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Building Resilience During the COVID-19 Pandemic

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Drs. Collins and Everly on a virtual chat

Dating back to our earliest times, humankind has experienced the psychological impact of a wide range of catastrophes, including famines, floods, earthquakes, wildfires, windstorms, wars, and, last but certainly not least, outbreaks of potentially deadly infectious diseases. We are certainly no exception today as people try to figure out how to cope—and help others cope—with the grief, stress, and anxiety caused by biggest health challenge of our time: the coronavirus 2019 (COVID-19) pandemic.

With more than 215,000 Americans having lost their lives and more than 7.8 million infected since COVID-19 first gripped our nation, the pandemic has taken a profound psychological and emotional toll on us all. Still, behavioral and social science researchers have identified some strategies to help us deal with our fears, and even rise to the challenge of supporting others during this unprecedented time.

Recently, I had an opportunity to discuss the science behind mental health responses to disasters with Dr. George Everly Jr., a psychologist and professor at the Johns Hopkins University Bloomberg School of Public Health, Baltimore. A world-renowned expert with more than 40 years experience studying the psychological impacts of disasters, he co-founded the International Critical Incident Stress Foundation, an organization affiliated with the United Nations. Our conversation took place via videoconferencing from our home offices in Maryland. Here’s a condensed transcript of our chat:

Collins: Good morning! At NIH, we are doing everything we can to keep our scientific mission going by supporting groundbreaking research into COVID-19 and a lot of other things. We’re also deeply committed to helping people manage stress and attend to mental health. So, we’ve invited Dr. Everly to share insights that I believe will help us learn some skills to build resilience. Goodness knows, this is a time where we all need resilience, as well as to help others around us. We’re all called upon, I think, to look after our friends and neighbors in the aftermath of a circumstance like the current pandemic.

Everly: It’s a privilege to spend some time with you today and chat about such an important topic. The topic we typically think about in terms of disasters is the physical response. Today, we’ll talk about the psychological impact of the COVID-19 pandemic. This is actually my third pandemic, having consulted in Hong Kong with SARS and Singapore with H1N1. I’ve also done consulting with Ebola.

However, I will tell you that this pandemic, COVID-19, has been the most challenging. I think we can we agree that mental health is an intrinsic value as it relates to us as humans. Anything that threatens mental health, especially in large numbers, threatens the core fabric of society.

According to the United Nations, we may now be looking at an impending international mental health crisis. Some have called this the “hidden” pandemic: people who previously coped well may have challenges and people who had challenges coping before COVID-19 may have increased challenges. Looking at first responders and frontline workers, we have seen heroic efforts on their part, but not without consequences—and mental exhaustion may be one of them

Collins: How is this crisis similar—and how is it different—from most of the disasters that people have dealt with?

Everly: The first thing is expectations. If we expected COVID-19 to be short lived, we have been remarkably, if not catastrophically, disappointed.

So, this connection occurred to me. A number of years ago, I was interested in the psychological impact of the London Blitz, and I went to England to interview people who went through that night upon night upon night of intractable bombing during World War II. I wanted to find out what helped people make it through. It was very clear that their initial belief that the bombing would be short-lived was tragically violated. They then as a community understood that they had to shift into a different mindset, and realize the Blitz wasn’t a sprint—it was marathon. They’d originally sent their children out into the countryside, but later decided to bring them back in the midst of bombing. I will suggest that psychologically, that was the turn of the war. In fact, research later by Anna Freud found that sending the kids away was psychologically more injurious than keeping them in the city. And I think that’s really important. Realizing that we are in for a long haul with COVID-19, in and of itself may be a game changer.

Collins: A very interesting comparison. I hadn’t thought about it that way—an acute disease becoming chronic.

Tell us a little bit more about the undercurrent of malaise in our country even before this COVID-19 pandemic hit—what economists Angus Deaton and Anne Case have recently written about as the “deaths of despair” and the opioid crisis. We are facing a pandemic from coronavirus, but it didn’t land on a completely blank page. It landed in a circumstance where many people were already feeling significant stress, and where depression was increasing risks of overdoses and suicide.

Everly: Fantastic question. You probably remember the work of Hans Selye, an endocrinologist who actually coined the term “stress.” He said, at any given point in time, we have a limited supply of what he called “adaptive energy.” In the best of conditions, this reservoir is quite high and will allow us to meet unusual challenges. However, I would suggest that the background noise of chronic issues that predated COVID-19 did begin to deplete that reservoir of adaptive energy, making us more vulnerable to things that turned out to be far more challenging than we thought. We were starting with one foot in the hole, so to speak.

Collins: All the more reason why our resilience is being called upon. Piled on top of it, many people are facing the serious challenge of trying to telework from home and trying to manage their responsibilities in terms of children or other family members who need care. My heart goes out to those folks as they struggle with this shared set of responsibilities, probably feeling as if there aren’t enough hours in the day and distractions are always getting in the way.

People are also feeling stressed now about the health of their children. What do we know—and what should we be thinking about—in terms of the mental health impact of the COVID-19 pandemic on kids?

Everly: In the spirit of full disclosure, I’m not a child psychologist. But I have studied trauma, crisis, and disaster for quite a while, and, invariably, children are part of that. One of the most powerful things I have seen in my career is that children often become reflections of their parents. Children not only desire, but they need, stability. My message to parents is that your children rely on you. You must be that strength for them. Even when you think you can’t be strong for yourself, reach down deep inside and say, “This isn’t just about you; it’s about others as well.”

I’ve got three young grandchildren, and this is the message I am telling their parents: “This is an important time. This may be one of the defining milestones in your children’s development. It’s an opportunity to show them how to cope.”

Collins: I have grandkids as well and have been watching how they have adapted. In some instances, I can see how they have actually gained in strength, as they’ve learned that this is an opportunity to face up to a challenge and learn how to cope. It does seem to be a mix of providing that foundation of support, but trying not to prevent children completely from having the experience of realizing they can get through some things themselves.

Everly: We can certainly be overprotective. From studying Olympic athletes, we learned that when they were asked what helped them reach the elite tier and win Olympic medals, they answered: challenge, plus adequate support. While well-intended, I think support alone is misdirected.

Collins: That makes sense. I know, during the current crisis, there is an interest in figuring out, in scientifically rigorous ways, what mental health interventions seem to produce good outcomes. Tell me a little bit more about where we stand as far as the opportunities to be doing these sorts of trials of various interventions. It would be a shame to go through this and then say to ourselves, “We missed a great opportunity there to learn more.”

Everly: It’s tough to do a randomized, controlled trial in the middle of a disaster. There are quite literally ethical issues at play. So, we approximate as best we can. For example, in the past, we built our own model of Psychological First Aid and tested it in two randomized controlled trials and three content validation studies, as well as in structural equation modeling studies. Have we tested it in this current environment? Not yet. There may be others doing that—I’m not sure.

If you take a look at the Cochrane Review on resiliency programs, you will perhaps be a little surprised. The review says there’s not a compelling body of evidence that resiliency programs work. However, we believe they work. We know there is this thing called human resilience and we encourage everyone to keep on trying to study it in scientifically rigorous ways.

Collins: I’m glad that you are. We should not miss the opportunity here to learn, because this is probably not our last pandemic—or our last crisis. Any final words?

Everly: So, with the caveat that I’m a diehard optimist …

Collins: That’s okay. I am too!

Everly: … I truly believe that from the greatest adversities, opportunities can emerge. When I spent three years in New York working after the 9/11 terrorist attack, I thought this is the defining moment, not just of my generation, but of others. I got to see it up close and personal, and worked intimately with various agencies. And I did see opportunities. As a result of 9/11, we changed not just the way we go through airports, but the way we look at trauma from a public health standpoint. Perhaps for the first time, we realized that we need to take a far more active preventative and interventional role.

Now, history repeats itself. I believe that this pandemic will change us for the rest of my life—and I don’t think all those changes need be negative. I think there are huge opportunities. I certainly am eager to investigate this at the highest levels of science. Let’s see why things work when they work and why things don’t work. Then, let’s use that information to build programs and test them in randomized, controlled trials.

I think we will come out of this pandemic better than we went into it. I would encourage people to understand that we’re in this together. Way back in the mid-1800s, Darwin told us that the greatest predictor of resilience was collaboration and cohesiveness. This is a time to reach out to each other.

Collins: I totally agree with that. You’re making a really good point: social distancing doesn’t have to mean anything more than physical distancing. We can stay socially close and reach out to each other in different ways.
We’re going to get through this, but get through it in a way that will change us. We will be changed by becoming stronger and more resilient, having learned some lessons about ourselves and about each other. We cannot simply hide our heads under our pillows and wait for this to pass. When you wake up in the morning, say to yourself: “I’m engaged in something that matters. I’m not just a passive victim of this terrible pandemic. I’m trying to do what I can and work toward getting us through.”

Many thanks, Professor Everly, for all your good work and for giving us this time to reflect on this important area of research and how to make the most of it.

Links:

Coronavirus (COVID-19) (NIH)

George S. Everly (Johns Hopkins University Bloomberg School of Public Health/Baltimore)

Video: Coping with the Mental Health Effects of COVID-19, George Everly with Francis Collins (NIH VideoCast)

The Power of Psychological First Aid. Dome. Minkove JF. March/April 2018. (Johns Hopkins Medicine/Baltimore)

Coping with Stress (Centers for Disease Control and Prevention)

Coping With Stress During Infectious Disease Outbreaks (Substance Abuse and Mental Health Services Administration)

Talking with Children: Tips for Caregivers, Parents, and Teachers during Infectious Disease Outbreaks. (SAMHSA)

National Suicide Prevention Lifeline

SAMHSA’s Disaster Distress Helpline, 1-800-985-5990

National Suicide Prevention Hotline, 1-800-273-TALK (8255); TTY number 1-800-799-4TTY (4889)


Addressing the Twin Challenges of Substance Use Disorders and COVID-19

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At home with Nora Volkow

The coronavirus disease 2019 (COVID-19) pandemic is having a wide range of negative impacts on people affected by a variety of health conditions. Among the hardest hit are individuals struggling with substance use disorders, with recent data indicating that suspected drug-related overdoses and deaths are on the rise across the United States [1].

One recent analysis of nationwide surveillance data, collected by the federal Overdose Detection Mapping and Application Program, found that suspected drug overdoses rose by 18 percent in March, 29 percent in April, and 42 percent in May compared to the same months in 2019 [2]. Another analysis of state and local mortality data showed that drug-related deaths have increased about 13 percent so far this year, compared to last year [3].

To find out what may be contributing to this tragic situation and learn what NIH-funded research is doing to help, I recently had a conversation with Dr. Nora Volkow, Director of NIH’s National Institute on Drug Abuse (NIDA). Here’s a condensed version of our interview, which took place via videoconference, with both of us linking in from our homes near NIH’s main campus in Bethesda, MD

Collins: Here we are today talking about two public health crises: the crisis of COVID-19 and another crisis that has been going on for quite some time, of drug overdoses and drug deaths. The opioid crisis is difficult in any circumstance, but when you add to it what’s happening right now with the global COVID-19 pandemic, it becomes difficult squared. What has happened during this pandemic?

Volkow: One of the first things that we’ve heard from the communities and the families afflicted by addiction is that the support systems that were there to help people achieve recovery are no longer present. At the same time, it’s been much harder to get access to some of the treatment programs, including hospital emergency departments that can initiate treatment. It’s also been more difficult to access syringe exchange programs and programs, like Narcotics Anonymous, that provide people with a mentor and a social support system that’s fundamental for recovery. Part of recovery is also for individuals to work at re-building their lives, and that too has become much more challenging due to the threat of COVID-19.

All of these aspects are translating into much more stress. And stress, as we know, is one of the factors that leads people to relapse. Stress is also a factor that leads many to increase the consumption of drugs.

Collins: What about the impact of the stay-at-home orders for people who are depending on social networks? You’ve talked about Narcotics Anonymous as an example. But for anybody who’s faced stress challenges, mental health issues, which often coexist with drug problems, what’s the effect of losing those face-to-face social connections?

Volkow: Isolation is difficult for anyone. We depend on others for our wellbeing. The harder our situation, the more vulnerable we are if we don’t have those support systems.

One of the major concerns that we’ve had all along is not just the enormous risk of relapse in many people, but also the risk of suicide—which is always much higher in individuals that are addicted to drugs, particularly to opioids. Indeed, there’s been an increase in the number of suicides associated with the COVID-19 pandemic, including among people that are addicted.

One of the elements we are using to try to overcome that is virtual interactions, like we are having right now. They are fulfilling, certainly for me. And when we’ve surveyed patients and families to see how much these virtual support systems are helping them, we see in many instances that this can be lifesaving. For example, with telehealth, a physician now can prescribe buprenorphine [a treatment medication] without necessarily having to see the individual physically. That’s a major breakthrough because it expands the number of people that can be treated. So, you can provide buprenorphine, and you can also provide support that someone with co-morbid mental illness may need. It’s not the same as physically being with others, but we have to recognize virtual technologies may enable greater equity in providing treatments.

Collins: What’s happened to methadone clinics, a place where people were required to show up in person every day? What’s become of people who depended on those?

Volkow: These spaces are small and there’s not enough staff, so it was very, very high risk. So, one of the positives of COVID-19 is that there was a change in the policy that enabled a methadone clinic to provide take-home methadone for patients, rather than have them come in daily and often at very restricted times, which made it incredibly difficult to comply.

We’re now trying to evaluate the outcomes when people are given take-home methadone. If we can show from evidence that the outcomes are as good as when you go in daily, then we hope that will help to transform these policies permanently.

Collins: So, there’s a silver lining in a few places. Are people who suffer from drug use disorders at increased risk of getting sick from COVID-19?

Volkow: There are many factors that place them at very, very high risk: pharmacological, structural, and social.

Pharmacological, because these drugs negatively affect multiple systems in your body and one of the main targets is the pulmonary system. If your pulmonary system already has pathology because of prior conditions, it’s much easier for the virus to actually infect you and lead to negative outcomes. That pertains to cigarette smoking that produces COPD and pulmonary damage, as well as to very toxic drugs like methamphetamine, which produces pulmonary hypertension; or opioids, which actually depress respiration and produce hypoxia.

You can see that the combination of depressed respiration and having a viral infection that attacks your lungs is not going to be positive. Indeed, it is very likely that that combination lowers the threshold for people to die from overdoses or to die from COVID-19. Drugs can also affect the cardiovascular system and the metabolic system, so all of the factors that we’ve identified as conditions that make you more vulnerable to COVID-19 are affected by drugs.

Then there are structural issues. We’ve already discussed methadone clinics, which put people together in very close spaces. Before COVID-19, one of our main priorities was to bring the treatment of substance use disorder and the screening into the healthcare system. But now the healthcare system is saturated and individuals who’ve gotten their treatment in healthcare systems no longer can access them and that restricts their ability to seek help. In our country, we basically criminalize people who take drugs, and many of them are in jail systems and prisons, where COVID-19 infections can rapidly occur. That is another element where they are at much higher risk.

Also, the number of individuals with substance use disorder who have medical insurance is much less than that of the general population. Not having such insurance is associated with a greater likelihood of having chronic medical conditions, which again is another risk factor for COVID-19. This mixes the structural with the social and, in the social category, you also have stigma.

Stigmatizing individuals with addiction makes them very vulnerable. That’s because, first of all, they are afraid to seek help—they don’t want to be discriminated against. Secondly, if they are in a situation where decisions are being made about providing medical care when resources are limited, that stigma can make them much more vulnerable.

While we are dealing with COVID-19, we cannot ignore the disparities that exist in our society. This pandemic has made it very clear how horrifically disparate health outcomes are between groups of people in our country.

Collins: Nora, you’ve been a real leader on what we might do to try to bring attention to helping people with drug use problems in the criminal justice system. This is often a point where an opportunity for treatment arises, but unfortunately that opportunity is often missed.

Volkow: One of our priorities as we address the opioid crisis is to do research in justice settings in order to be able to identify the models that lead to the best outcomes and to understand how to implement them. This has resulted in the creation of a research network that enables us to connect across the justice and the healthcare systems.

The network that started to emerge before COVID-19 hit has given us an opportunity to get direct information about what’s happening out there. From what we know, because prisons and jails are at such high risk for infection, many states—if not all—are releasing people that are not violent into their communities. Many of them have a substance use disorder. If someone has a long history of a substance use disorder, you cannot release them into the community without a support system, especially in the midst of the COVID-19 pandemic, where it’s hard to find a job and their families may be rejecting them. You can predict the outcome is going to be very poor, including dying from overdoses.

So, we now have a chance to show that treating these people in their community with appropriate support is going to lead to much better outcomes than leaving them in jail or prison. We are now working with our researchers and with appropriate agencies to figure out how to provide the support that’s necessary as individuals with substance use disorders are released into their communities. It can go both ways. Without support, the outcomes may be very poor. With support, we have the opportunity of transforming the way that we deal with addiction in this country.

Collins: A lot of people may not realize that effective medical treatment for substance use disorders does exist. Treatment has been demonstrated to change lives and improve outcomes over the long term. Still, a lot of folks out there think it’s just hopeless, or, alternatively, if someone just had a little bit more willpower, he or she would be able to take care of this. Please say a little bit about what the current treatment options are, and what the evidence is that they’re needed if you’re going to help somebody recover from a substance use disorder.

Volkow: There are medications for alcoholism and medications for nicotine use disorders. But, by far, the most effective medications are for opioid addiction. It’s very frustrating these medications are not necessarily given to patients—or sometimes even given to patients, but they reject them. I think part of the issue is because of the stigma against the medications. The opioid crisis has helped smooth that out somewhat, so there’s been a greater acceptance of medication. In partnership with the pharmaceutical industry, we have also been working towards developing extended-release formulations that make it much easier for people to take these medications.

In parallel, not just for opioid addiction, we have built up the scientific evidence for behavioral interventions that can improve outcomes for people with substance use disorder in general, if provided concurrently with medical treatment. Recognizing that there is a high risk of comorbidity with mental illness, we also need to provide treatments to address psychiatric disease problems or symptoms, as well as the addiction process. A lot of the work right now is going into creating models that allow this comprehensive treatment, tailored to the needs of the person.

Collins: Where can people who have a family member or friend who’s struggling with substance use disorder in the midst of COVID-19 go to get reliable evidence-based information about treatment programs?

Volkow: They can go to the NIDA website or the website of NIH’s sister agency, the Substance Abuse and Mental Health Services Administration (SAMHSA). One of the problems is that there hasn’t been any way of assessing the quality of treatment for substance use disorder. For many other conditions, you can check the track records of this or that hospital for this or that surgery, but such information does not exist for substance use disorder.

So, we’ve been funding researchers to develop metrics that can predict good outcomes in treatment programs. These metrics can be based on the experiences of people and family that actually took these services, and from the structural characteristics of the program, such as whether they have the evidence-based components shown by research to lead to better outcomes. Researchers are now developing “report cards” for treatment programs that hopefully will do two things: give a family member a sense of how others are rating a program, and, importantly, incentivize treatment programs to do better.

Collins: It would be wonderful to have more objective data for people searching for good answers. Now, let’s talk about HEAL, which stands for Helping to End Addiction Long-term. HEAL is a trans-agency initiative funded by the Congress to support research to address, from multiple different directions, multiple different problems relating to addiction and chronic pain.

How does the HEAL initiative need to adapt to the current health crisis of COVID-19? And what’s your institute doing to try to address some of the significant problems that have emerged in just the last two or three months?

Volkow: COVID-19 has placed HEAL and much of our other research on a very slow trajectory. For example, one program that we were very interested in expanding was the use of the emergency department for the screening of opioid use disorder and the initiation of treatment medications. Another major HEAL program was going to start using the justice system to conduct clinical trials to evaluate the outcomes of different types of medication for opioid use disorder. They are all basically on hold.

Collins: Nora, what’s your hope going forward over the next few months? What can NIH do to try to address this situation in the most effective way possible?

Volkow: I am optimistic because I can see how science can help to solve extremely challenging problems. I think this is the time for science to shine again and show us that methodologies aimed at gathering objective data to develop optimal solutions can resolve problems. But the question is: how long will it take?

I’ve been very impressed about how these devastating circumstances have led us to question the pace at which we moved projects in the past. I think it is wonderful that we have recognized that time is a luxury, that we need to move rapidly. With respect to the issue of substance use disorders, I would hope that, as we as a nation become aware of the suffering that the COVID-19 pandemic is putting on all of us, we become more empathetic to the suffering of others.

And as I see the movements across the country speaking out against injustice, I would hope that this will also extend to diseases that have been stigmatized. We need to modify our stigma so we provide the same level of importance to treating these diseases and supporting people afflicted by them.

I think that science will prevail. What is going to be important is that we also allow for our humanity in order to use that science in a way that everyone can take advantage of it.

Collins: That’s a wonderful way to wind up because I think the calling to bring together science and compassion is what drives all of us who have the privilege of working at NIH, the largest supporter of biomedical research in the world. Our purpose is clear: to find answers for all of these difficult problems that cause suffering and early death for people who deserve better.

Our vision is set on helping the most vulnerable populations right now. COVID-19 has pointed us toward that, and our discussion about those who suffer from substance use disorders also focuses on that.

I’m always one who likes to talk about hope, because, after all, that’s what we get up in the morning thinking about at NIH. We hope that our research efforts are going to lead to a new vaccine or a new treatment for COVID-19, or a better way of helping people who have been afflicted with drug problems.

Yet one of my favorite sayings is that “hope is a privilege that attaches to action.” This means that you can’t just say “Well, I hope for something,” unless you attach that hope to concrete actions you’re going to take.

Nora, your institute has been living that out. You don’t just hope that something good will happen to turn the tide of this terrible crisis of suffering and death from opioid overdoses, you’re all about action. So, thank you for your incredible dedication to the science and to the people whom we are trying to serve.

Volkow: Francis, thanks very much for your support.

References:

{1] Issue brief: Reports of increases in opioid-related overdose and other concerns during COVID pandemic, American Medical Association. Updated July 20, 2020

[2] “Cries for help’: Drug overdoses are soaring during the coronavirus pandemic.” William Wan, Healther Long. The Washington Post, July 1, 2020.

[3] “In the shadow of the pandemic, U.S. drug overdose deaths resurge to record.” Josh Katz, Abby Goodnough, Margot Sanger-Katz. July 15, 2020.

Links:

Coronavirus (COVID-19) (NIH)

Overdose Mapping Application Program (White House Office of National Drug Control Policy, Washington, D.C.)

Helping to End Addiction Long-term (HEAL) Initiative (NIH)

National Institute on Drug Abuse (NIH)

Video: Effects of COVID-19 on the Opioid Crisis: Francis Collins with Nora Volkow (National Institute on Drug Abuse/NIH)

Substance Abuse and Mental Health Services Administration (SAMHSA)


What We Know About COVID-19’s Effects on Child and Maternal Health

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At Home with Diana Bianchi

There’s been a lot of focus, and rightly so, on why older adults and adults with chronic disease appear to be at increased risk for coronavirus disease 2019 (COVID-19). Not nearly as much seems to be known about children and COVID-19.

For example, why does SARS-CoV-2, the novel coronavirus that causes COVID-19, seem to affect children differently than adults? What is the psychosocial impact of the pandemic on our youngsters? Are kids as infectious as adults?

A lot of interesting research in this area has been published recently. That includes the results of a large study in South Korea in which researchers traced the person-to-person spread of SARS-CoV-2 in the early days of the pandemic. The researchers found children younger than age 10 spread the virus to others much less often than adults do, though the risk is not zero. But children age 10 to 19 were found to be just as infectious as adults. That obviously has consequences for the current debate about opening the schools.

To get some science-based answers to these and other questions, I recently turned to one of the world’s leading child health researchers: Dr. Diana Bianchi, Director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Dr. Bianchi is a pediatrician with expertise in newborn medicine, neonatology, and reproductive genetics. Here’s a condensed transcript of our chat, which took place via videoconference, with Diana linking in from Boston and me from my home in Chevy Chase, MD:

Collins: What is the overall risk of children getting COVID-19? We initially heard they’re at very low risk. [NOTE: Since the recording of this interview, new data has emerged from state health departments that suggest that as much as 10 percent of new cases of COVID-19 occur in children.]

Bianchi: Biological factors certainly play some role. We know that the virus often enters the body via cells in the nasal passage. A recent study showed that, compared to adults, children’s nasal cells have less of the ACE2 receptor, which the virus attaches to and uses to infect cells. In children, the virus probably has less of an opportunity to grab onto cells and get into the upper respiratory tract.

Importantly, social reasons also play a role in that low percentage. Children have largely been socially isolated since March, when many schools shut down. By and large, young kids have been either home or playing in their backyards.

Collins: If kids do get infected with SARS-CoV-2, the virus that causes COVID-19, what kind of symptoms are displayed?

Bianchi: Children tend to be affected mildly. Relatively few children end up in intensive care units. The most common symptoms are: fever, in about 60 percent of children; cough; and a mild respiratory illness. It’s a different clinical presentation. Children seem to be more prone to vomiting, diarrhea, severe abdominal pain, and other gastrointestinal problems.

Collins: Are children as infectious as adults?

Bianchi: We suspect that older kids probably are. A recently published meta-analysis, or systematic review of the medical literature, also found about 20 percent of infected kids are asymptomatic. There are probably a lot of kids out there who can potentially infect others.

Collins: Do you see a path forward here for schools in the fall?

Bianchi: I think the key word is flexibility. We must remain flexible in the months ahead. Children have struggled from being out of school, and it’s not just the educational loss. It’s the whole support system, which includes the opportunity to exercise. It includes the opportunity to have teachers and school staff looking objectively at the kids to see if they are psychologically well.

The closing of schools has also exacerbated disparities. Schools provide meals for many kids in need, and some have had a lot of food insecurity for the past several months. Not to mention kids in homeless situations often don’t have access to the internet and other learning tools. So, on the whole, being in school is better for children than not being there. That’s how most pediatricians see it. However, we don’t want to put children at risk for getting sick.

Collins: Can you say a little bit more about the consequences, particularly for young children, of being away from their usual areas of social interaction? That’s true this summer as well. Camps that normally would be a place where lots of kids would congregate have either been cancelled or are being conducted in a very different way.

Bianchi: Thus far, most of the published information that we have has really been on the infection and the clinical presentations. Ultimately, I think there will be a lot of information about the behavioral and developmental consequences of not being exposed to other children. I think that older children are also really suffering from not having a daily structure, for example, through sports.

For younger children, they need to learn how to socialize. There are advantages to being with your parents. But there are a lot of social skills that need to be learned without them. People talk about the one-eyed babysitter, YouTube. The American Academy of Pediatrics has issued recommendations for limiting screen time. That’s gone out the window. I’ve talked with a lot of my staff members who are struggling with this balance between educating or entertaining their children and having so-called quality time, and the responsibility to do their jobs.

Collins: What about children with disabilities? Are they in a particularly vulnerable place?

Bianchi: Absolutely. Sadly, we don’t hear a lot about children with disabilities as a vulnerable population. Neither do we hear a lot about the consequences of them not receiving needed services. So many children with disabilities rely on people coming into their homes, whether it’s to help with respiratory care or to provide physical or speech therapy. Many of these home visits are on hold during the pandemic, and that can cause serious problems. For example, you can’t suction a trachea remotely. Of course, you can do speech therapy remotely, but that’s not ideal for two reasons. First, face-to-face interactions are still better, and, secondly, disparities can factor into the equation. Not all kids with disabilities have access to the internet or all the right equipment for online learning.

Collins: Tell me a little bit more about a rare form of consequences from COVID-19, this condition called MIS-C, Multi-System Inflammatory Syndrome of Children. I don’t think anybody knew anything about that until just a couple of months ago.

Bianchi: Even though there were published reports of children infected with SARS-CoV-2 in China in January, we didn’t hear until April about this serious new inflammatory condition. Interestingly, none of the children infected with SARS-CoV-2 in China or Japan are reported to have developed MIS-C. It seemed to be something that was on the European side, predominantly the United Kingdom, Italy, and France. And then, starting in April and May, it was seen in New York and the northeastern United States.

The reason it’s of concern is that many of these children are gravely ill. I mentioned that most children have a mild illness, but the 0.5 percent who get the MIS-C are seriously ill. Almost all require admission to the ICU. The scary thing is they can turn on a dime. They present with more of a prolonged fever. They can have very severe abdominal pain. In some cases, children have been thought to have appendicitis, but they don’t. They have serious cardiac issues and go into shock.

The good news is the majority survive. Many require ventilators and blood-pressure support. But they do respond to treatment. They tend to get out of the hospital in about a week. However, in two studies of MIS-C recently published in New England Journal of Medicine, six children died out of 300 children. So that’s what we want to avoid.

Collins: In terms of the cause, there’s something puzzling about MIS-C. It doesn’t seem to be a direct result of the viral infection. It seems to come on somewhat later, almost like there’s some autoimmune response.

Bianchi: Yes, that’s right. MIS-C does tend to occur, on an average, three to four weeks later. The NIH hosted a conference a couple weeks ago where the top immunologists in the world were talking about MIS-C, and everybody has their piece of the elephant in terms of a hypothesis. We don’t really know right now, but it does seem to be associated with some sort of exuberant, post-infectious inflammatory response.

Is it due to the fact that the virus is still hiding somewhere in the body? Is the body reacting to the virus with excessive production of antibodies? We don’t know. That will be determined, hopefully, within weeks or months.
Collins: And I know that your institute is taking a leading role in studying MIS-C.

Bianchi: Yes. Very shortly after the first cases of MIS-C were being described in the United States, you asked me and Gary Gibbons, director of NIH’s National Heart Lung and Blood Institute, to cochair a taskforce to develop a study designed to address MIS-C. Staff at both institutes have been working, in collaboration with NIH’s National Institute of Allergy and Infectious Diseases, to come up with the best possible way to approach this public health problem.

The study consists of a core group of kids who are in the hospital being treated for MIS-C. We’re obtaining biospecimens and are committed to a central platform and data-sharing. There’s an arm of the study that’s looking at long-term issues. These kids have transient coronary artery dilation. They have a myocarditis. They have markers of heart failure. What does that imply long-term for the function of their hearts?

We will also be working with several existing networks to identify markers suggesting that a certain child is at risk. Is it an underlying immune issue, or is it ethnic background? Is it this a European genomic variant? Exactly what should we be concerned about?

Collins: Let me touch on the genomics part of this for a minute, and that requires a brief description. The SARS-CoV-2 novel coronavirus is crowned in spiky proteins that attach to our cells before infecting them. These spike proteins are made of many amino acids, and their precise sequential order can sometimes shift in subtle ways.

Within that sequential order at amino acid 614, a shift has been discovered. The original Chinese isolate, called the D version, had aspartic acid there. It seems the virus that spread from Asia to the U.S. West Coast also has aspartic acid in that position. But the virus that traveled to Italy and then to the East Coast of the U.S. has a glycine there. It’s called the G version.

There’s been a lot of debate about whether this change really matters. More data are starting to appear suggesting that the G version may be more infectious than the D version, although I’ve seen no real evidence of any difference in severity between the two.

Of course, if the change turned out to be playing a role in MIS-C, you would expect not to have seen so many cases on the West Coast. Has anyone looked to see if kids with the D version of the virus ever get MIS-C?

Bianchi: It hasn’t been reported. You could say that maybe we don’t get all the information from China. But we do get it from Japan. In Japan, they’ve had the D version, and they haven’t had MIS-C.

Collins: Let’s talk about expectant mothers. What is the special impact of COVID-19 on them?

Bianchi: Recently, a lot of information has come out about pregnant women and the developing fetus. A recent report from the Centers for Disease Control and Prevention suggested that pregnant women are at a greatly increased risk of hospitalization. However, the report didn’t divide out hospitalizations that would be expected for delivering a baby from hospitalizations related to illness. But the report did show that pregnant women are at a higher risk of needing respiratory support and having serious illness, particularly if there is an underlying chronic condition, such as chronic lung disease, diabetes or hypertension.

Collins: Do we know the risk of the mother transmitting the coronavirus to the fetus?

Bianchi: What we know so far is the risk of transmission from mother to baby appears to be small. Now, that’s based on the fact that available studies seem to suggest that the ACE2 receptor that the virus uses to bind to our cells, is not expressed in third trimester placental tissue. That doesn’t mean it’s not expressed earlier in gestation. The placenta is so dynamic in terms of gene expression.

What we do know is there’s a lot of ACE2 expression in the blood vessels. An interesting recent study showed in the third trimester placenta, the blood vessels had taken a hit. There was actual blood vessel damage. There was evidence of decreased oxygenation in the placenta. We don’t know the long-term consequences for the baby, but the placentas did not look healthy.

Collins: I have a friend whose daughter recently was ready to deliver her baby. As part of preparing for labor, she had a COVID-19 test. To her surprise and dismay, she was positive, even though she had no symptoms. She went ahead with the delivery, but then the baby was separated from her for a time because of a concern about the mother transmitting the virus to her newborn. Is separation widely recommended?

Bianchi: I think most hospitals are softening on this. [NOTE: The American Academy of Pediatrics recently issued revised recommendations about labor and delivery, as well as about breastfeeding, during COVID-19]

In the beginning, hospitals took a hard line. For example, no support people were allowed into the delivery room. So, women were having more home deliveries, which are far more dangerous, or signing up to give birth at hospitals that allowed support people.

Now more hospitals are allowing a support person in the room during delivery. But, in general, they are recommending that the mother and the support person get tested. If they’re negative, everything’s fine. If the support person is positive, he or she’s not allowed to come in. If the mother is positive, the baby is separated, generally, for testing. In many hospitals, mothers are given the option of reuniting with the baby.

There’s also been a general discussion about mothers who test positive breastfeeding. The more conservative recommendation is to pump the milk and allow somebody else to bottle-feed the baby while the mother recovers from the infection. I should also mention a recent meta-analysis in the United Kingdom. It suggested that a cesarean section delivery is not needed because of SARS-CoV-2 positivity alone. It also found there’s no reason for SARS-CoV-2 positive women not to breast feed.

Collins: Well, Diana, thank you so much for sharing your knowledge. If there’s one thing you wanted parents to take away from this conversation, what would that be?

Bianchi: Well, I think it’s natural to be concerned during a pandemic. But I think parents should be generally reassuring to their children. We’ll get through this. However, I would also say that if a parent notices something unusual going on with a child—skin rashes, the so-called blue COVID toes, or a prolonged fever—don’t mess around. Get your child medical attention as soon as possible. Bad things can happen very quickly to children infected with this virus.

For the expectant parents, hopefully, their obstetricians are counseling them about the fact that they are at high risk. I think that women with chronic conditions really need to be proactive. If they’re not feeling well, they need to go to the emergency room. Again, things can happen quickly with this virus.

But the good news is the babies seem to do very well. There’s no evidence of birth defects so far, and very limited evidence, if at all, of vertical transmission. I think they can feel good about their babies. They need to pay attention to themselves.

Collins: Thank you, Diana, for ending on those wise words.

Bianchi: Thanks, Francis.

Links:

Coronavirus (COVID-19) (NIH)

Diana W. Bianchi, MD, Biosketch of the NICHD Director (Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH)

Responding to COVID-19, Director’s Corner, NICHD, June 3, 2020

National Child & Maternal Health Education Program (NICHD)

Pregnancy (NICHD)


Meet the Researcher Leading NIH’s COVID-19 Vaccine Development Efforts

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A Conversation with John Mascola

A safe, effective vaccine is the ultimate tool needed to end the coronavirus disease 2019 (COVID-19) pandemic. Biomedical researchers are making progress every day towards such a vaccine, whether it’s devising innovative technologies or figuring out ways to speed human testing. In fact, just this week, NIH’s National Institute of Allergy and Infectious Diseases (NIAID) established a new clinical trials network that will enroll tens of thousands of volunteers in large-scale clinical trials testing a variety of investigational COVID-19 vaccines.

Among the vaccines moving rapidly through the development pipeline is one developed by NIAID’s Dale and Betty Bumpers Vaccine Research Center (VRC), in partnership with Moderna, Inc., Cambridge, MA. So, I couldn’t think of a better person to give us a quick overview of the COVID-19 vaccine research landscape than NIH’s Dr. John Mascola, who is Director of the VRC. Our recent conversation took place via videoconference, with John linking in from his home in Rockville, MD, and me from my place in nearby Chevy Chase. Here’s a condensed transcript of our chat:

Collins: Vaccines have been around since Edward Jenner and smallpox in the late 1700s. But how does a vaccine actually work to protect someone from infection?

Mascola: The immune system works by seeing something that’s foreign and then responding to it. Vaccines depend on the fact that if the immune system has seen a foreign protein or entity once, the second time the immune response will be much brisker. So, with these principles in mind, we vaccinate using part of a viral protein that the immune system will recognize as foreign. The response to this viral protein, or antigen, calls in specialized T and B cells, the so-called memory cells, and they remember the encounter. When you get exposed to the real thing, the immune system is already prepared. Its response is so rapid that you clear the virus before you get sick.

Collins: What are the steps involved in developing a vaccine?

Mascola: One can’t make a vaccine, generally speaking, without knowing something about the virus. We need to understand its surface proteins. We need to understand how the immune system sees the virus. Once that knowledge exists, we can make a candidate vaccine in the laboratory pretty quickly. We then transfer the vaccine to a manufacturing facility, called a pilot plant, that makes clinical grade material for testing. When enough testable material is available, we do a first-in-human study, often at our vaccine clinic at the NIH Clinical Center.

If those tests look promising, the next big step is finding a pharmaceutical partner to make the vaccine at large scale, seek regulatory approval, and distribute it commercially. That usually takes a while. So, from start to finish, the process often takes five or more years.

Collins: With this global crisis, we obviously don’t have five years to wait. Tell us about what the VRC started to do as soon as you learned about the outbreak in Wuhan, China.

Mascola: Sure. It’s a fascinating story. We had been talking with NIAID Director Dr. Anthony Fauci and our colleagues about how to prepare for the next pandemic. Pretty high on our list were coronaviruses, having already worked on past outbreaks of SARS and MERS [other respiratory diseases caused by coronaviruses]. So, we studied coronaviruses and focused on the unique spike protein crowning their surfaces. We designed a vaccine that presented the spike protein to the immune system.

Collins: Knowing that the spike protein was likely your antigen, what was your approach to designing the vaccine?

Mascola: Our approach was a nucleic acid-based vaccine. I’m referring to vaccines that are based on genetic material, either DNA or RNA. It’s this type of vaccine that can be moved most rapidly into the clinic for initial testing.

When we learned of the outbreak in Wuhan, we simply accessed the nucleic acid sequence of SARS-CoV-2, the novel coronavirus that causes COVID-19. Most of the sequence was on a server from Chinese investigators. We looked at the spike sequence and built that into an RNA vaccine. This is called in silico vaccine design. Because of our experience with the original SARS back in the 2000s, we knew its sequence and we knew this approach worked. We simply modified the vaccine design to the sequence of the spike protein of SARS-CoV-2. Literally within days, we started making the vaccine in the lab.

At the same time, we worked with a biotechnology company called Moderna that creates personalized cancer vaccines. From the time the sequence was made available in early January to the start of the first in-human study, it was about 65 days.

Collins: Wow! Has there ever been a vaccine developed in 65 days?

Mascola: I don’t think so. There are a lot of firsts with COVID, and vaccine development is one of them.

Collins: For the volunteers who enrolled in the phase 1 study, what was actually in the syringe?

Mascola: The syringe included messenger RNA (mRNA), the encoded instructions for making a specific protein, in this case the spike protein. The mRNA is formulated in a lipid nanoparticle shell. The reason is mRNA is less stable than DNA, and it doesn’t like to hang around in a test tube where enzymes can break it down. But if one formulates it just right into a nanoparticle, the mRNA is protected. Furthermore, that protective particle allows one to inject it into muscle and facilitates the uptake of the mRNA into the muscle cells. The cells translate the mRNA into spike proteins, and the immune system sees them and mounts a response.

Collins: Do muscle cells know how to take that protein and put it on their cell surfaces, where the immune system can see it?

Mascola: They do if the mRNA is engineered just the right way. We’ve been doing this with DNA for a long time. With mRNA, the advantage is that it just has to get into the cell [not into the nucleus of the cell as it does for DNA]. But it took about a decade of work to figure out how to do nucleotide silencing, which allows the cell to see the mRNA, not destroy it, and actually treat it as a normal piece of mRNA to translate into protein. Once that was figured out, it becomes pretty easy to make any specific vaccine.

Collins: That’s really an amazing part of the science. While it seems like this all happened in a blink of an eye, 65 days, it was built on years of basic science work to understand how cells treat mRNA. What’s the status of the vaccine right now?

Mascola: Early data from the phase 1 study are very encouraging. There’s a manuscript in preparation that should be out shortly showing that the vaccine was safe. It induced a very robust immune response to that spike protein. In particular, we looked for neutralizing antibodies, which are the ones that attach to the spike, blocking the virus from binding to a cell. There’s a general principle in vaccine development: if the immune system generates neutralizing antibodies, that’s a very good sign.

Collins: You’d be the first to say that you’re not done yet. Even though those are good signs, that doesn’t prove that this vaccine will work. What else do you need to know?

Mascola: The only real way to learn if a vaccine works is to test it in people. We break clinical studies into phases 1, 2, and 3. Phase 1 has already been done to evaluate safety. Phase 2 is a larger evaluation of safety and immune response. That’s ongoing and has enrolled 500 or 600 people, which is good. The plan for the phase 3 study will be to start in July. Again, that’s incredibly fast, considering that we didn’t even know this virus existed until January.

Collins: How many people do you need to study in a phase 3 trial?

Mascola: We’re thinking 20,000 or 30,000.

Collins: And half get the vaccine and half get a placebo?

Mascola: Sometimes it can be done differently, but the classic approach is half placebo, half vaccine.

Collins: We’ve been talking about the VRC-Moderna nucleic acid vaccine. But there are others that are coming along pretty quickly. What other strategies are being employed, and what are their timetables?

Mascola: There are many dozens of vaccines under development. The response has been extraordinary by academic groups, biotech companies, pharmaceutical companies, and NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership. I don’t think I’ve ever seen so much activity in a vaccine space moving ahead at such a rapid clip.

As far as being ready for advanced clinical trials, there are a just handful and they involve different types of vaccines. At least three nucleic acid vaccines are in clinical trials. There are also two vaccines that use proteins, which is a more classic approach.

In addition, there are several vaccines based on a viral vector. To make these, one puts the genes for the spike protein inside an adenovirus, which is an innocuous cold virus, and injects it into muscle. In regard to phase 3 trials, there are maybe three or four vaccines that could be formally in such tests by the fall.

Collins: How is it possible to do this so much more rapidly than in the past, without imposing risks?

Mascola: It’s a really important question, Francis. A number of things are being done in parallel, and that wouldn’t usually be the case. We can get a vaccine into a first-in-human study much more quickly because of time-saving technologies.

But the real important point is that for the phase 3 trial, there are no timesavers. One must enroll 30,000 people and watch them over months in a very rigorous, placebo-controlled environment. The NIH has stood up what’s called a Data Safety Monitoring Board for all the trials. That’s an independent group of investigators that will review all vaccine trial data periodically. They can see what the data are showing: Should the trial be stopped early because the vaccine is working? Is there a safety signal that raises concern?

While the phase 3 trial is going on, the U.S. government also will be funding large-scale manufacture of the vaccine. Traditionally, you would do the vaccine trial, wait until it’s all done, and analyze the data. If it worked, you’d build a vaccine plant to make enough material, which takes two or three years, and then go to the Food and Drug Administration (FDA) for regulatory approval.

Everything here is being done in parallel. So, if the vaccine works, it’s already in supply. And we have been engaging the FDA to get real-time feedback. That does save a lot of time.

Collins: Is it possible that we’ll manufacture a whole lot of doses that may have to be thrown out if the vaccine doesn’t work?

Mascola: It certainly is possible. One would like to think that for coronaviruses, vaccines are likely to work, in part because the natural immune response clears them. People get quite sick, but eventually the immune system clears the virus. So, if we can prime it with a vaccine, there is reason to believe vaccines should work.

Collins: If the vaccine does work, will this be for lifelong prevention of COVID-19? Or will this be like the flu, where the virus keeps changing and new versions of the vaccine are needed every year?

Mascola: From what we know about coronaviruses, we think it’s likely COVID-19 is not like the flu. Coronaviruses do have some mutation rate, but the data suggest it’s not as rapid as influenza. If we’re fortunate, the vaccine won’t need to be changed. Still, there’s the matter of whether the immunity lasts for a year, five years, or 10 years. That we don’t know without more data.

Collins: Do we know for sure that somebody who has had COVID-19 can’t get it again a few months later?

Mascola: We don’t know yet. To get the answer, we must do natural history studies, where we follow people who’ve been infected and see if their risk of getting the infection is much lower. Although classically in virology, if your immune system shows neutralizing antibodies to a virus, it’s very likely you have some level of immunity.

What’s a bit tricky is there are people who get very mild symptoms of COVID-19. Does that mean their immune system only saw a little bit of the viral antigen and didn’t respond very robustly? We’re not sure that everyone who gets an infection is equally protected. That’s going to require a natural history study, which will take about a year of follow-up to get the answers.

Collins: Let’s go back to trials that need to happen this summer. You talked about 20,000 to 30,000 people needing to volunteer just for one vaccine. Whom do you want to volunteer?

Mascola: The idea with a phase 3 trial is to have a broad spectrum of participation. To conduct a trial of 30,000 people is an enormous logistical operation, but it has been done for the rotavirus and HPV vaccines. When you get to phase 3, you don’t want to enroll just healthy adults. You want to enroll people who are representative of the diverse population that you want to protect.

Collins: Do you want to enrich for high-risk populations? They’re the ones for whom we hope the vaccine will provide greatest benefit: for example, older people with chronic illnesses, African Americans, and Hispanics.

Mascola: Absolutely. We want to make sure that we can feel comfortable to recommend the vaccine to at-risk populations.

Collins: Some people have floated another possibility. They ask why do we need expensive, long-term clinical trials with tens of thousands of people? Couldn’t we do a human challenge trial in which we give the vaccine to some healthy, young volunteers, wait a couple of weeks, and then intentionally expose them to SARS-CoV-2. If they don’t get sick, we’re done. Are challenge studies a good idea for COVID-19?

Mascola: Not right now. First, one has to make a challenge stock of the SARS-CoV-2 that’s not too pathogenic. We don’t want to make something in the lab that causes people to get severe pneumonia. Also, for challenge studies, it would be preferable to have a very effective small drug or antibody treatment on hand. If someone were to get sick, you could take care of the infection pretty readily with the treatments. We don’t have curative treatments, so the current thinking is we’re not there yet for COVID-19 challenge studies [1]. If you look at our accelerated timeline, formal vaccine trials still may be the fastest and safest way to get the answers.

Collins: I’m glad you’re doing it the other way, John. It’s going to take a lot of effort. You’re going to have to go somewhere where there is still ongoing spread, otherwise you won’t know if the vaccine works or not. That’s going to be tricky.

Mascola: Yes. How do we know where to test the vaccine? We are using predictive analytics, which is just a fancy way of saying that we are trying to predict where in the country there will be ongoing transmission. If we can get really good at it, we’ll have real-time data to say transmission is ongoing in a certain area. We can vaccinate in that community, while also possibly protecting people most at risk.

Collins: John, this conversation has been really informative. What’s your most optimistic view about when we might have a COVID-19 vaccine that’s safe and effective enough to distribute to the public?

Mascola: An optimistic scenario would be that we get an answer in the phase 3 trial towards the end of this year. We have scaled up the production in parallel, so the vaccine should be available in great supply. We still must allow for the FDA to review the data and be comfortable with licensing the vaccine. Then we must factor in a little time for distributing and recommending that people get the vaccine.

Collins: Well, it’s wonderful to have someone with your skills, experience, and vision taking such a leading role, along with your many colleagues at the Vaccine Research Center. People like Kizzmekia Corbett, Barney Graham, and all the others who are a part of this amazing team that you’ve put together, overseen by Dr. Fauci.

While there is still a ways to go, we can take pride in how far we have come since this virus emerged just about six months ago. In my 27 years at NIH, I’ve never seen anything quite like this. There’s been a willingness among people to set aside all kinds of other concerns. They’ve gathered around the same table, worked on vaccine design and implementation, and gotten out there in the real world to launch clinical trials.

John, thank you for what you are doing 24/7 to make this kind of progress possible. We’re all watching, hoping, and praying that this will turn out to be the answer that people desperately need after such a terribly difficult time so far in 2020. I believe 2021 will be a very different kind of experience, largely because of the vaccine science that we’ve been talking about today.

Mascola: Thank you so much, Francis. And thanks for recognizing all the people behind the scenes who are making this happen. They’re working really hard!

Reference:

[1] Accelerating Development of SARS-CoV-2 Vaccines—The Role for Controlled Human Infection Models. Deming ME, Michael, NL, Robb M, Cohen MS, Neuzil KM. N Engl J Med. 2020 July 1. [Epub ahead of print].

Links:

Coronavirus (COVID-19) (NIH)

John R. Mascola (National Institute of Allergy and Infectious Diseases/NIH)

Novel Vaccine Technologies for the 21st Century. Mascola JR, Fauci AS. Nat Rev Immunol. 2020 Feb;20(2):87-88.

Vaccine Research Center (NIAID/NIH)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)


Swimming with the High-Tech Sharks to Improve COVID-19 Testing

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At Home with Bruce Thromburg

So much has been reported over the past six months about testing for coronavirus disease 2019 (COVID-19) that keeping up with the issue can be a real challenge. To discuss the latest progress on new technologies for SARS-CoV-2 diagnostic testing in the United States, I spoke recently with NIH’s Dr. Bruce Tromberg, director of the National Institute of Biomedical Imaging and Bioengineering (NIBIB). Not only does Bruce run a busy NIH institute, he is helping to coordinate the national response for expanded testing during the COVID-19 pandemic.

Bruce also has a leading role in one of NIH’s most-exciting new initiatives. It’s called the Rapid Acceleration of Diagnostics (RADx) initiative, and it is on the fast track to bolster the country’s diagnostic testing capacity within months. Here’s a condensed transcript of our chat, which took place via videoconference, with Bruce linking in from Bethesda, MD and me from my home in Chevy Chase, MD:

Collins: Let’s start with how many COVID-19 tests are being done right now per day in the United States. By that, I’m referring to testing for the presence of the novel coronavirus, not antibodies as a sign of a previous infection.

Tromberg: The numbers fluctuate—anywhere from around 400,000 to 900,000 tests per day. So, the national capacity, with all these complex laboratory tests and emerging point-of-care assays, is getting close to 1 million a day. That’s substantially higher than in mid-April, when the nation was doing about 150,000 tests per day. But most testing is still being done in laboratories or complex facilities, and it can take a while for those tests to be run and for people to get answers. What we’d like to have are more convenient tests. We’d like to have tests that people can have at the point of care, where you get an answer on the spot and very quickly, or tests that can be performed easily in their homes.

Collins: Yes, we’d all love to have point-of-care tests for COVID-19. And there are some out there already. Every time I go to the White House, they have this gadget, called Abbott ID Now, that gives a result in about 15 minutes. That sounds pretty good. Do we just need to make more of those machines to solve the problem?

Tromberg: Abbott ID Now is one of the first point-of-care technologies. It’s not complicated, so a specialized laboratory isn’t required to run them. That’s what makes Abbott ID Now very appealing, but its performance could be better. There’s a bit of a risk when it’s used in individuals for which you really need to know, with absolute certainty, if they have the virus or not. Those performance issues have created opportunities to build platforms that are better, faster, and possible for people to do on their own.

Collins: Congress provided a big infusion of resources last April to assist in the development of new diagnostic technologies for COVID-19. A lot of that infusion came to NIH, and, Bruce, you were asked to step in and make something amazing happen on a timetable that’s pretty breathtaking. It’s called the RADx Initiative. Tell us a little about that.

Tromberg: RADx is short for Rapid Acceleration of Diagnostics. The goal of the initiative is to make it possible for everyone to have access to diagnostic testing for COVID-19 as easily and quickly as possible. As we pivot to doing surveillance in large populations, we will need greater testing capacity to help optimize the management of each individual. So, that’s really the aim of RADx, or RADx-tech, which is a special flavor of RADx.

Collins: Right, the goal of RADx-tech, which you are overseeing, is to identify some of these exciting new technologies and help scale them up quickly to the point where they can help people across the nation. Could you give us some examples?

Tromberg: Sure. One general class of technologies is called a lateral flow assay. These tests are small enough to fit in your hand and come in a convenient container. Basically, you can use a swab from your oral cavity and place it on one of the pads, and then you add a little bit of solution. The actual assay itself has a membrane inside of a little plastic container. The fluid flows across the membrane, and there’s chemistry that goes on inside the container to detect, for example, genetic material from the coronavirus. So, it can tell you if there is a presence of virus inside the swab. It’s very quick and straightforward. A line will “light up” if virus is present.

Another type of lateral flow assay, also small enough to hold in your hand, looks for proteins on the surface of the virus. You don’t have to break up the virus particle itself, but in this specific example, what captures the virus in this membrane is what’s called an aptamer. An aptamer is similar to an antibody, except it’s made from nucleic acid. It’s designed to bind very tightly with any molecule of interest. If you put a saliva sample into this assay, it moves up the membrane and some chemistry takes place. And then, you’ll see a line appear if there’s presence of a virus.

Collins: You just said saliva. I think a lot of people would much prefer, if they had to provide a sample, to use saliva instead of having a swab stuck in their nose, especially if it has to go all the way to the back of the nose. Does saliva work?

Tromberg: We hope so. Right now, RADx-tech has at least nine companies that are in what we call phase one, which is a significant step towards commercialization. Of those companies, more than half are looking at saliva or other kinds of sampling that’s not sticking swabs way up into the nasal cavity.

Another type of test is a lateral flow assay that fits directly into a mobile device like a tablet. It has a separate lateral flow apparatus, which looks like an elongated zip drive, and it slides right into the tablet itself. It’s something that’s not complicated. It would be easy to do at home. But rather than watching for the presence of a reaction, you look for a light inside the tablet to say the result is ready. And then, there is another color of light that comes directly from the lateral flow strip, that’s an indicator that the virus is present.

One last example is a nucleic acid test. This rectangular, hand-held device (see photo), reminiscent of a computer disc, looks inside the virus to amplify small traces of its nucleic acid to detectable levels. It is completely self-contained. To find that technology today, you generally must go to complex laboratories where the test is done on big machines, operated in multiple steps. Efforts are being made to reduce the size and the complexity of these devices so they can move out to point of care, without sacrificing the performance that we expect from a laboratory-based device.

Collins: That’s totally cool. Is the nucleic-acid test device that you just mentioned made for one-time use, and then you throw it away?

Tromberg: That’s their business model right now. I should probably mention something about cost. For example, you can imagine scaling up lateral flow assays very quickly to make tens of millions of tests. The components are inexpensive, and the tests may cost just a few dollars to make.

If you’re throwing away a nucleic acid test with its more-expensive components, obviously, the cost will be higher. Right now, if you go to a laboratory for a nucleic acid test, the cost may be on the order of $40 or so. With these one-time-use nucleic acid tests, the aim is to scale up the manufacturing to produce larger volumes that will bring the cost down. The estimates are maybe $60 per test.

Collins: That needs to come down more, obviously. In the months ahead, we’re talking about testing millions of people, maybe even fairly often to make sure that they haven’t been infected by SARS-CoV-2, the novel coronavirus that causes COVID-19. Is frequent testing the kind of thing that you’d like to be able to do by next fall?

Tromberg: Yes, and I think that that really speaks to the diversity of the types of tests that we need. I think there is a market, or the capacity, for some of the more expensive tests, if they’re extremely accurate and convenient. So, the nucleic acid test may cost more, but it will give you an answer very quickly and with very high sensitivity. It’s also very convenient. But the performance of that test may be very different from a standard lateral flow assay. Those tests will be far more accessible and very, very inexpensive, but they may have a higher false negative rate. We envision that every test that comes out of our innovation funnel will have documentation about its best-use case.

Collins: You mentioned your innovation funnel, sometimes called a “shark tank.” Say a little more about the RADx-tech shark tank. Who gets into it, and what happens when they get there?

Tromberg: At NIH, we’re into processes, and NIBIB created a very effective one 13 years ago with the Point of Care Technology Research Network (POCTRN). We’ve now leveraged this network to focus almost exclusively on COVID testing. POCTRN has five sites in the US. All have core resources, personnel, and expertise that are contributing to RADx-tech. Those include the ability to validate tests independently, the ability to do clinical studies in real-world samples and patients, and the ability to analyze manufacturing and scale-up needs while creating a roadmap for every project team to follow.

We have more than 200 people around the country working day and night on this process. If anyone has an idea about a COVID-19 test, you can and apply for funding on the POCTRN website. Your application will be reviewed by a panel of 30 experts within a day and, if approved, will move to the next stage, which is the shark tank.

In the shark tank [also called phase zero], a team of experts will spend about 150 to 200 person-hours with you evaluating the strengths and weaknesses of your test technically, clinically, and commercially. From this careful analysis, a detailed proposal will be presented to a steering committee, then sent to NIH. If we think it’s a great idea, the project will enter what we call phase one, with considerable financial support and the expectation that the company will hit its validation milestones within a month.

Collins: How far have things progressed, given that you just started RADx on April 29?

Tromberg: We have almost 60 projects that have entered or emerged from this shark-tank stage. I’m expecting that we’ll have around 15 projects in the phase one stage this month, and it’s very exciting to see them move there. If they can reach their validation milestones in that first month, they will be eligible to move to phase two. It involves a much larger chunk of money, so companies can move into manufacturing and scale up for distribution. We’re hoping to have between five and 10 companies emerge over time from this innovation funnel. But, by the end of the summer, we’d like to see at least two come out with products that will make a difference.

Collins: Wow, that’s just a few months away. How will you can get there so fast?

Tromberg: Sure. Some companies are further along than others. I can think of one that is quite far along with an established platform concept. This company has lots of expertise and has raised lots of money. We may be able to give them the surge that they need, plus the additional support with regulatory issues, commercialization, and manufacturing, in that short period of time to go to market.

Complementing that work is another of our initiatives called Advanced Technology Platforms (RADx-ATP). It’s designed to scale up existing technologies. For example, I mentioned a one-time-use nucleic acid test. It still needs validation, emergency use authorization, a little bit of manufacturing optimization. But we have other platforms out there that are much closer to commercialization, and RADx-ATP could be very impactful in getting some of those technologies out earlier.

Collins: You mentioned RADx-ATP, and we’ve been talking about RADx-tech, which is your shark tank approach. But there are a couple of other RADx components. Say something about those, please.

Tromberg: Our centerpiece component for doing demonstration projects is called RADx-UP. This is an effort across NIH to provide cutting-edge testing technologies in underserved populations. If I’m allowed to be the interviewer and turn the tables, I might bounce the question back to you. This is where your thinking directly influenced the whole RADx portfolio. So, maybe you can tell us more.

Collins: I can try. It’s very clear that COVID-19 has hit certain populations particularly hard, especially African American and Hispanic communities. And yet, those communities often have the least access to testing, which is sort of upside-down. We want to help identify people who are infected quickly, do the quarantining, and prevent the infection from spreading. That has simply not worked very well in a lot of underserved communities.

With resources from Congress, we made it a very high priority to set up demonstration projects of these advanced technologies in communities that would benefit significantly from them. We’re trying to bring together two really important NIH priorities: technology development and addressing health disparities. I’ve got to say, at this particular moment, when we’re all really focused on the fact that our nation is still riddled with health disparities, health inequities, and even racism, this is a moment where we should be doing everything we can to try to take our scientific capabilities and apply them to finding solutions.

So, we’re all pretty excited about RADx-UP. But there’s one other RADx, and I’ll throw this one back to you. It’s called RADx-rad. What the heck is that, Bruce?

Tromberg: Well, RADx-rad is the home for the technologies that are really far forward and futuristic. These are the technologies that won’t quite be ready for the time pressure of the innovation funnel. But they’re fantastic ideas. They’re projects that may be non-traditional in terms of the application of technology. They have been generated largely by other NIH institutes and centers. They’re important ideas and projects that just need to be supported with a longer time-window of return. We don’t want to lose out on the energy and the ideas and the creativity of those concepts.

Collins: Right now, the focus is on COVID-19 and the need for testing, especially within this calendar year. We hope, by the end of 2020 or the early part of 2021, to have vaccines for COVID-19 ready to go. But, moving forward, there will be other events that will probably make us wish that we had point-of-care diagnostics. So, in the process of doing what you’re doing with all of these components, hopefully we’re also preparing for future challenges.

Bruce, you’re an optimistic guy. At the same time, we’ve got to be realistic. Around September, when schools and colleges are contemplating whether it’s safe to open up, what would we hope that RADx could contribute to make that a better outcome?

Tromberg: That’s a tough question to answer, but I have a lot of confidence in our process. I’m confident that we’re engaging the innovation and entrepreneurial community in such a way that a lot of these ideas will move out and give us better performing tests and more of them. A rough number that I like to think about is the capacity to test roughly 2 percent of the population, around 6 million people per day. I think we’ll hit that target by the end of the year.

I’d like to see testing technologies move away from being based predominantly in laboratories. I’d like to see them more accessible to people as technologies that they can use in their homes. We’re now doing so many things from home. We’re working from home, we’re talking from home, we get our entertainment from home. Home-based testing is really the direction a lot of healthcare is going. We need to have these technologies. I think the level of sophistication and performance that we’re hoping for is possible, and the innovation and entrepreneurial community is working extremely hard to make it happen. No one has really asked us to do anything of this scale before, and I like to compare it to our Super Bowl.

Collins: Well, this is one exciting Super Bowl, that’s for sure! You’ve applied the venture capitalist strategy to RADx of trying to discover what’s out there, while not being afraid to invest in risky endeavors. You’re figuring out how to help promising technologies take their best shot and fail early, if they’re going to fail. And for technologies that are further along, you give them the needed resources to advance to commercialization.

We have great hopes and expectations that RADx will make a real difference. What we’re doing here is not just about cool science, it’s also about saving lives. I want to thank you for your incredible dedication, and your intellectual and engineering contributions to this initiative, which make it one of the most exciting things that NIH is doing right now.

Tromberg: Thank you, Francis.

Links:

Coronavirus (COVID-19) (NIH)

Rapid Acceleration of Diagnostics (RADx)

Social engineering and bioengineering together can thwart the COVID-19 pandemic,” Director’s Corner, National Institute of Biomedical Imaging and Bioengineering/NIH)

Video: RADx Tech and POCTRN: Diagnosing Disease-Delivering Health (NIBIB/NIH)


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