person, $46-billion interagency effort to track the virus and help steer the U.S. — and the world — out of the pandemic.

“I feel very lucky at this relatively late point in my career to be part of this,” said Winslow, who joined Stanford as a professor of medicine and as a senior fellow at the Freeman Spogli Institute for International Studies in 2013. “I had a wonderful 35 years in the military, and [serving in this role] almost feels like that, with the sense of purpose and camaraderie. And nobody’s shooting rockets at me.”

In November, with infections surging before vaccines were available, he wrote to Anne Schuchat, MD, the principal deputy director of the Centers for Disease Control and Prevention, volunteering to serve. But creating an official job within the federal government would take months.

Winslow couldn’t wait.

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Joining the state guard

Winslow retired from the Air National Guard in 2015, but he came out of retirement in March 2020, joining the California State Guard to help with California’s COVID-19 response and train California Air National Guard members. After the CDC asked him to join the working group, the California State Guard put him on state active duty orders and sent him to the working group.

“When I joined the working group in April, I was probably the oldest officer on active duty in the United States,” the 68-year-old Winslow said.

“I got to wear camouflage pajamas to work again,” he added, using airmen’s vernacular for the uniforms they wear while deployed.

Winslow took a leave from Stanford to join the group and began leading the team July 1. By that point, he had an official civilian job, so he started dressing like the rest of the team that includes scientists from various specialties, data analysts, and acquisitions and logistics experts from the CDC, the Department of Health and Human Services, the National Institutes of Health,  the Food and Drug Administration, and the Department of Defense.

The working group distributes testing resources, facilitates testing nationally, and tracks data from testing sites to know where the virus is infecting new communities and where new cases are occurring. The work has taken on increasing urgency in the past few weeks because of the more transmissible delta variant: Cases are surging again in parts of the country, especially where fewer residents are vaccinated.

Anthony Fauci and Dean Winslow share a friendship as well as a history of serving their country.

“As vaccination continues to slowly increase, the way we’re going to finally eliminate this pandemic, at least from the U.S., is by focusing on these hot spots, particularly among vulnerable populations,” Winslow said.

The group is also working with manufacturers to stockpile diagnostic testing equipment, which was in critically short supply during the height of the pandemic. Part of the longer-term goal is to provide incentives for U.S. manufacturers to keep their operations in the United States.

“We’re looking to make sure that we do a much, much better job in being prepared for the next pandemic,” Winslow said.

If tracking the current pandemic while also preparing for future events seems like an impossibly big job, it’s also a job that requires the rare combination of skills that Winslow has accumulated throughout his career. Even leading personnel with diverse skill sets — all on loan from other agencies — is in his wheelhouse.

“He’s got this ability to connect with everyone involved in this process,” said Julie Parsonnet, MD, professor of medicine and of health research and policy. (She’s also Winslow’s spouse.)

“He’s a welcoming collaborator, and he’s completely nonjudgmental,” she said.

A different virus

Winslow graduated from Pennsylvania State University and Jefferson Medical College before starting his internal medicine residency in Wilmington, Delaware. As a third-year resident, he was responsible for inviting speakers to give grand rounds, at which experts present medical cases and discuss treatment options. When a speaker backed out with only two days’ notice, Winslow called an immunologist at the National Institutes of Health who studied necrotizing vasculitis, a disorder that causes inflammation of the blood vessels.

The immunologist, Anthony Fauci, MD, agreed to give the talk if Winslow could pick him up at the Amtrak station and give him a lift back. Winslow accepted the deal, and the two men have been friends ever since. (Inviting Fauci to deliver the Thomas Merigan Lecture at Stanford in 2012, Winslow gave his old friend more notice.)

Winslow and Fauci, who is now chief medical adviser to President Joe Biden, are members of the last generation to train before the AIDS epidemic. The disease shaped both of their careers.

Winslow launched the first HIV clinic in Delaware. He had seen a patient with a compromised immune system and lesions on his brain during his first week in private practice in July 1981. There was no test for the virus at the time, but Winslow saved some of the patients’ blood serum and later learned that the man was, in fact, his first AIDS patient.

When AIDS testing became more readily available, Winslow started seeing more cases in socially vulnerable individuals and persuaded the administration of the Medical Center of Delaware to start the clinic. Later, while working in pharmaceutical-biotech industry, he also helped oversee trials of inhibitors to treat HIV and helped gain FDA clearance for a device that tests resistance to HIV drugs.

For his part, Fauci in 1984 became the director of the National Institute of Allergy and Infectious Diseases, a position he still holds, and oversaw much of the AIDS research for the country.

Winslow joined the Louisiana Air National Guard in 1980, became a flight surgeon, then served as the state air surgeon in the Delaware National Guard. In 2008 he served as the commander at a combat hospital in Baghdad. He deployed four times to Iraq and twice to Afghanistan after 9/11 as a flight surgeon supporting combat operations.

“From the bottom airman on the ladder to the airmen wearing stars on their collars, Dean showed no preferential treatment,” said retired Brig. Gen. Bruce Thompson, who was Winslow’s commanding officer and has known him for 30 years. “Dean oozes compassion.”

When Winslow saw Iraqi children who could not receive the medical care they needed in Iraq, he arranged for them to be flown to the U.S. where hospitals could provide treatment.

In 2015, Winslow and Parsonnet created the Eagle Fund, a charitable trust that helps victims of war around the world.

“His whole career is about stepping up to the plate when asked,” Parsonnet said. “And even when he’s not asked.”

An honest answer

Four years ago, Winslow was nominated to become assistant secretary of defense for health affairs. In his senate confirmation hearing, Winslow fielded a question about a mass shooting that had just occurred in Texas. He answered honestly.

“I’d also like to … just say how insane it is that in the United States of America a civilian can go out and buy a semiautomatic weapon like an AR-15,” he said.

The late Sen. John McCain, R-Arizona, interrupted him to say this was not Winslow’s area of expertise, and soon the confirmation was put on indefinite hold. Winslow withdrew his name for consideration and turned his attention to helping victims of gun violence.

He worked with medical students and faculty to launch SAFE, Scrubs Addressing the Firearms Epidemic, a nonprofit organization of health care professionals dedicated to reducing gun violence and protecting the victims. SAFE now has chapters at more than 50 U.S. medical schools.

Winslow expects to stay with the working group for a year, then return to Stanford. The experience is reminiscent of other adventures he’s had in the military, in the clinic and in academia, he said. He’s surrounded by smart and dedicated colleagues, working together for a cause greater than themselves.

“I’ve had so many wonderful experiences in my life,” Winslow said. “I almost feel guilty for it. It’s like I’ve had more fun than any five people should have.”

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With herd immunity elusive, vaccination best defense against COVID-19, Stanford epidemiologist says

Epidemiology expert Julie Parsonnet warns that COVID-19 vaccine hesitancy has probably made herd immunity unattainable, which makes vaccination all the more important for personal health.

MAY 27 2021 | By HANAE ARMITAGE

COVID-19 vaccinations are now readily available to all Americans, so herd immunity should be attainable, right?

Probably not, says Julie Parsonnet, MD, professor of medicine and of epidemiology and population health. Paradoxically, it may be the very concept of herd immunity that is thwarting the uptake of vaccinations in the United States.

“We need to stop pushing herd immunity to the public,” Parsonnet said, as it may discourage some people from getting vaccinated in the mistaken belief that, if other people get vaccinated, they can just wait for herd immunity. “Public health departments don’t talk about herd immunity because it’s not helpful for the immediate protection of individuals and the overall response to the pandemic. What’s important is getting as many people vaccinated as you possibly can.”

Herd immunity is reached when the number of people in a population who are susceptible to disease drops to such a low level, usually due to vaccination, that any new cases cannot spread. Parsonnet, the George DeForest Barnett Professor in Medicine, said the concept of herd immunity is best used to model disease and figure out a public health strategy. Herd immunity is a nice idea, she said, but in reality, it’s a concept best applied to cow herds — or perhaps to nursing homes, ships, boarding schools or islands — but not to an entire country or the world.

Nevertheless, the concept caught the public’s attention last year as cases skyrocketed. Some have latched onto the idea, thinking that once the population reaches a certain threshold, the coronavirus will dissipate. But, while almost half the population of the United States has received at least one dose of a COVID-19 vaccine, hesitancy is high — about 30% — and a vaccine rate of 70% won’t bring us close to herd immunity, Parsonnet said.

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COVID-19 is not measles

Diseases such as measles and smallpox have been nearly eradicated, or at least heavily tamped down, thanks to widespread and effective vaccination. It’s unlikely the United States has actually reached herd immunity for measles, as many children are now unvaccinated, Parsonnet said. “Measles cases are currently quite rare, and when they do occur, they’re always symptomatic. This allows for those who’ve been exposed to be isolated, and those at risk can be protected through something called ‘ring vaccination,’ in which people who may encounter a sick individual are vaccinated,” she said.

Julie Parsonnet

But COVID-19 is not measles. Unlike measles, not all cases of COVID-19 are symptomatic, so sick individuals can’t all be isolated; the COVID-19 vaccine is not 100% effective, and it’s unknown how long it bestows protection; there are many variants of the virus; and the virus can infect animals. “It took 40 years to control measles; for COVID, it is likely to take a lot longer to control,” Parsonnet said.

“The other important thing to remember is that herd immunity is not this ah-ha moment where suddenly there’s no more disease and we don’t have to worry about it anymore,” Parsonnet said. “It’s something that must be maintained, mostly through vaccinations, once transmission has slowed down.”

The need for immunological upkeep is due to new “susceptibles,” or individuals who have no immunity to a given disease, in a population. And with regard to COVID-19, there are a lot of susceptibles, such as newborns or immunosuppressed individuals. “We don’t live in isolation, and to get herd immunity in such an interconnected world is extremely challenging,” Parsonnet said.

It’s true that susceptible individuals who acquire COVID-19 will have natural immunity, but it’s not enough to protect the herd. Parsonnet uses measles to illustrate her point. The disease was introduced in the Americas in the 1500s, but even after hundreds of years, the U.S. population never developed natural herd immunity, likely due to newborns’ natural susceptibility, among other reasons. Only after 1963, when a measles vaccine was developed, did the United States start seeing large-scale immunity. For SARS-CoV-2, it’s even trickier, as variants could evade natural or vaccine-derived immunity, and natural immunity doesn’t seem to be as potent, Parsonnet said.

Stop planning on herd immunity

Parsonnet also is concerned that vaccine hesitancy remains high in the United States. Using an equation that estimates the transmissibility COVID-19 and the effectiveness of the available vaccines, her latest calculations show that about 90% of the United States would need to be fully vaccinated to reach herd immunity. There are other challenges as well.

 “What if vaccine immunity starts to wane? What if we all need booster shots for a different variant?” she said. Every time booster shots are required, she noted, there’s likely to be a dip in the number of people showing up to receive them.

So, what are we to do?

“The best way to handle this is to vaccinate the people who are most likely to transmit the virus — young adults, people who have a lot of contacts, people who live with a lot of other people in their households,” Parsonnet said.

People who are reluctant to get the vaccine and people who face obstacles to receiving it, such as immigrants who experience language barriers, are most likely to transmit the virus. Vaccination campaigns should focus on those groups, Parsonnet said.

“If we want to approach this in a realistic way, the focus shouldn’t be on herd immunity. It should be on vaccinating as many people as possible — especially the people who will have the biggest impact on a population level,” Parsonnet said. “That’s what will make the biggest impact on significantly diminishing the rates of COVID-19.”

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5 Questions: David Relman on investigating origin of coronavirus

Microbiologist David Relman explores how the coronavirus could have emerged and why we need to know.

MAY 20 2021 | By BRUCE GOLDMAN

    On May 13, the journal Science published a letter,On May 13, the journal Science published a letter, signed by 18 scientists, stating that it was still unclear whether the virus that causes COVID-19 emerged naturally or was the result of a laboratory accident, but that neither cause could be ruled out. David Relman, MD, the Thomas C. and Joan M. Merigan Professor and professor of microbiology and immunology, spearheaded the effort.

    Relman is no stranger to complicated microbial threat scenarios and illness of unclear origin. He has advised the U.S. government on emerging infectious diseases and potential biological threats. He served as vice chair of a National Academy of Sciences committee reviewing the FBI investigation of letters containing anthrax that were sent in 2001. Recently, he chaired another academy committee that assessed a cluster of poorly explained illnesses in U.S. embassy employees. He is a past president of the Infectious Diseases Society of America.

    Stanford Medicine science writer Bruce Goldman asked Relman to explain what remains unknown about the coronavirus’s emergence, what we may learn and what’s at stake.

1. How might SARS-CoV-2, which causes COVID-19, have first infected humans?

Relman: We know very little about its origins. The virus’s closest known relatives were discovered in bats in Yunnan Province, China, yet the first known cases of COVID-19 were detected in Wuhan, about 1,000 miles away.

There are two general scenarios by which this virus could have made the jump to humans. First, the jump, or “spillover,” might have happened directly from an animal to a human, by means of an encounter that took place within, say, a bat-inhabited cave or mine, or closer to human dwellings — say, at an animal market. Or it could have happened indirectly, through a human encounter with some other animal to which the primary host, presumably a bat, had transmitted the virus.

Bats and other potential SARS-CoV-2 hosts are known to be shipped across China, including to Wuhan. But if there were any infected animals near or in Wuhan, they haven’t been publicly identified.

Maybe someone became infected after contact with an infected animal in or near Yunnan, and moved on to Wuhan. But then, because of the high transmissibility of this virus, you’d have expected to see other infected people at or near the site of this initial encounter, whether through similar animal exposure or because of transmission from this person.

2. What’s the other scenario?

Relman: SARS-CoV-2 could have spent some time in a laboratory before encountering humans. We know that some of the largest collections of bat coronaviruses in the world — and a vigorous research program involving the creation of “chimeric” bat coronaviruses by integrating unfamiliar coronavirus genomic sequences into other, known coronaviruses — are located in downtown Wuhan. And we know that laboratory accidents happen everywhere there are laboratories.

Humans are fallible, and laboratory accidents happen — far more often than we care to admit.

All scientists need to acknowledge a simple fact: Humans are fallible, and laboratory accidents happen — far more often than we care to admit. Several years ago, an investigative reporter uncovered evidence of hundreds of lab accidents across the United States involving dangerous, disease-causing microbes in academic institutions and government centers of excellence alike — including the Centers for Disease Control and Prevention and the National Institutes of Health.

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SARS-CoV-2 might have been lurking in a sample collected from a bat or other infected animal, brought to a laboratory, perhaps stored in a freezer, then propagated in the laboratory as part of an effort to resurrect and study bat-associated viruses. The materials might have been discarded as a failed experiment. Or SARS-CoV-2 could have been created through commonly used laboratory techniques to study novel viruses, starting with closely related coronaviruses that have not yet been revealed to the public. Either way, SARS-CoV-2 could have easily infected an unsuspecting lab worker and then caused a mild or asymptomatic infection that was carried out of the laboratory.

3. Why is it important to understand SARS-CoV-2’s origins?

Relman: Some argue that we would be best served by focusing on countering the dire impacts of the pandemic and not diverting resources to ascertaining its origins. I agree that addressing the pandemic’s calamitous effects deserves high priority. But it’s possible and important for us to pursue both. Greater clarity about the origins will help guide efforts to prevent a next pandemic. Such prevention efforts would look very different depending on which of these scenarios proves to be the most likely.

Evidence favoring a natural spillover should prompt a wide variety of measures to minimize human contact with high-risk animal hosts. Evidence favoring a laboratory spillover should prompt intensified review and oversight of high-risk laboratory work and should strengthen efforts to improve laboratory safety. Both kinds of risk-mitigation efforts will be resource intensive, so it’s worth knowing which scenario is most likely.

4. What attempts at investigating SARS-CoV-2’s origin have been made so far, with what outcomes?

Relman: There’s a glaring paucity of data. The SARS-CoV-2 genome sequence, and those of a handful of not-so-closely-related bat coronaviruses, have been analyzed ad nauseam. But the near ancestors of SARS-CoV-2 remain missing in action. Absent that knowledge, it’s impossible to discern the origins of this virus from its genome sequence alone. SARS-CoV-2 hasn’t been reliably detected anywhere prior to the first reported cases of disease in humans in Wuhan at the end of 2019. The whole enterprise has been made even more difficult by the Chinese national authorities’ efforts to control and limit the release of public health records and data pertaining to laboratory research on coronaviruses.

In mid-2020, the World Health Organization organized an investigation into the origins of COVID-19, resulting in a fact-finding trip to Wuhan in January 2021. But the terms of reference laying out the purposes and structure of the visit made no mention of a possible laboratory-based scenario. Each investigating team member had to be individually approved by the Chinese government. And much of the data the investigators got to see was selected prior to the visit and aggregated and presented to the team by their hosts.

The recently released final report from the WHO concluded — despite the absence of dispositive evidence for either scenario — that a natural origin was “likely to very likely” and a laboratory accident “extremely unlikely.” The report dedicated only 4 of its 313 pages to the possibility of a laboratory scenario, much of it under a header entitled “conspiracy theories.” Multiple statements by one of the investigators lambasted any discussion of a laboratory origin as the work of dark conspiracy theorists. (Notably, that investigator — the only American selected to be on the team — has a pronounced conflict of interest.)

Given all this, it’s tough to give this WHO report much credibility. Its lack of objectivity and its failure to follow basic principles of scientific investigation are troubling. Fortunately, WHO’s director-general recognizes some of the shortcomings of the WHO effort and has called for a more robust investigation, as have the governments of the United States, 13 other countries and the European Union.

5. What’s key to an effective investigation of the virus’s origins?

Relman: A credible investigation should address all plausible scenarios in a deliberate manner, involve a wide variety of expertise and disciplines and follow the evidence. In order to critically evaluate other scientists’ conclusions, we must demand their original primary data and the exact methods they used — regardless of how we feel about the topic or about those whose conclusions we seek to assess. Prior assumptions or beliefs, in the absence of supporting evidence, must be set aside.

Investigators should not have any significant conflicts of interest in the outcome of the investigation, such as standing to gain or lose anything of value should the evidence point to any particular scenario.

There are myriad possible sources of valuable data and information, some of them still preserved and protected, that could make greater clarity about the origins feasible. For all of these forms of data and information, one needs proof of place and time of origin, and proof of provenance.

To understand the place and time of the first human cases, we need original records from clinical care facilities and public health institutions as well as archived clinical laboratory data and leftover clinical samples on which new analyses can be performed. One might expect to find samples of wildlife, records of animal die-offs and supply-chain documents.

Efforts to explore possible laboratory origins will require that all laboratories known to be working on coronaviruses, or collecting relevant animal or clinical samples, provide original records of experimental work, internal communications, all forms of data — especially all genetic-sequence data — and all viruses, both natural and recombinant. One might expect to find archived sequence databases and laboratory records.

Needless to say, the politicized nature of the origins issue will make a proper investigation very difficult to pull off. But this doesn’t mean that we shouldn’t try our best. Scientists are inquisitive, capable, clever, determined when motivated, and inclined to share their insights and findings. This should not be a finger-pointing exercise, nor an indictment of one country or an abdication of the important mission to discover biological threats in nature before they cause harm. Scientists are also committed to the pursuit of truth and knowledge. If we have the will, we can and will learn much more about where and how this pandemic arose.  

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Stanford Medicine begins enrolling for COVID-19 vaccine trial

Stanford plans to enroll about 1,000 people as part of a large Phase 3 trial to determine whether a vaccine can protect against infection with the coronavirus.

OCT 30 2020 | by KRISTA CONGER

Stanford Medicine has joined a large, Phase 3 clinical trial of an experimental vaccine against COVID-19.

The trial will test whether the vaccine, which is produced by the Janssen Pharmaceutical Companies of Johnson & Johnson, protects people from the disease. It will enroll some 60,000 people at about 180 sites around the world. The Stanford site is expected to enroll about 1,000 participants.  

Participants will receive either the vaccine or a placebo, and their health and immune responses will be monitored for about one year after their initial visits. If any participants become ill with symptoms of COVID-19, a health care provider will go to their homes to assess their health and collect a nasal sample to test for the presence of the novel coronavirus. If they are infected, Stanford physicians will monitor their disease progression. 

“We’re enrolling a wide variety of participants, but we are particularly interested in those who feel like their home or workplace exposure puts them at risk,” said Philip Grant, MD, assistant professor of medicine and the trial’s principal investigator at Stanford. “Teachers, grocery store workers, people who live in multigenerational households, health care workers and students on campus would all be good candidates for participation.”

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Participants will be followed for two years and one month. They are expected to visit the trial site eight times: six in the first year and two in the second year. The initial visit will last about two hours; subsequent visits will consist of a short blood draw and symptom screening. If a participant develops COVID-19 during the study period, additional visits may be required.

The Janssen vaccine uses the shell of a virus called an adenovirus, but the adenovirus genes have been replaced with genetic material that serves as a blueprint for the spike protein of the SARS-CoV2 coronavirus. After injection, the modified adenovirus delivers the blueprint for the spike protein into the cells of trial participants. The cells generate the protein, which alerts the immune system to prepare to fight off infection by the coronavirus. A similar technique has been used for vaccines against other diseases, including Ebola.

“This modified virus can’t replicate inside the body after injection, but it produces a strong immune response to the spike protein, similar to that seen in people who have recovered from an infection with SARS-CoV-2,” Grant said. “Our hope is that the immune response will provide durable protection against subsequent infection with COVID-19.”

Initial Phase 1 and 2 trials of the Janssen vaccine uncovered no major side effects or safety concerns when used in humans, and animal studies suggested that, unlike other vaccine candidates, one dose of the Janssen vaccine was sufficient to trigger a potentially protective immune response.

For information about enrolling, https://www.ensemblestudy.com/.

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Stanford researchers conduct clinical trials for REGN-COV2, experimental drug given to Trump

Stanford plans to enroll about 1,000 people as part of a large Phase 3 trial to determine whether a vaccine can protect against infection with the coronavirus.

OCT 6 2020 | by TAMMER BAGDASARIAN

A Stanford-led study earlier this year sought to assess the local prevalence of COVID-19. (Photo: KATE SELIG/The Stanford Daily)

Stanford researchers are conducting inpatient and outpatient clinical trials of Regeneron’s REGN-COV2, an experimental “antibody cocktail” administered to President Donald Trump. 

Stanford researchers noted that many of the newest drugs Trump has access to are still being tested in clinical trials and are unavailable to most COVID-19 patients. 

The University joins 84 sites across the country in conducting clinical trials of the REGN-COV2 drug. Early results from outpatient trials, in which the drug is administered to non-hospitalized COVID-19 patients, suggest that the drug may aid the recovery of patients with mild to moderate symptoms. 

“Those who received the antibodies did much better in terms of having the amount of virus that they have come down quickly and having their symptoms resolved faster,” said infectious disease clinical professor Aruna Subramanian.

For the past three weeks, the School of Medicine has been administering the treatment intravenously to outpatients who have received their first positive COVID-19 test result within seven days of starting treatment.

The medical school is also conducting inpatient trials, which study the effects of the drug on hospitalized patients, but the results have not yet been released. Subramanian, who is the principal investigator in the inpatient clinical trial, said that she expects similar results to those of the outpatient trial.

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REGN-COV2 is designed to boost patient immune systems by introducing two monoclonal, or cloned, antibodies — one copied from a recovered COVID-19 patient and another from a genetically modified mouse. The antibodies bind to spike proteins, which the virus uses to attach to host receptors, preventing the virus from interacting with human cells. The two antibodies target different parts of the virus, giving the immune system the ability to defend itself with a “one-two punch,” according to professor of pediatrics and health research and policy Yvonne Maldonado, who is codirecting the REGN-COV2 outpatient clinical trial.

Although the drug is still in the clinical trial stages of development and has not been authorized for emergency use, it is available through a “compassionate use” request, which is granted under rare circumstances on a case-by-case basis. The Food and Drug Administration (FDA) granted such a request to Regeneron which allowed Trump to have access to the drug. Trump was administered the maximum dosage of 8 grams, according to a statement released by the White House on Friday. In the clinical trials, patients are randomized to receive an infusion of 8 grams, 2.4 grams or a placebo.

“Eight grams is a lot of antibody to give somebody,” Maldonado said. “We generally don’t give that much protein infusion to people, and we still don’t know which one is more effective, and [Regeneron] is studying whether a lower dose would be as effective.”

REGN-COV2 is just one of several drugs that Trump took while in the hospital. In addition to the antibody cocktail, he received dexamethasone and remdesivir, an antiviral medication studied by Stanford researchers in April. 

Clinical professor of infectious disease Shanthi Kappogoda, who has helped develop COVID-19 treatment guideline, said that doctors generally administer the remdesivir and dexamethasone treatments to patients who need significant supplemental oxygen or who have an abnormal chest X-ray.

“Remdesivir and steroids are the standard of care for a moderate to severe case of COVID-19 pneumonia,” Kappogoda said. “It seems that either he was really sick and he needed them still in the hospital or he wasn’t that sick and was getting them at an earlier stage.”

Subramanian criticized a tweet that Trump sent advising Americans not to let the virus “dominate your lives,” adding that even if Trump makes a full recovery, he should not be advising the country to take the virus lightly.

“Not everybody has access to [his treatment options],” Subramanian said. “He got them extremely early, and he got them when other sick people are only maybe getting placebo. We have had patients die on the study, and we don’t know the efficacy yet.” 

Stanford researchers are seeking approval from the FDA to conduct another clinical trial of the REGN-COV2 drug, which they hope will begin within the next month. The trial would test the efficacy of the antibody drug on people who have been in “close household contact” with COVID-19 carriers, but who have not yet tested positive for the virus, according to Maldonado. The trial would test the short- and long-term efficacy of the drug’s potential to prevent infections in the first place.

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5 Questions: Flu vaccination in a time of COVID-19

It’s time to get a flu shot. In a Q&A, Shanthi Kappagoda, MD, clinical associate professor of infectious diseases, explains why it’s especially important to be vaccinated this year.

SEP 23 2020 | by MANDY ERICKSON

By getting a flu vaccination, "you are not just protecting yourself; you are also protecting other people you may come into contact with," Shanthi Kappagoda said.
DonyaHHI/Shutterstock.com

In this year of shuttered schools, empty restaurants, mask wearing and hand sanitizing, nearly all the inoculation talk has centered on the development of a coronavirus vaccine: When will it be ready so we can get back to normal? 

Thinking about the flu shot may seem trivial by comparison.

But Shanthi Kappagoda, MD, a clinical associate professor of medicine who cares for patients at Stanford Health Care's Infectious Disease Clinic, says that it’s critical to be vaccinated against the flu this year to stay as healthy as possible during the pandemic, protect people who are vulnerable, and keep hospitals from being inundated with both flu and COVID-19 patients. The flu season peaks from December through February in the United States, sickens between 9 million and 49 million people each year, and sends an average of 200,000 to the hospital annually, according to the Centers for Disease Control and Prevention.

Associate editor Mandy Erickson recently reached out to Kappagoda to get her thoughts on the convergence of flu season and the COVID-19 pandemic.

 1. Why is it important to get a flu shot when everyone’s social distancing?

Unfortunately, I don’t think everyone is social distancing. There is still a risk of getting the flu this year, especially with the holidays coming up. 

The flu is most dangerous for older adults and young children. By being vaccinated, you are not just protecting yourself; you are also protecting other people you may come into contact with, including people who are not able to get the vaccine.

In addition, every fall and winter, hospitals see an increase in patients because of the flu, and there’s concern they will become overwhelmed with COVID-19 and flu patients. 

2. Do we know the risks of having flu and COVID-19 at the same time? 

There have been only a handful of reports in medical literature about patients infected with SARS-CoV2, the virus that causes COVID-19, and an influenza virus at the same time. Several patients ended up in intensive care, but because the numbers are so small, and most reports are on hospitalized patients and not outpatients, I don’t think we know enough about this topic yet to draw any conclusions.

3. How do the flu and COVID-19 differ?

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As far as symptoms, loss of taste and sense of smell appears to be more common with COVID-19 than with influenza, but it’s important to know that not everyone with COVID-19 notices a change in their sense of taste or smell. 

Other important differences relate to transmission, which is why it has been so hard to control COVID-19. The period of time that you are infectious appears to be longer with COVID-19 than with influenza. With a flu, people typically become contagious about a day before they have symptoms and remain contagious for about seven days after symptoms start. With COVID-19, our best estimate is that you can become infectious about two days before symptoms start, and remain contagious for up to 10 days afterward, although new information is coming out on this topic frequently.

There also appears to be a greater number of asymptomatic COVID-19 cases than asymptomatic flu cases. And the death rate for COVID-19 appears to be higher than the death rate for flu. There also appears to be more super-spreading events with COVID-19 than with flu: It seems to be transmitted more easily through the air, although both viruses are primarily spread by droplets. Finally, the risk of complications and death in healthy infants and children appears to be higher for flu than for COVID-19.

4. Is COVID-19 changing anything about this year’s flu vaccine?

The flu vaccine was developed this year in the same way it’s developed every year. The four strains of influenza that are going into this year’s flu shot were decided on in March, and the vaccine was distributed starting this month. I think it is unlikely that vaccinating for flu would cause any shortages or changes to the rollout of a COVID-19 vaccine. 

Given concerns about an overburdened hospital system this fall and winter with admissions for both COVID-19 and influenza, an increased amount of flu vaccine is being made. The CDC reports that there will be 194 million to 198 million doses of flu vaccine available for this season, which is a record number. Unfortunately, only about 40% to 50% of adults in the United States get the vaccine, with rates commonly lower among low-income people and people of color — those most impacted by COVID-19.

5. Why do we need to get a flu shot every year? 

The antibodies your immune system makes in response to the vaccine last only about six months. But also, influenza is a very tricky virus. Individual strains circulating in the community switch from year to year, so the vaccine from last year may not contain the strains that are circulating this year. In addition, individual strains of the virus constantly mutate, enabling them to evade our immune system and cause disease.

Stanford Health Care patients can contact their primary care physicians for information about scheduling a flu vaccination, which will be offered at clinics and drive-up locations. Stanford Health Care also addresses frequently asked questions about the vaccination.

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Rosenkranz Prize Winner Leads Effort to Protect Health-Care Workers from COVID-19 in Under-Resourced Countries

Stanford postdoc Ashley Styczynski and collaborators build a website devoted to protecting health-care workers in under-resourced countries, using infographics and videos to show them how to create, wear and preserve personal protective equipment.

AUG 22 2020 | by BETH DUFF-BROWN

Ashley Styczynski shows her Bengali tutor, Marioum Akhi, how to properly use a mask during the COVID-19 pandemic.

Stanford postdoc Ashley Styczynski was working on newborn antimicrobial resistance in Bangladesh when the pandemic hit. The infectious disease physician realized she had to switch gears and began working with the ministry of health to prepare hospitals for the onslaught of COVID-19 patients.

“During my trainings on infection control in Bangladeshi hospitals, I learned that many health-care workers were paralyzed by the fear of not knowing how to protect themselves against COVID-19 while caring for patients, especially during shortages of PPE,” she said. “I think this has substantially contributed to the large number of health-care workers becoming infected during the pandemic. In fact, Bangladesh has the highest rate of physician mortality from COVID of any country.”

So Styczynski turned to her Stanford colleagues back home and proposed a set of infographics that could help health-care workers in Bangladesh and other under-resourced countries. Armed with a seed grant from the Stanford Center for Innovation in Global Health, they have established a website devoted to the creation and use of personal protective equipment (PPE). Bangladesh Ministry of Health has adopted their guidelines and Styczynski hopes other health ministries will do the same.

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“I want them to be a tool to empower health-care workers — not just in Bangladesh but also in other low- and middle-income countries — to protect themselves with whatever resources they have access to,” Styczynski said. She said the team of collaborators from Stanford grew when researchers from other institutions heard about the research and wanted to get involved.

The website also includes a video on PPE donning-and-doffing techniques, illustrations for building ultraviolet germicidal irradiation (UVGI) cabinets to decontaminate masks, and the PPE infographics in other languages.

Stephen P. Luby, MD, a core faculty member at Stanford Health Policy and senior fellow at the Freeman Spogli Institute for International Studies and the Woods Institute for the Environment, said the project grew out of Styczynski’s background in infectious disease epidemiology and her deep engagement with collaborators in Bangladesh.

“These scientifically sound, easy-to-understand visuals provide a clear example of how deep engagement in a high-need context allows Stanford researchers to make contributions that impact lives globally,” Luby said.

Styczynski is this year’s Rosenkranz Prize winner for her ongoing research into why Bangladesh is among the top 10 countries with the highest number of stillbirths. She believes intrauterine infections may be an underrecognized factor contributing to the stillbirths and is performing metagenomic sequencing on placental tissues of stillborn babies to examine the genetic and bacterial diversity.

She recently returned to the States to marry her now-husband, Adam Gsellman, a graphic designer who did all the infographics pro bono for the project. Styczynski met him in Bangladesh, where he was working at an IT startup focused on developing travel management software.

“After having lived in Bangladesh for nearly 6 years, he is intimately connected to the country and cares deeply about the people there as well,” she said.

Other Stanford faculty involved in the project include bioengineer Manu Prakash, one of the inventors of the cheap paper microscope, the Foldscope, now used around the world, and Thomas Baer, director of the Stanford Photonics Research Center.

During the initial planning stages, Styczynski connected with Thomas Weiser, MD, MPH, a general and trauma surgeon at Stanford Medicine and the consulting medical officer for Lifebox, a nonprofit working to improve surgical safety in resource-limited settings.

"Lifebox's work is focused on infection prevention in surgery, including decontamination of surgical instruments and appropriate PPE use for surgery,” Weiser said. "We had experience doing this in the operating room, so with Ashley's help we expanded the work to include other health-care workers at risk of infection."

He added that COVID-19 presented them with additional challenges.

"But we felt it was important to prepare the surgical ecosystem to help respond to the new demands for PPE and decontamination processes that would need to be put in place," he said.

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Stanford Team Uses Data to Help California Track & Prevent COVID-19

A team of Stanford researchers is working with the State of California on a new COVID-19 assessment tool to help hospitals and public health officials in their pandemic preparedness planning.

JUL 13 2020 | by BETH DUFF-BROWN

As the COVID-19 pandemic begins to spike again in California, a team of Stanford modeling experts is working around the clock to pump data into a new assessment tool that is helping California hospitals and public health officials determine their next moves.

The California COVID Assessment Tool, or CalCAT, contains assessments of the spread of COVID-19 in short-term forecasts of disease trends, and presents scenarios of the course of the disease across the 21 counties that represent 95% of the cumulative cases in the Golden State.

Instead of relying on one or two projection models — as some countries and U.S. states did when the pandemic first hit their shores — the CalCAT tool incorporates COVID-19 estimates from a number of respected organizations, including Stanford, UCLA, MIT, Johns Hopkins University and the Imperial College of London. The RAND Corporation focuses on long-term scenarios if shelter-in-place orders are lifted and non-essential business and schools reopen.

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“It’s like using the wisdom of the crowd,” said Jeremy Goldhaber-Fiebert, an associate professor of medicine at Stanford Health Policy and one of the principal investigators of the Stanford-CIDE Coronavirus Simulation Model, or SC-COSMO. “Instead of hanging your hat on one model, you’re looking at a range of predictions to help you do planning and forecasting — and leverage the whole community of researchers and analysts who are working on this problem.”

The SC-COSMO project has pulled in Stanford faculty, researchers, graduate and medical students to work on the disease estimates. They are also working with the California prison system and public health officials in India and Mexico to help prevent the spread of COVID-19.

The SC-COSMO model also incorporates non-pharmaceutical interventions, such as recommendations on social distancing, and the timing and effects on reductions in contacts which may differ by demography.

When Governor Gavin Newsom unveiled CalCAT at a news conference in late June, he instructed all state agencies and departments to make COVID-19 data publicly accessible, provided it does not include information that would violate privacy.

“California is home to some of the world’s most accomplished researchers, technologists, scientists, acclaimed universities, and leading technology companies,” Newsom. “While these models and forecasts make different assumptions, all of them show that individual actions can dramatically change the trajectory of the virus.”

The CalCAT tool includes:

• “Nowcasts,” the rate at which COVID-19 is estimated to be spreading;
• Short-term forecasts, which show what various models predict will happen over the next few weeks in California;
• And scenarios showing what could happen over the next few months under various conditions.

Some 20 Stanford faculty and graduate, law and medical students are involved in the project.

“I love modeling infectious diseases because I get to focus on impactful research and work with great, interdisciplinary teams of researchers like the SC-COSMO team,” said Anneke Claypool, a PhD student in management science and engineering. “COVID-19 has affected everyone’s daily life — and I’m glad to be helping the state of California fight this deadly virus.”

The project provides the state with county-level COVID-19 estimates, including the number of infections and detected cases and projections of future needs for hospitals. They are also developing intuitive tools for those who are not themselves modeling experts.

Tess Ryckman, a PhD student at Stanford Health Policy focused on decision science, said working on the team has taught her new skills and burnished her expertise. "I’ve been on an accelerated learning trajectory these past few months and have picked up a lot of coding and modeling skills that will be valuable for me not only in my current research but in future career,” she said. “I also feel that I’m putting a lot of what I’ve learned during my PhD training to good use by applying it to such a pressing and important issue.”

How to Read CalCAT — Ingredients of a Model

For those who aren’t modeling experts, reading the CalCAT tool can be challenging.

Goldhaber-Fiebert explains that the main measurement of the tool is the effective reproduction number — known as the R-effective — which is the average number of people onto which each infected person is likely to pass the virus. It also represents the rate at which COVID-19 is spreading.

He explains that if the R-effective is above 1, that means the infection is growing and would be one signal for concern. That might help the state focus on the counties that are of particular concern and hospitals prepare their ICUs and build up their PPE supply.

As of Tuesday, July 13, for example, the R-effective number was 1.09 for Los Angeles County, as compared to 1.05 in San Francisco County. The overall R-effective for California was 1.12.

The team gets its data from a bundle of data sources.

“The first is paying attention to the clinical and epidemiological literature that’s being published and pre-published, and that’s where Jason comes in.” Jason Andrews, another principal investigator for the SC-COSMO modeling project, is an infectious disease physician and associate professor of medicine at Stanford Medicine.

They also get secure data feeds from the state. Then the team data analysts, SHP’s Kim Babiarz and Lea Prince, do a granular analysis case, testing, hospitalization, and death series to create targets for model calibration and refine model inputs.

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Stanford Medicine trial to test favipiravir for treating COVID-19 outpatients

Researchers want to determine whether favipiravir, an oral drug, is effective in reducing the severity of symptoms and shortening the duration of COVID-19.

JUN 30 2020 | by TRACIE WHITE

Stanford Medicine researchers are launching a clinical trial to test whether an oral drug can reduce symptoms and viral shedding in people with COVID-19.

The researchers aim to enroll 120 participants, beginning July 6, who have been recently diagnosed with the disease but not been hospitalized.

Favipiravir, an antiviral medication, was first approved to treat influenza in Japan. Researchers are hoping it will be effective in reducing the severity of symptoms and in shortening the duration of COVID-19, which could help limit spread of the coronavirus, said Aruna Subramanian, MD, clinical professor of medicine.

“We hope that this drug can help to reduce transmission within families, groups and schools,” said Subramanian, one of the investigators for the study. “Plus, it would be really nice to have pills that can be given early on to make people get better faster.”

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Yvonne Maldonado, MD, professor of pediatrics and of health research and policy, is the principal investigator for the double-blind, placebo-controlled trial.

The drug has not been approved by the Food and Drug Administration. There are other trials investigating the drug, but this is the first time it will be tested in outpatients in the U.S., Subramanian said. It has been approved to treat COVID-19 in Russia, China and India. 

 “Many really important studies are going on right now to help us understand how to emerge from this pandemic,” said Marisa Holubar, MD, clinical associate professor of infectious disease and an investigator for the study. “These early-phase studies are important to inform larger clinical trials. We need to understand if favipiravir shortens the duration of viral shedding. It could be a key to protecting both ourselves and the broader community.”

Yvonne Maldonado is the principal investigator of the double-blind, placebo-controlled trial.
Steve Fisch

Viral shedding is the release of a virus into the environment from an infected person.

Stanford participated in earlier clinical trials that found that another antiviral, remdesivir, was effective in treating coronavirus patients. That drug has since been approved for use in the U.S. but is not available orally and, so far, can be administered only intravenously and only to those in a hospital.

 “Favipiravir could be very important for symptom relief, especially for patients with mild cases who can have symptoms for a long time,” Subramanian said. “We’ve seen a number of symptoms continue, such as coughs, shortness of breath, fatigue.” 

At a molecular level, the drug works by blocking a viral enzyme that makes viral RNA, halting the virus’s ability to replicate itself, Holubar said. Like other antivirals, it’s presumed to work better the earlier it’s prescribed.

Researchers are enrolling those who have been diagnosed with COVID-19 within the past 72 hours. Each participant will receive either a 10-day course of favipiravir or a placebo, and they will be evaluated for health outcomes over 28 days. 

People can enroll by emailing treatcovid@stanford.edu.

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Stanford Medicine tests remdesivir for COVID-19

With no approved treatments for COVID-19, Stanford Medicine has joined large-scale clinical trials to determine if remdesivir, an experimental anti-viral medication, works.

APR 17 2020 | by TRACIE WHITE

Philip Grant and Aruna Subramanian are conducting a clinical trial of remdesivir at Stanford as part of a multicenter study of the drug sponsored Gilead Sciences.

In early March, when patients with the coronavirus started arriving at Stanford Hospital, a team of infectious disease researchers at the university put their heads together and made a quick decision. Among the potential treatments for COVID-19, the disease caused by the virus, their first choice to investigate was the experimental anti-viral drug remdesivir. They jumped right in.

Within a week, Stanford Medicine had joined a number of other medical centers around the world in global trials sponsored by Gilead Sciences Inc., the maker of the drug, which is not yet approved as a treatment for COVID-19. By the end of March, the infectious disease doctors had enrolled 30 participants in two trials — one for severe and the other for moderately ill patients — who were receiving the drug intravenously.  In addition, another group of Stanford scientists began enrolling participants in a similar, large-scale clinical trial of remdesivir, this one sponsored by the National Institutes of Health. 

“We brought this on fast,” said Aruna Subramanian, MD, clinical professor of infectious disease and principal investigator of the Gilead trials at Stanford. “We got everything together in a week and were ready to roll. This was record time. This type of thing normally takes two to three months to get on board.” 

 More Worldwide push

During normal times, a phase 3 clinical trial — the final step in the process of drug approval — typically takes months of planning, after years of research, before it’s underway. But these aren’t normal times. With a fast-moving pandemic bearing down and no approved treatments available, researchers are, like everyone else, desperate for answers, and they have ramped up their efforts to find solutions. Remdesivir jumped to the top of the list of potential treatments in part because it was farthest along in the approval process, Subramanian said. By the end of February, as the virus spread in the United States, there were at least five clinical trials of remdesivir underway. China initiated the first two studies in February, followed later that month by the Gilead trials for severe and moderate patients and the NIH trial. By the end of March, Gilead had expanded to 100 testing sites both in the United States and abroad, and the NIH trial had expanded to 60 sites, 50 of those in the United States. 

Gilead recently reported that it is expecting to have preliminary data from the study of severe patients by the end of April. The two studies in China, though, were halted due to lack of patients. “We urgently need a safe and effective treatment for COVID-19,” said Anthony Fauci, MD, the director of the National Institute of Allergy and Infectious Diseases, in a press release announcing the start of the NIH’s remdesivir trial. “A randomized, placebo-controlled trial is the gold standard for determining if an experimental treatment can benefit patients.” That same month, while speaking about the coronavirus, Bruce Aylward of the World Health Organization announced, “There’s only one drug right now that we think may have real efficacy, and that’s remdesivir.”

How does remdesivir work?

There are multiple reasons for remdesivir’s current reputation as a potential treatment for COVID-19, among them the anecdotal stories that have appeared in the media. While the drug is not commercially available, it is being used to treat patients with COVID-19 through a compassionate care program on a case-by-case basis, with approval from the Food and Drug Administration. In late January, reports out of Washington State that the first person in the nation diagnosed with COVID-19 had been treated with remdesivir, and recovered, made headlines. But scientists are quick to warn against basing treatment guidelines on anecdotal evidence and reports in the news media.

“We have had patients hospitalized at Stanford who got remdesivir under compassionate care guidelines,” said Stanley Deresinski, MD, associate chief of the division of infectious diseases at Stanford. “Some got better. Some got worse. At this point, we just don’t know. We hope to have results soon for remdesivir, and by then we should have another trial in the works for the next best thing.”

An illustration of SARS-CoV-2, the novel coronavirus.
Alissa Eckert and Dan Higgins/Centers for Disease Control and Prevention

At Stanford, the team of infectious disease scientists running the Gilead trials say that, like other scientists, they picked remdesivir as their first choice based on promising results from years of lab and animal research. Often referred to as the Ebola drug, remdesivir was also previously tested in a clinical trial for treating that disease. It failed to show that it was effective for Ebola in comparison with two other drugs, but based on the study, it’s generally known to be safe in humans, said Philip Grant, MD, assistant professor of infectious diseases at the School of Medicine and co-principal investigator of the Gilead trial.

For years, remdesivir has shown potential in cell cultures and animals infected by other coronaviruses, such as SARS and MERS, said Robert Shafer, MD, professor of medicine at the School of Medicine, whose lab recently created a coronavirus anti-viral research database. “Remdesivir looks very good in the lab. In cell cultures, it’s also been more active in fighting the coronavirus than other drugs. That’s why I think it’s promising. I’m looking forward to seeing what the clinical trials show.”

The science

A coronavirus infection occurs when the germ enters the body’s airways through the nose, mouth or eyes, then lodges in the cells in the lining of the lung’s airways, where it quickly starts to make millions of copies of itself, wreaking havoc on the lungs, Subramanian said. 

The virus makes copies of itself by inserting its own genes into the human cell’s genetic machinery, basically hijacking the replication process of the human cell. Remdesivir, like other anti-virals, is designed to target the system the virus uses to replicate, acting as a cap that prevents the virus from making new copies of itself or infecting other cells. Whether this works in people to reduce symptoms of COVID-19 or shorten the length of the disease is not known yet.

“We need the data, the scientific rigor of doing randomized clinical trials,” said Robert Harrington, MD, the Arthur L. Bloomfield Professor in Medicine and chair of the department of medicine at Stanford. “That’s how clinical science and patient care advances. We can’t depend on anecdotal stories in order to practice the best clinical medicine. We have to wait for the science.”

Other potential treatments

But scientists around the world aren’t standing still, waiting for the results of remdesivir trials. All kinds of studies are moving ahead at breakneck speed to find the next best treatment or vaccine for the disease. 

“A variety of drugs have been suggested,” Deresinski said. “Hydroxychloroquine has been known for 50 years to have nonspecific anti-viral properties. But for now, remdesivir is our preferred agent.”

The anti-malarial drugs chloroquine and hydroxychloroquine also have made headlines as potential treatments for COVID-19. The drugs are currently used off-label in certain cases to treat the disease. But with only a few anecdotal studies showing benefits, they have not received approval from the FDA for COVID-19. Reports have warned of dangerous side effects that need to be studied before widespread use. Recently, a small study of chloroquine in Brazil was halted for safety reasons due to high doses causing irregular heart rhythms. “Chloroquine is being used a little bit too widely without proper study,” Subramanian said, adding that there’s also a growing concern that stockpiling and hoarding of the drugs are limiting supplies for people with lupus and rheumatoid arthritis who are prescribed the medication. “We prefer to be data-driven as much as possible.”

The next step for FDA approval of these anti-malarial drugs to treat — or prevent — COVID-19 depends on data-driven evidence from similar large-scale clinical trials, some of which are currently in the planning process. Whether chloroquine is Stanford’s next best guess for potential treatment, though, is still up for debate.

“Ours is an adaptive trial, which means that if remdesivir doesn’t work, we can quickly move on to testing the next, most promising drug without any gap in time,” said Neera Ahuja, MD, principal investigator of the NIH-sponsored remdesivir trial at Stanford and chief of the division of hospital medicine. She is working with Kari Nadeau, MD, PhD, professor of medicine and of pediatrics, and others on  the trial, which includes participants recruited at Stanford Health Care – ValleyCare.

“We’re hopeful about remdesivir, but we are already planning for what the next drug might be,” Ahuja said. “We want patients to get any possible treatments that might benefit them as soon as possible.”

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