Developing Antivirals for COVID-19 and Beyond

Jeffrey Glenn, MD, PhD (Photo by Steve Fisch)

Almost every day, news outlets report on highly infectious COVID-19 variants threatening to sneak past the front-line antibody defenses developed by our bodies after vaccination or previous infection. That’s because the coronavirus strain responsible for COVID-19, SARS-CoV-2, is doing what most viruses do: evolving and naturally selecting toward becoming more resistant to vaccines and antiviral drugs.

This isn’t surprising to Stanford researcher Jeffrey Glenn, MD, PhD, professor of medicine and of microbiology and immunology, who has spent years developing novel antiviral therapies for hepatitis, influenza, and enteroviruses. Fortunately, he and his international collaborators quickly pivoted and applied their expertise to COVID-19 too.

“When all of Stanford was shut down, we were considered essential. In fact, we’d never been busier. We worked 24/7 in shifts, wearing masks and social distancing,” describes Glenn, the Joseph D. Grant Professor. “This is what we’ve trained our whole lives to do — help develop drugs that could counter this and future pandemics. It’s an honor and privilege to do this work.”

Glenn’s research focuses on two approaches for creating antivirals for various diseases. The first strategy targets factors in the host that the virus depends on. The second one targets the structure of the virus itself.

Targeting Factors in the Host to Treat Hepatitis

Although viruses mutate quickly, they rely on their hosts’ cells to reproduce. So, researchers are developing host-targeting drugs. These are novel antivirals that interfere with host factors essential for the life cycle of the virus or that boost the host’s innate immunity. For example, some antivirals target specific proteins in the host to prevent the virus from replicating its genome inside the host’s cells.

Host-targeting drugs have several advantages. They act on something in the host that isn’t under the genetic control of the virus, Glenn explains, so it’s much harder for the virus to mutate, escape the drug, and still be viable.

“Another advantage is in the biology,” he says. “If one virus has evolved to depend on a particular host factor, many other viruses may have too. So, you can create a broad-spectrum antiviral therapy: one drug for multiple bugs.”

Glenn’s team pursued this strategy for hepatitis delta, the most severe form of viral hepatitis.

First they discovered a specific process occurring inside a host’s liver cells that the virus depends on. Then they performed animal studies and human clinical trials to test the safety and effectiveness of treating hepatitis delta with lonafarnib, a drug originally designed to treat various cancers. They demonstrated that lonafarnib inhibits the identified host-cell process and prevents the virus from replicating.

“Our phase 2 trial showed no evidence of drug resistance — one of the first examples in humans to validate this advantage of a host-targeting drug,” Glenn says. “A company that I founded, Eiger Biopharmaceuticals, is completing by year’s end a phase 3 trial. Hopefully, lonafarnib will become the first oral drug approved by the U.S. Food and Drug Administration (FDA) for hepatitis delta based on that data.”

Glenn takes this success to heart, as evidenced by a photograph on his cell phone of three Turkish young men standing together in Ankara, where the study was conducted. “They are the first three patients in history to have their hepatitis delta virus become undetectable from lonafarnib,” he says. “There is nothing cooler for a physician-scientist than seeing something you’ve made actually make a difference in patients’ lives.”

Lonafarnib also demonstrates the potential advantage of using host-targeting drugs for nonviral applications. The FDA has approved the drug to treat Hutchinson-Gilford progeria syndrome, a rare genetic condition that causes children to prematurely age and die, and lonafarnib was shown to prolong their lives.

Pivoting to Treat COVID-19

Glenn and his collaborators have developed other host-targeting drugs — including peginterferon lambda, which was originally designed to treat hepatitis delta by boosting a host’s immune system.

When the pandemic hit, they realized peginterferon lambda may be the perfect drug to treat COVID-19, because it is a broad-spectrum antiviral that targets the body’s first line of defense against viruses. Importantly, it had already been safely given to more than 3,000 patients in 20 different clinical trials, mostly treating chronic hepatitis, for which it is administered weekly for up to a year, he says.

Since Eiger Biopharmaceuticals wasn’t funded for COVID-19 studies, it made peginterferon lambda available at no cost to outside researchers. Glenn’s colleagues responded with tremendous interest within minutes of getting his email offer. Stanford was the first site to finish a phase 2, randomized, placebo-controlled clinical trial, but other studies soon followed, including one in Toronto.

These phase 2 trials treated COVID-19 outpatients. Collectively, they showed a single dose of peginterferon lambda was well tolerated and significantly reduced the amount of SARS-CoV-2 virus in the nasal passages — particularly for patients who initially had a high level of detectable virus, Glenn explains.

Next, his colleagues in Brazil performed a large, randomized, placebo-controlled outcomes study to evaluate the effectiveness of peginterferon lambda. This TOGETHER Trial uses an adaptive trial design that analyzes data as it emerges rather than waiting until the end of the study, saving valuable time and money. The study ran from June 2021 to February 2022.

Even though the majority of more than 1,900 patients enrolled were vaccinated, a single dose of peginterferon lambda reduced the number of COVID-related hospitalizations by 51% and deaths by 61%, as reported in a Grand Rounds presentation. For unvaccinated patients treated early, there was an 89% reduction in COVID-19 hospitalizations or death. And it worked across all variants, including omicron.

“This has been a frustrating journey in the sense that I know this drug could have saved millions of lives if we had it ready at the beginning of the pandemic,” says Glenn. “But it can still save many lives. The phase 3 study is done, and hopefully that’ll be the basis of an emergency use authorization before the end of this year.”

Once approved, peginterferon lambda could be used on its own or in combination with Pfizer’s Paxlovid, an antiviral with a different underlying mechanism. Giving both antivirals together could help prevent drug resistance to Paxlovid from developing, says Glenn.

Glenn is also looking beyond COVID-19 treatment uses for the drug, believing it should work against influenza and other viruses too. In the future, he envisions a patient with a respiratory virus getting a shot of peginterferon lambda at a clinic, going home, and having the doctors sort out later which virus caused the infection.

Targeting RNA Structures in the Virus

In addition to developing host-targeting drugs, Glenn’s team is developing programmable antivirals that target a virus’s genome structure. After identifying essential RNA secondary structures for a virus, they design or “program” a drug to act against these structures. The aim is to use the virus’s own biology against itself, limiting its ability to mutate to escape the effect of the drug.

Glenn and his collaborators have developed such antivirals for influenza A and COVID-19 and have shown drug efficacy in animal models, but not in people yet.

In the influenza study, a single intranasal injection of the antiviral allowed mice to survive a lethal dose of influenza A virus — when the drug was given 14 days before or even three days after viral inoculation. Additionally, the antiviral provided immunity against a tenfold lethal dose of influenza A given two months later.

“We call this a single-dose preventive, therapeutic, and just-in-time universal vaccination that works against all influenza A virus strains, including drug-resistant ones,” says Glenn. “The primary goal is to prevent a severe influenza pandemic, but the same drug could be used for regular seasonal flu.”

Preparing for Future Pandemics

Glenn hopes the current pandemic is a wake-up call to better prepare against future pandemics.

“COVID-19 is tragic, but it isn’t what keeps me up at night,” admits Glenn. “We are extremely vulnerable to a highly pathogenic, drug-resistant influenza virus. That fear is really what motivates us.”

Fear of an influenza and other serious pandemics also inspired Glenn to start ViRx@Stanford, a Stanford Biosecurity and Pandemic Preparedness Initiative. Its goal is to proactively build up our collective antiviral tool kit to protect against future pandemics.

ViRx@Stanford’s subsection SyneRx was recently selected as one of nine Antiviral Drug Discovery Centers by the National Institutes of Health. Stanford’s center will involve more than 60 faculty and consultants working on seven research projects and three scientific cores. And ViRx@Stanford is now expanding, establishing hubs in Vietnam, Israel, Brazil, Singapore, and beyond.

“Innovative drug development is expensive. This is the kind of support that can actually help us do what we’ve never been able to do here before,” says Glenn. “The goal of all of this is to develop real-world drugs that can make a big difference for patients across the world. And I think we’re on track to do that.”

This is a reposting of my feature article in the recent Stanford Medicine annual report, courtesy of Stanford Medicine.

Team Science: Battling Kidney and Heart Diseases

Team members Tara Chang, MD, Glenn Chertow, MD, and Marco Perez, MD (Photo by Steve Fisch)

Physicians are often faced with critically ill patients who have more than one disease, which complicates treatment decisions. A cardiologist who wants to prescribe a diuretic to a patient with high blood pressure, for example, may need to worry about the medication causing kidney damage. So, she consults with the patient’s care team.

Designing and testing new therapies also requires a team, as evidenced by the large team science initiatives being conducted by the Stanford Center for Clinical Research (SCCR). For example, Stanford researchers are collaborating across different sectors (such as academia and industry), institutions, disciplines, and countries to find more effective treatments for kidney and cardiovascular diseases.

“Since early in my career, I saw that the lives of patients with kidney failure are very difficult and their life spans on dialysis are sadly very short. I’ve spent 30 years trying to improve their treatment and quality of life,” says Glenn Chertow, MD, the Norman S. Coplon/Satellite Healthcare Professor of Medicine in the division of nephrology.

Patients with end-stage kidney disease also have a high risk of cardiovascular disease, but they are typically excluded from studies due to the complexity of their health problems. That’s why Chertow is excited to help launch one of the few randomized clinical trials focused on patients receiving dialysis, he says.

The clinical trial will study the effects of clazakizumab—a monoclonal antibody that reduces inflammation—in patients with kidney failure. Scientists know that inflammation is a contributing cause of cardiovascular disease and that patients on dialysis have exceptionally high rates of both chronic and severe inflammation. So, they hypothesize that using clazakizumab could prolong and improve the quality of these patients’ lives.

After receiving final funding notification from the biopharmaceutical company CSL Behring, the team will begin with a phase 2B trial to figure out the appropriate dose of clazakizumab, followed by a larger phase 3 trial to measure the drug’s effect on patient outcomes.

Chertow and Myles Wolf, MD, chief of nephrology at Duke University School of Medicine, are co-principal investigators of the overall study. Kenneth Mahaffey, MD, professor of cardiovascular medicine and director of SCCR, will serve on the trial’s executive committee.

“Myself, Dr. Mahaffey, and others at SCCR have been involved in the design of the study from day one. It is a real partnership between academics and industry, between Stanford and Duke, and between nephrology and cardiology,” says Chertow. “It shows we actually work together — it’s not siloed to just one institution or one division.”

Collaborating Across Institutions

The infrastructure and expertise of SCCR is helping Stanford to design, fund, and conduct large collaborative studies involving many institutions — including industry and academic partners.

One example is a multi-institutional project that SCCR is facilitating with $37 million in funding from the National Institutes of Health. Rhythm Evaluation for Anticoagulation with Continuous Monitoring-Atrial Fibrillation (REACT-AF) is a clinical trial that will build on Stanford’s Apple Heart Study, which showed that a heart rate pulse sensor on the Apple Watch can identify a common irregular heart rhythm called atrial fibrillation (A-fib).

The REACT-AF clinical trial will study stroke prevention using blood thinners in patients with A-fib. A-fib patients take anticoagulating medications to reduce the risk of having a stroke, but the medications increase the risk of major bleeding events. So, the researchers hope to balance these competing risks with personalized treatment. Half of the study participants will get blood thinners only during the short periods when the Apple Watch indicates they have A-fib. The other half will get blood thinners all the time, following the current standard of care in medical practice.

The REACT-AF project represents an academic partnership among Stanford, Johns Hopkins, and Northwestern universities. Rod Passman, MD, professor of cardiology and preventive medicine at Northwestern University’s Feinberg School of Medicine, will oversee the overall initiative, while Mahaffey and Marco Perez, MD, associate professor of cardiovascular medicine, will co-lead Stanford’s efforts.

Collaborating Across Specialties

SCCR’s new initiatives include novel research performed at multiple institutions, but they also represent collaborations across many specialties.

For example, the REACT-AF project will involve cardiologists with different subspecialties, neurologists who specialize in stroke, internal medicine physicians who manage A-fib patients, quantitative scientists who help analyze the data, and research staff.

“If that isn’t team science, I’m not sure what is,” says Mahaffey.

According to Mahaffey, the synergy developed among this diverse team improves the quality of the studies.

“The faculty bring a lot of clinical and scientific expertise, and the operational research staff understand the regulations, policies, and procedures,” he says. “Together, they create synergies to enhance the design, conduct, and quality of clinical trials.”

Collaborating Across Experience Levels

Although led by senior faculty, these large studies will also provide junior faculty, operational staff, and fellows with critical research training.

“Stanford is a learning environment. Dr. Mahaffey and I feel very strongly that we have a responsibility to train the next generation of scientists,” says Chertow. “For example, Dr. Tara Chang, associate professor and chief of nephrology, is a shining example of a physician who completed training at Stanford and is now a national leader at the crossroads of kidney and cardiovascular disease.”

In addition to providing funding and research opportunities, these projects allow Stanford patients to enroll in the studies — a fundamental incentive for the researchers who want to give their patients more options.

“Patients are dying or suffering miserably from complications of diseases,” Mahaffey says. “Finding safe and effective therapies to treat these patients is a motivating force for me every day.”

This is a reposting of my feature article in the recent Stanford Medicine Annual Report, courtesy of Stanford Medicine.

Proton Therapy Use Increases and Reveals Cancer Health Disparity

The number of cancer patients receiving proton beam therapy (PBT) – a newer, more targeted form of radiation therapy – is increasing, but Black patients are less likely to get this treatment than white patients, according to two recent studies published in JAMA Network Open.


Mental Health Services Under Strain in Rural America

Maria Vega, a member of Montana’s Fort Peck Assiniboine and Sioux Tribes, was jailed in 2015 after a suicide attempt. She is now part of a group of tribal members, academics, and policy experts proposing alternatives to the tribal policy of treating suicide as a crime. Photo by Sara Reardon / Kaiser Health News

The gap between suicide rates in rural and urban areas has grown, in part due to limited access to mental health services and privacy concerns in rural settings. Read more in my article in the American Journal of Nursing.

Staying active is important — especially for older adults

Photo by Arek Adeoye

Did you make a New Year’s resolution to exercise more? And perhaps the more important question: Will you stick to your goal?

These questions are especially important for older adults, who are at a higher risk for chronic diseases such as dementia, cardiovascular disease, depression and anxiety. Physical activity can help reduce the risk for many of these conditions.

“We need to start thinking about these diseases [as diseases] of neglect, not necessarily of aging, that occur because people have not been able to maintain a lifelong pattern of healthy behavior,” said Randall Stafford, MD, PhD, a professor of medicine, in an article originally reported by Stanford’s BeWell.

Evolving intensity

Stafford explained that the exercises appropriate for any one person will likely evolve over his or her lifetime, but increasing physical activity at any age can quickly improve health.  

Take my 92-year old relative Al, for instance. He started training and running marathons when he turned 40. In his 80s, he stopped running based on his doctor’s advice but kept hiking. These days, he walks a mile or rides his exercise bike for 30 minutes at a slow pace with breaks, along with strength and training exercises. His goal: Live an active, independent life.

But even if you’re not like Al (yet), it’s not too late; exercise doesn’t have to be something as intense as running a marathon.

“Even incorporating a few minutes of walking into one’s daily routine can be quite beneficial,” said Stafford. “Physical activity has benefits that are immediate as well as sustained.” And people often become better or more comfortable doing physical activities with practice, he said.  

Expanding your mindset

Stafford’s other good news? You don’t have to do vigorous, gym-based exercises; joyful movements like gardening or dancing count. You’ll also get an extra social benefit if you share these physical activities with friends or family members, plus you are more likely to stick with the healthy behavior if you do it with others.

Stafford, however, stressed the importance of including strength training, core exercises and stretching — especially for people over 40 — to reduce muscle loss, maintain balance and stay flexible.

Finally, Stafford advised not to beat yourself up if you slide back into sedentary habits. Setbacks happen. Just try to get back into a routine as soon as you’re able.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

A new take on virtual education can promote breastfeeding

 Mentor mothers using MOVIE videos during a training session (Photo by Maya Adam). 

Feeding infants formula with invisible pathogens can cause life-threatening diarrhea, and introducing solid foods too early can result in nutrient deficiencies. For reasons like these, the World Health Organization and UNICEF recommend feeding infants only breast milk for the first six months, when possible.

But this guideline is rarely followed in developing countries with limited access to health care and education. In South Africa, for instance, less than a third of new mothers exclusively breastfeed for that long.

Now, Stanford Medicine researchers are trying to improve breastfeeding outcomes in South Africa by developing and testing an educational video series. These videos discuss topics such as the health benefits of breastfeeding and what to do if breastfeeding isn’t possible. After running a 19-month study, they found that video-based counseling using computer tablets can promote breastfeeding in under-resourced settings as effectively as in-person counseling.

The study was led by Maya Adam, MD, a clinical assistant professor of pediatrics and the director of Health Media Innovation at Stanford. Adam and the research team partnered with health care workers from Philani Maternal Child Health and Nutrition Trust who shared the video series — called the Philani MObile Video Intervention for Exclusive breastfeeding (MOVIE) — with new and expecting mothers in their South African communities.

“Thankfully, more and more mothers even in the hardest-to-reach communities are gaining access to mobile technology,” said Adam. This access opens up the opportunity to promote breastfeeding in these communities by designing entertaining, educational content and delivering it on mobile devices, she said.

Details of the study were published September 28 in PLOS Medicine.

Entertainment education

To create the videos, Adam collaborated with Stanford’s Digital Medic team in South Africa to harness the power of “entertainment-education.” The idea is to draw learners in with dramatic narratives, compelling visuals and soundtracks, Adam said.

The 13 videos are short: four minutes or less. A local South African artist illustrated the health and motivational messages and other local women narrated them. For example, one animated video depicts the story of a mother explaining to her daughter why she breastfed against her own mother’s advice. These illustrations were interspersed with personal narratives from three South African celebrities and four community mothers.

“Some videos were more geared towards the early newborn phase, like the common challenges video. And some were geared towards later phases, like the one aimed at supporting moms who need to return to work,” said Adam.

To test the video series’ ability to provide effective education and encourage breastfeeding, Adam’s team ran a controlled trial involving 84 community health workers, or “mentor mothers,” from the Philani Maternal Child Health and Nutrition Trust. Each mentor recruited and counseled a group of mothers in her community, with 1502 mothers participating in the study.

The mentors were randomly assigned to either the control or intervention group. One half, the traditional mentors, used only face-to-face breastfeeding counseling, while the intervention mentors spent part of their home visits showing Stanford’s videos on tablets that the study provided. The videos were viewed a total of 6,435 times during the visits.

As good as face-to-face

Throughout the study, all mentor mothers counseled their clients on infant feeding during regular home visits starting in the last trimester of pregnancy and lasting until the baby was 5 months old. The intervention mentors chose specific videos to meet the client’s needs.

Each time a baby turned 1 month old or 5 months old, the mentors surveyed the mother’s feeding practices and maternal knowledge.

The researchers observed no significant differences between breastfeeding outcomes for both mentor groups. For example, overall, about 54% of all participants reported during the 5-month survey that they were breastfeeding exclusively. The similarity of these outcomes suggests that the videos were as effective as traditional counseling when used to replace part of the home visit.

However, the videos had the benefit of allowing intervention mentors to do other health-related tasks for the families, including monitoring other children’s growth, updating and keeping medical records and completing referral forms, Adams said.

Mentor mothers also reported that carrying a tablet increased their credibility within the community, said Adam.  “My hope is this research will help policymakers and funders see the great potential in equipping community health workers of all levels with mobile devices,” said Adam. “The mentors are heroes, fighting for their communities at the frontlines of health. They deserve to have the technological tools they need.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

New approach effectively relieves chronic low back pain

Anyone with an aching back knows just how debilitating that pain can be. Now, Stanford Medicine researchers may have good news for the 500 million people worldwide experiencing low back pain.  

Stanford pain psychologist Beth Darnall, PhD, has developed a single-session, two-hour class called Empowered Relief, which aims to rapidly equip patients with pain management skills. The first randomized, controlled clinical trial suggests this new method may be as effective at reducing chronic low back pain as weeks of traditional therapies, a paper in JAMA Network Open recently reported.    

Empowered Relief stems from a traditional therapy called cognitive behavioral therapy, which relies on the interconnection between thoughts, feelings, physical sensations and actions. Both treatments can help patients identify and change thoughts and behaviors that increase their pain, as well as learn coping skills to better control pain response and improve quality of life.

“The problem is CBT isn’t broadly accessible,” said Darnall. “There are only a small number of behavioral specialists, and yet millions of Americans live with ongoing pain. And many under-served communities in the U.S. don’t know how to find a trained therapist.”

Another major barrier, said Darnall, is time commitment — cognitive behavioral therapy patients attend a two-hour group session each week for two to three months.

To address this problem, Darnall combined what she believed were the most critical skills from cognitive behavioral therapy, such as identifying unhelpful and stressful thought patterns, with information about the science of pain, mindfulness principles, and the relaxation response. With the help of an instructor, patients then translate their new skills and knowledge into a personalized plan to manage their pain at home.

“The goal is to align our treatments with what’s feasible for patients and make it broadly accessible,” Darnall said. It’s possible, she said, to teach 85 people in a one-and-done Empowered Relief class. And if taught weekly, 680 patients could be treated in eight weeks, compared with 10-15 who could be treated during that time with cognitive behavioral therapy.

Pain treatment with lasting effects

Darnall conducted the clinical study with Sean Mackey, MD, PhD, professor of anesthesiology, perioperative and pain medicine at Stanford. In it, 263 adults with chronic low back pain — most of whom had this pain for more than five years and almost half of whom had additional chronic pain conditions — were randomly assigned to eight cognitive behavioral therapy sessions, one Empowered Relief session or one traditional health education session, which acted as a control. (In health education, participants learned basic information, such as the definition and warning signs of back pain, but not actionable skills or the neurobiology of pain.)

For three months after the treatment, the participants reported information about their pain, such as its intensity and whether it disturbed their sleep. According to patient reporting, Darnall’s course relieved pain as effectively as cognitive behavioral therapy and better than the health education session.

“I was pleasantly surprised that people’s back pain improved as well as their sleep, depression and anxiety symptoms,” said Mackey. “I can easily see this integrating with standard medical care to provide benefits for many patients.”

The results are promising, but the study will need to be replicated in a larger and more diverse population, said Darnall.

The success of the course doesn’t mean cognitive behavioral therapy will be eliminated, Darnall said. Instead, the researchers want to determine how to match individual patients with treatment options that work best for them. That, she said, could inform pain treatment protocols, resource allocations and other medical decision-making.

Now, Darnall’s team is expanding access to the Empowered Relief program to help address existing disparities in pain care. The class is already available in five languages and seven countries to treat chronic pain — and the team has certified 300 healthcare clinicians around the world as Empowered Relief instructors.

“I hope expanded, online access to the course will provide more equitable access to evidence-based pain care for people living in rural areas, prisons and other settings that lack trained pain professionals,” she said.

Photo by Sasun Bughdaryan

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

How to talk with someone about COVID-19 vaccine hesitancy

With less than half of the United States fully vaccinated, you’ve probably wondered, “How should I talk to hesitant friends or family members about getting their COVID-19 shot?” Now, Stanford Medicine researchers specializing in health education have developed guidelines to help facilitate those awkward conversations.

“We’re trying to find common ground between different audiences to create guidelines that catalyze conversation about vaccination, not stifle it,” said Rachelle Mirkin, MPH, administrative director of health education, engagement and promotion at Stanford Health Care, who led the effort.

Moreover, these conversations either aren’t happening or they’re often ineffectively divisive, said Emilie Wagner, a healthcare strategy consultant who teaches at Stanford and who helped Mirkin and Nicole Altamirano, program manager for digital experience strategy, conduct the research. “There’s so much tension that people don’t want to risk a relationship. Yet, if it goes unaddressed, the tension just naturally mounts.”

The team wanted to understand why some people are reluctant to adopt COVID-19 prevention measures — including wearing a mask, social distancing and being vaccinated — and wanted to learn how to facilitate better communication with vaccine-hesitant individuals.

So far, they’ve discovered that traditional messages — such as the need to protect yourself and others or the enticement of getting kids back to school — don’t move the needle when it comes to persuading hesitant people to get a vaccine. Having a personal, empathetic conversation with people works better than presenting statistics and facts at them.

Needing a new approach

Mirkin and her team conducted an extensive literature review of vaccine hesitancy, using the information to create a list of 25 talking points they thought might sway those who are vaccine hesitant.

They then interviewed health care providers, hospital administrators and a small group of older white adults who were vaccine hesitant, but only regarding COVID-19. Somewhat surprisingly, these participants weren’t generally against vaccines, said Mirkin. Some had already received a two-part shingles vaccines, which can have significant side effects including fatigue, muscle pain and fever.

But when it came to COVID-19 shots, the traditional messaging did not resonate with the target group, said Wagner.

“They had a response for everything,” she said. “They thought the vaccine wasn’t a means for returning to normal. It wasn’t their responsibility to keep others safe. And they believed the risk of the vaccine outweighed the risk of COVID.”

So, the team switched from drawing on knowledge to drawing on empathy. Instead of focusing primarily on facts, they suggest having open-ended conversations that validate feelings and personalize the vaccine experience. And they recommend talking about how everyday life is easier once you’re vaccinated.

According to Wagner, they found that the appeal of hassle-free travel can motivate this group to get vaccinated. Visiting with grandkids can also nudge older adults into getting their shots. But generally, it takes a combination of incentives. The researchers also realized that many short conversations over time are needed. “It takes persistence, so talking with friends and family members can be more effective than a single conversation with a provider,” Wagner said.  

To share their approach more broadly, the researchers translated their new strategy into two practical guides — one for health care providers and one for friends and family — and are now disseminating them.

“We need to make space for these discussions,” Mirkin explained. “The more non-judgmental conversations you have with an individual, the more likely they are to protect themselves and others from COVID.”

Encouraging vaccine acceptance, one group at a time

Mirkin’s team is also trying to understand the drivers of vaccine acceptance in two other groups: Latino Spanish speakers and Pacific Islanders. They are working with community partners to create social media campaigns, including Facebook ads, Twitter and Instagram posts, as well as public service announcements. So far, the Latino public service announcements have been picked up by Telemundo, a Spanish-language television network, and the Facebook ads have more than 3 million hits.

Based on initial data, the main issue for Latinos and Pacific Islanders is access to personal protective equipment — such as masks — COVID-19 testing and vaccines, Mirkin said. “In general, the concerns are very logistics-based, whereas the Caucasian hesitant group is philosophically- and identity-based,” she said.

Vaccine acceptance is often complicated by a larger erosion of trust of science and health care systems that have failed many people, especially those of color, said Mirkin. “As an academic medical center, we have to understand what’s going on to begin to reshape the conditions to help rebuild trust.”

This is a reposting of my Scope blog story courtesy of Stanford School of Medicine.

Photo by Mattia Ascenzo  

Lung Organoids: A Novel Way to Model COVID Infection

Calvin Kuo, MD, PhD, with Shannon Choi, MD, PhD, a student in the Kuo lab. Courtesy Steve Fisch

A year into the pandemic, we’ve all heard the stories. A patient is a little short of breath but appears to have a mild case of COVID-19. The next day, she deteriorates so rapidly that she’s rushed to intensive care, put on a ventilator, and hooked up to a dialysis machine to prevent kidney failure. Her overzealous immune system has gone rogue, attacking healthy cells instead of just fighting off the virus.

What triggers this devastating immune response, called a cytokine storm? Researchers are still struggling to identify the underlying processes that initiate a COVID infection and subsequent cytokine storm.

Biologists use advanced technologies and cell cultures in petri dishes to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus strain responsible for COVID-19, identifying its key characteristics such as the famous crownlike spikes on their surfaces. But these short-lived cultures don’t act like real organs. And scientists are limited by their samples.

“When you analyze samples from patients, they’re often at the end stage of the disease, and many of the samples are from autopsy. You can’t understand the initiation process because the tissue is essentially destroyed,” says Calvin Kuo, MD, PhD, professor of hematology.

Understanding how the disease develops and testing potential treatments require better ways to model this coronavirus.

Miniature Organs in a Dish

Kuo’s laboratory develops organoids—three-dimensional miniature organs grown in a petri dish that mimic the shape, structure, and tissue organization of real organs.

Grown from human tissue samples using precisely defined ingredients, these organoids are little spheres of gel up to 1 millimeter in diameter. Healthy tissue samples are mechanically minced and enzyme digested to get to single cells, and then the organoids are grown from single stem cells. They last about six months, significantly longer than the few-weeks lifetime of traditional cell cultures.

Kuo initially developed organoids to study stem cell biology and model cancer. His team was the first to use organoids to convert normal tissues to cancer, as previously reported in Nature Medicine.

But he was passionate about using organoids to model infectious diseases. In 2015, he led a National Institute of Allergy and Infectious Diseases U19 research program, recently renewed for an additional five years, in collaboration with Stanford researchers Manuel Amieva, MD, professor of pediatrics and of microbiology and immunology; Harry Greenberg, MD, the Joseph D. Grant Professor in the Stanford University School of Medicine and professor of microbiology and immunology; Elizabeth Mellins, MD, professor of pediatrics; and Sarah Heilshorn, PhD, professor of materials science and engineering. Focusing mainly on the gastrointestinal tract, this multidisciplinary team provided proof of principle that organoids could model infectious diseases.

“With an organoid system, you can start at the infection and look at the very earliest events that occur after infection. And those can give insights as to what needs to be blocked therapeutically,” Kuo explains.

Distal Lung Organoids

After the initial success with gastrointestinal organoids, Ameen Salahudeen, MD, PhD, a hematology and oncology postdoctoral fellow working in Kuo’s lab, led efforts to expand this work by developing distal lung organoids. He partnered with lung stem cell expert Tushar Desai, MD, associate professor of pulmonary, allergy, and critical care medicine at Stanford.

The distal lung is composed of terminal bronchioles and alveolar air sacs, where inhaled air passes through the tiny ducts from the bronchioles into the elastic air sacs. It performs essential respiratory functions that can be compromised by inflammatory or infectious disorders, such as COVID-19 pneumonia.

“Growing distal lung cultures in a pure way that doesn’t require any supporting feeder cells and is in a chemically defined media had not been possible,” Kuo says. “We were able to do this very beautifully—to grow alveoli at the terminal bronchioles as long-term human cultures.”

The team developed two types of distal lung organoids. Both were made from human distal lung samples provided by Stanford cardiothoracic surgeon Joseph Schrager, MD.

They grew the first type, alveolar organoids, from single alveolar type 2 (AT2) stem cells. AT2 cells have several important functions that together help control the immune response to decrease lung injury and repair. The scientists then induced the AT2 cells to produce alveolar type 1 (AT1) cells, which are the thin-walled cells lining the alveolar air sacs; they are essential for the lung’s gas-exchange function.

“The second type are the basal organoids, which grow from single basal stem cells. They give rise to the mucus-secreting club cells and the ciliated cells with beating hair. And we can see the beating hair under the microscope—it’s quite dramatic,” describes Kuo. “That’s a very nice reproduction of the differentiation and function of the lung.” The team also grows a mixture of alveolar and basal organoids.

They selected these organoid types to determine which cell types in the bronchioles and alveoli were infectible—in hopes of identifying the different mechanisms for how viruses cause respiratory compromise.

Initially, they tested the distal lung organoids using the H1N1 influenza virus, collaborating with Stanford molecular virology expert Jeff Glenn, MD, PhD.

The team fluorescently labeled the virus and infected the lung organoids, demonstrating that the virus replicated in both basal and alveolar organoids. Next, they did more sophisticated PCR-based testing to show that the virus replicated its genome.

COVID-19 Model

“But then the COVID-19 pandemic hit, so we initiated a fabulous collaboration with infectious disease expert Catherine Blish, MD, PhD, in the Department of Medicine, to infect our lung organoids with SARS-CoV-2. This was driven by a talented MD-PhD student in my lab, Shannon Choi,” says Kuo. “She worked with Arjun Rustagi, an infectious disease fellow in Catherine Blish’s lab, who infected the organoids in a biosafety-level-3 lab.”

Another partnership was critical, though. An important coronavirus receptor, called angiotensin-converting enzyme 2, or ACE2, resides inside the lung organoids. But ACE2 needed to be on the outside of the organoid to get the infection going.

Luckily, Amieva previously devised a way to flip intestinal organoids inside out. Working together, Choi and Amieva turned the lung organoids inside out.

As reported in Nature in November 2020, the team demonstrated that the coronavirus infected their distal lung organoids, including the alveolar air sacs, where COVID-19 pneumonia originates. They also identified a new airway subpopulation as a COVID-19 virus target cell.

“Everyone knew basal cells were stem cells in the lung, but they thought they were all equivalent. Using our organoids, we discovered an unknown basal cell subpopulation containing the stem cell activity. And then we showed this subpopulation actually existed in human lungs in very interesting anatomic locations,” Kuo says.

COVID-19 Applications

According to Kuo, their distal lung organoids have three major applications for COVID-19.

They are using them to screen potential coronavirus therapeutic antibodies and to understand how these treatments work. Although initially focused on COVID-19, this screening will likely expand to other kinds of lung infections in the future.

Because the distal lung with the alveoli is the site of the COVID-19 pneumonia, they also plan to use the organoids to identify the underlying biological mechanisms behind coronavirus infection. Finally, they plan to extend their organoid system to incorporate immune cells and understand more complex processes. In particular, they plan to model the dreaded cytokine storm.

Overall, Kuo emphasizes that this organoid research represents a huge team effort involving many investigators with wide-ranging expertise from various departments at Stanford, as well as an “interesting evolution of events.” “Now we have a human experimental system to model SARS-CoV-2 infection of the distal lung with alveoli, which is the site of the lung disease that kills patients,” he summarizes. “We know patients die because of severe pneumonia and lung failure. We can now recapitulate this in the dish. So, we can study how it works, and also test drug treatments.” 

This is a reposting of my feature article in the recent Stanford Medicine Annual Report. Check it out to see videos of these lung organoids.

Innovative Antibody Treatment Proves Safe and Effective for Immune Disorders

Many blood and immune disorders could be cured by transplanting healthy blood stem cells from a matched donor. But first the patients need a pretreatment procedure to eliminate their own blood stem cells, making room in the bone marrow for the donor cells to take their place.

The problem is that the standard pretreatments—chemotherapy or radiation—are very toxic. Doctors don’t want to give them to vulnerable children, such as those with a rare genetic disorder called severe combined immunodeficiency (SCID).

Infants with SCID have compromised immune systems that struggle to fight off even common infections caused by viruses and fungi. These babies have many chronic and life-threatening problems, including frequent lung infections, chronic diarrhea, and recurrent sinus infections.

Judy Shizuru, MD, PhD, reviews data with Wendy Pang, PhD

“Without treatment, SCID infants usually die from infections within the first two years of life. Blood stem cell transplants are the only definitive cure for this disease,” says Judith Shizuru, MD, PhD, professor of blood and marrow transplantation and cellular therapy and of pediatrics. “But transplants usually involve chemotherapy, and we don’t want to give these agents to these children because they’re particularly susceptible to the damaging short-term and long-term effects—including growth defects, neurological problems, and increased risk of cancers. This is especially true for certain subtypes of SCID.”

Instead, SCID patients are often given a blood stem cell transplant without pretreating with chemotherapy to create space in their bone marrow. But then the donors’ self-renewing blood stem cells may not fully engraft, so the kids can’t robustly regenerate their immune systems. These children have to rely on regular intravenous immunoglobulin infusions to boost their immune response, and the effectiveness of donor immune cells can wane over time.

The great need for a less toxic pretreatment for blood stem cell transplants inspired Shizuru to initiate a Stanford study testing a novel antibody pretreatment in SCID patients—in collaboration with Rajni Agarwal-Hashmi, MD, associate professor of pediatrics, and other stem cell transplantation and regenerative medicine specialists at Stanford and UC-San Francisco.  

Targeting Blood Stem Cells

The novel pretreatment uses the JSP191 antibody to target a protein called CD117, found on the surface of blood stem cells. The antibody binds to this protein, which then blocks CD117 from binding to a stem cell factor critical for keeping blood stem cells alive. When the interaction between CD117 and the essential stem cell factor is interrupted, the patient’s blood stem cells are depleted—making space for the donor’s healthy cells to engraft.

“It’s not like chemotherapy or radiation,” says Shizuru. “It’s a targeted way to deplete the blood stem cells without damaging normal healthy cells.”

The Stanford team chose SCID patients for their first human JSP191 clinical trial in part because these children have a unique biology—they lack lymphocytes, so they are less likely to immunologically reject the blood stem cells from a donor. Since immune suppressive medications aren’t necessary, the researchers can more easily see if the antibody therapy clears space in the bone marrow and the transplant works.

Initially, the clinical trial studied older children and adults with SCID whose first blood stem cell transplant had failed, so that they could evaluate whether JSP191 therapy was safe and well tolerated. The participants ranged in age from 3 years old to mid-30s, but most were between 11 and 13 years old. According to Shizuru, many of these kids had chronic infections and also wanted to be liberated from having intravenous immunoglobulin infusions.  

Rajni Agarwal-Hashmi, MD

Promising Results

The results are very promising, as Shizuru reported in 2019 at the American Society of Hematology annual conference. The antibody safely created room in the patients’ bone marrow, allowing healthy donor stem cell engraftment without common side effects like transfusion reactions, treatment-related toxicities, or bone marrow suppression.

“The wonderful thing about the antibody JSP191 is it’s super-safe. This conditioning agent doesn’t affect the DNA or any other organ, as far as we can tell,” explains Shizuru. “We give it as a onetime, really low dose. And it’s not showing any side effects. It’s an amazing drug.” 

The study’s clinicians even remarked that the re-transplant kids looked bored in the hospital because the expected complications didn’t happen, says Shizuru. “The patients’ counts didn’t drop. They didn’t have increased infections. They didn’t need blood transfusions,” she says. “So, we decided to give the antibody as an inpatient treatment and then do everything else as outpatient after 48 hours.”

The results were promising from the start. The first participant pretreated with JSP191 was a 3-year-old girl with chronic diarrhea and infections. After about a year, she no longer had diarrhea and started going to school for the first time. In fact, her family was infected with COVID-19 and she did fine, as Shizuru learned during a public discussion.

Expanding the Clinical Trial

Based on the safety and success of the first phase, the JSP191 trial expanded to include infants newly diagnosed with SCID. Two infants have received the antibody pretreatment followed by a blood stem cell transplant.

The first infant did really well, demonstrating signs that his donor cells may fully restore his immune function. The second infant’s response was more complicated; the researchers determined that she had some immune function that may have rejected the maternal stem cells. She subsequently underwent another transplant without the antibody agent, using a mix of chemotherapies.  

After their initial success, Shizuru’s team expanded the use of JSP191 to include other vulnerable populations—older adults with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). AML is a type of leukemia in which DNA mutations cause the rapid growth of abnormal cells that build up in the bone marrow. Although it starts in the bone marrow, AML often quickly moves to the blood and sometimes spreads to other parts of the body. MDS are a group of diverse bone marrow disorders in which the bone marrow does not produce enough healthy blood cells. Both AML and MDS primarily occur in people over 65 years old.

This adult study is based on the preclinical work of Wendy Pang, MD, PhD, who was a postdoctoral fellow in the Shizuru laboratory. She showed that the disease-causing MDS and AML stem cells express CD117, so they can be targeted by JSP191. Further, the team observed synergistic eradication of stem cells when these anti-CD117 antibodies were combined with low-dose radiation.

The ongoing clinical trial utilizing JSP191 combined with low-dose radiation is led by Lori Muffly, MD, assistant professor of blood and marrow transplantation and cellular therapies. The preliminary results are encouraging based on the first six participants, who were older adults (64–74 years old) with AML or MDS. The researchers observed no side effects associated with JSP191, and the patients’ blood stem cell transplants were successful.

“We transplanted our first SCID babies and then opened the trial up to older patients with AML and MDS. So, now we’re covering the full spectrum for this targeted therapy: from a 3-month-old infant with SCID to a 74-year-old with AML,” Shizuru says.

The JSP191 project has now moved to a biotechnology company, Jasper Therapeutics. Shizuru expects that in the future, the studies will expand to include sickle cell disease, a group of inherited red blood cell disorders, where the JSP191 antibody can help to engraft the donor cells.

“In terms of pretreatment, there’s been no innovation on transplant agents in decades. People have been innovating on transplant by simply reducing the dose of chemotherapies, but we haven’t seen a successful new agent,” explains Shizuru. “The development of JSP191 leverages our understanding of the biology of blood stem cells by targeting a critically important molecule. JSP191 antibody is now the platform agent.”

This is a reposting of my feature article in the recent Stanford Medicine Annual Report.

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