ACTIV
Meet the Researcher Leading NIH’s COVID-19 Vaccine Development Efforts
Posted on by Dr. Francis Collins
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)
Finding Antibodies that Neutralize SARS-CoV-2
Posted on by Dr. Francis Collins
It’s now clear that nearly everyone who recovers from coronavirus disease 2019 (COVID-19) produces antibodies that specifically target SARS-CoV-2, the novel coronavirus that causes the infection. Yet many critical questions remain. A major one is: just how well do those particular antibodies neutralize the virus to fight off the infection and help someone recover from COVID-19? Fortunately, most people get better—but should the typical antibody response take the credit?
A new NIH-funded study of nearly 150 people who recovered from COVID-19 offers some essential insight. The study, published in the journal Nature, shows that most people, in fact, do produce antibodies that can effectively neutralize SARS-CoV-2. But there is a catch: 99 percent of the study’s participants didn’t make enough neutralizing antibodies to mount an ideal immune response.
The good news is that when researchers looked at individuals who mounted a strong immune response, they were able to identify three antibodies (depicted above) that were extremely effective at neutralizing SARS-CoV-2. By mass-producing copies of these antibodies as so-called monoclonal antibodies, the researchers can now better evaluate their potential as treatments to help people who don’t make strongly neutralizing antibodies, or not enough of them.
These findings come from a team led by Michel Nussenzweig, Paul Bieniasz, and Charles Rice at The Rockefeller University, New York, and Pamela Bjorkman at the California Institute of Technology, Pasadena. In the Nussenzweig lab, the team has spent years searching for broadly neutralizing antibodies against the human immunodeficiency virus (HIV). In response to the COVID-19 pandemic and its great urgency, Nussenzweig and team shifted their focus recently to look for promising antibodies against SARS-CoV-2.
Antibodies are blood proteins that the immune system makes to neutralize viruses or other foreign invaders. The immune system doesn’t make just one antibody to thwart an invader; it makes a whole family of antibodies. But not all antibodies in that family are created equal. They can vary widely in where they latch onto a virus like SARS-CoV-2, and that determines how effective each will be at blocking it from infecting human cells. That’s one reason why people respond differently to infections such as COVID-19.
In early April, Nussenzweig’s team began analyzing samples from volunteer survivors who visited The Rockefeller Hospital to donate plasma, which contains the antibodies. The volunteers had all recovered from mild-to-severe cases of COVID-19, showing their first signs of illness about 40 days prior to their first plasma collection.
Not surprisingly, all volunteers had produced antibodies in response to the virus. To test the strength of the antibodies, the researchers used a special assay that shows how effective each one is at blocking the virus from infecting human cells in lab dishes.
Overall, most of the plasma samples—118 of 149—showed at best poor to modest neutralizing activity. In about one-third of individuals, their plasma samples had below detectable levels of neutralizing activity. It’s possible those individuals just resolved the infection quickly, before more potent antibodies were produced.
More intriguing to the researchers were the results from two individuals that showed an unusually strong ability to neutralize SARS-CoV-2. Among these two “elite responders” and four other individuals, the researchers identified 40 different antibodies that could neutralize SARS-CoV-2. But again, not all antibodies are created equal. Three neutralized the virus even when present at extremely low levels, and they now will be studied further as possible monoclonal antibodies.
The team determined that those strongly neutralizing antibodies bind three distinct sites on the receptor-binding domain (RBD) of the coronavirus spike protein. This portion of the virus is important because it allows SARS-CoV-2 to bind and infect human cells. Importantly, when the researchers looked more closely at plasma samples with poor neutralizing ability, they found that they also contained those RBD-binding antibodies, just not in very large numbers.
These findings help not only to understand the immune response to COVID-19, they are also critical for vaccine design, revealing what a strong neutralizing antibody for SARS-CoV-2 should look like to help the immune system win. If a candidate vaccine can generate such strongly neutralizing antibodies, researchers will know that they are on the right track.
While this research showed that there’s a lot of variability in immune responses to SARS-CoV-2, it appears that most of us are inherently capable of producing antibodies to neutralize this devastating virus. That brings more reason for hope that the many vaccines now under study to elicit such neutralizing antibodies in sufficient numbers may afford us with much-needed immune protection.
Reference:
[1] Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Robbiani DF, Gaebler C, Muecksch F, et al. Nature. 2020 Jun 18. [Published online ahead of print].
Links:
Coronavirus (COVID-19) (NIH)
Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)
Nussenzweig Lab (The Rockefeller University, New York)
Bjorkman Lab (California Institute of Technology, Pasadena)
NIH Support: National Institute of Allergy and Infectious Diseases
Searching for Ways to Prevent Life-Threatening Blood Clots in COVID-19
Posted on by Dr. Francis Collins
Six months into the coronavirus disease 2019 (COVID-19) pandemic, researchers still have much to learn about the many ways in which COVID-19 can wreak devastation on the human body. Among the many mysteries is exactly how SARS-CoV-2, which is the novel coronavirus that causes COVID-19, triggers the formation of blood clots that can lead to strokes and other life-threatening complications, even in younger people.
Recently, I had a chance to talk with Dr. Gary Gibbons, Director of NIH’s Heart, Lung, and Blood Institute (NHLBI) about what research is being done to tackle this baffling complication of COVID-19. Our conversation took place via videoconference, with him connecting from his home in Washington, D.C., and me linking in from my home just up the road in Maryland. Here’s a condensed transcript of our chat:
Collins: I’m going to start by asking about the SARS-CoV-2-induced blood clotting not only in the lungs, but in other parts of the body. What do we know about the virus that would explain this?
Gibbons: It seems like every few weeks another page gets turned on COVID-19, and we learn even more about how this virus affects the body. Blood clots are one of the startling and, unfortunately, devastating complications that emerged as patients were cared for, particularly in New York City. It became apparent that certain individuals had difficulty getting enough oxygen into their system. The difficulty couldn’t be explained entirely by the extent of the pneumonia affecting the lungs’ ability to exchange oxygen.
It turned out that, in addition to the pneumonia, blood clots in the lungs were compromising oxygenation. But some patients also had clotting, or thrombotic, complications in their veins and arteries in other parts of the body. Quite puzzling. There were episodes of relatively young individuals in their 30s and 40s presenting with strokes related to blood clots affecting the arterial circulation to the brain.
We’re still trying to understand what promotes the clotting. One clue involves the endothelial cells that form the inner lining of our blood vessels. These cells have on their surface a protein called the angiotensin-converting enzyme 2 (ACE2) receptor, and this clue is important for two reasons. One, the virus attaches to the ACE2 receptor, using it as an entry point to infect cells. Two, endothelial-lined blood vessels extend to every organ in the body. Taken together, it seems that some COVID-19 complications relate to the virus attaching to endothelial cells, not only in the lungs, but in the heart and multiple organs.
Collins: So, starting in the respiratory tree, the virus somehow breaks through into a blood vessel and then gets spread around the body. There have been strange reports of people with COVID-19 who may not get really sick, but their toes look frostbitten. Is “COVID toes,” as some people call it, also part of this same syndrome?
Gibbons: We’re still in the early days of learning about this virus. But I think this offers a further clue that the virus not only affects large vessels but small vessels. In fact, clots have been reported at the capillary level, and that’s fairly unusual. It’s suggestive that an interaction is taking place between the platelets and the endothelial surface.
Normally, there’s a tightly regulated balance in the bloodstream between pro-coagulant and anticoagulant proteins to prevent clotting and keep the blood flowing. But when you cut your finger, for example, you get activation for blood clots in the form of a protein mesh. It looks like a fishing net that can help seal the injury. In addition, platelets in the blood stream help to plug the holes in that fishing net and create a real seal of a blood vessel.
Well, imagine it happening in those small vessels, which usually have a non-stick endothelial surface, almost like Teflon, that prevents clotting. Then the virus comes along and tips the balance toward promoting clot formation. This disturbs the Teflon-like property of the endothelial lining and makes it sticky. It’s incredible the tricks this virus has learned by binding onto one of these molecules in the endothelial lining.
Collins: Who are the COVID-19 patients most at risk for this clotting problem?
Gibbons: Unfortunately, it appears right now that older adults are among the most vulnerable. They have a lot of the risks for the formation of these blood clots. What’s notable is these thrombotic complications are also happening to relatively young adults or middle-aged individuals who don’t have a lot of other chronic conditions, or comorbidities, to put them at higher risk for severe disease. Again, it’s suggestive that this virus is doing something that is particular to the coagulation system.
Collins: We’d love to have a way of identifying in advance the people who are most likely to get into trouble with blood clotting. They might be the ones you’d want to start on an intervention, even before you have evidence that things are getting out of control. Do you have any kind of biomarker to tell you which patients might benefit from early intervention?
Gibbons: Biomarkers are being actively studied. What we do know from some earlier observations is that you can assess the balance of clotting and anticlotting factors in the blood by measuring a biomarker called D-dimer. It’s basically a protein fragment, a degradation product, from a prior clot. It tells you a bit about the system’s activity in forming and dissolving clots.
If there’s a lot of D-dimer activity, it suggests a coagulation cascade is jazzed up. In those patients, it’s probably a clue that this is a big trigger in terms of coagulation and thrombosis. So, D-dimer levels could maybe tell us which patients need really aggressive full anticoagulation.
Collins: Have people tried empirically using blood thinners for people who seem to be getting into trouble with this clotting problem?
Gibbons: There’s a paper out of the Mount Sinai in New York City that looked at thousands of patients being treated for COVID-19 [1]. Based on clinical practice and judgments, one of the striking findings is that those who were fully anticoagulated had better survival than those who were not. Now, this was not a randomized, controlled clinical trial, where some were given full anticoagulation and others were not. It was just an observational study that showed an association. But this study indicated indirectly that by giving the blood thinners, changing that thrombotic risk, maybe it’s possible to reduce morbidity and mortality. That’s why we need to do a randomized, controlled clinical trial to see if it can be used to reduce these case fatality rates.
Collins: You and your colleagues got together and came up with a design for such a clinical trial. Tell us about that.
Gibbons: My institute studies the heart, lung, and blood. The virus attacks all three. So, our community has a compelling need to lean in and study COVID-19. Recently, NIH helped to launch a public-private partnership called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV). As the name spells out, this initiative provides is a clinical platform to generate life-saving treatments as we wait for the development of a vaccine.
Through ACTIV, a protocol is now in the final stages of review for a clinical trial that will involve a network of hospitals and explore the question: is it sufficient to try a low-dose thrombo-prophylactic, or clot preventative, approach versus full anticoagulation? Some think patients ought to have full anticoagulation, but that’s not without risk. So, we want to put that question to the test. As part of that, we’ll also learn more about biomarkers and what could be predictive of individuals getting the greatest benefit.
If we find that fully anticoagulating patients prevents clots, then that’s great. But it begs the question: what happens when patients go home? Is it sufficient to just turn off the drip and let them go their merry way? Should they have a low dose thrombo-prophylactic regimen for a period of time? If so, how long? Or should they be fully anticoagulated with oral anticoagulation for a certain period of time? All these and other questions still remain.
Collins: This can make a huge difference. If you’re admitted to the hospital with COVID-19, that means you’re pretty sick and, based on the numbers that I’ve seen, your chance of dying is about 12 percent if nothing else happens. If we can find something like an anticoagulant that would reduce that risk substantially, we can have a huge impact on reducing deaths from COVID-19. How soon can we get this trial going, Gary?
Gibbons: We have a sense of urgency that clearly this pandemic is taking too many lives and time is of the essence. So, we’ve indeed had a very streamlined process. We’re leveraging the fact that we have clinical trial networks, where regardless of what they were planning to do, it’s all hands on deck. As a result, we’re able to move faster to align with that sense of urgency. We hope that we can be off to a quick launch within the next two to three weeks with the anticoagulation trials.
Collins: This is good because people are waiting on the vaccines, but realistically we won’t know whether the vaccines are working for several more months, and having them available for lots of people will be at the very end of this year or early 2021 at best. Meanwhile, people still are going to be getting sick with COVID-19. We want to be able to have as many therapeutic options as possible to offer to them. And this seems like a pretty exciting one to try and move forward as quickly as possible. You and your colleagues deserve a lot of credit for bringing this to everybody’s attention.
But before we sign off, I have to raise another issue of deep significance. Gary, I think both of us are struggling not only with the impact of COVID-19 on the world, but the profound sorrow, grief, frustration, and anger that surrounds the death of George Floyd. This brings into acute focus the far too numerous other circumstances where African Americans have been mistreated and subjected to tragic outcomes.
This troubling time also shines a light on the health disparities that affect our nation in so many ways. We can see what COVID-19 has done to certain underrepresented groups who have borne an undue share of the burden, and have suffered injustices at the hands of society. It’s been tough for many of us to admit that our country is far from treating everyone equally, but it’s a learning opportunity and a call to redouble our efforts to find solutions.
Gary, you’ve been a wonderful leader in that conversation for a long time. I want to thank you both for what you’re doing scientifically and for your willingness to speak the truth and stand up for what’s right and fair. It’s been great talking to you about all these issues.
Gibbons: Thank you. We appreciate this opportunity to fulfill NIH’s mission of turning scientific discovery into better health for all. If there’s any moment that our nation needs us, this is it.
Reference:
[1] Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19. Paranjpe I, Fuster V, Lala A, Russak A, Glicksberg BS, Levin MA, Charney AW, Narula J, Fayad ZA, Bagiella E, Zhao S, Nadkarni GN. J Am Coll Cardiol. 2020 May 5;S0735-1097(20)35218-9.
Links:
Coronavirus (COVID-19) (NIH)
“Rising to the Challenge of COVID-19: The NHLBI Community Response,” Director’s Messages, National Heart, Lung, and Blood Institute/NIH, April 29, 2020.
Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)
Discussing the Need for Reliable Antibody Testing for COVID-19
Posted on by Dr. Francis Collins
There’s been a great deal of discussion about whether people who recover from coronavirus disease 2019 (COVID-19), have neutralizing antibodies in their bloodstream to guard against another infection. Lots of interesting data continue to emerge, including a recent preprint from researchers at Sherman Abrams Laboratory, Brooklyn, NY [1]. They tested 11,092 people for antibodies in May at a local urgent care facility and found nearly half had long-lasting IgG antibodies, a sign of exposure to the novel coronavirus SARS-CoV-2, the cause of COVID-19. The researchers also found a direct correlation between the severity of a person’s symptoms and their levels of IgG antibodies.
This study and others remind us of just how essential antibody tests will be going forward to learn more about this challenging pandemic. These assays must have high sensitivity and specificity, meaning there would be few false negatives and false positives, to tell us more about a person’s exposure to SARS-CoV-2. While there are some good tests out there, not all are equally reliable.
Recently, I had a chance to discuss COVID-19 antibody tests, also called serology tests, with Dr. Norman “Ned” Sharpless, Director of NIH’s National Cancer Institute (NCI). Among his many talents, Dr. Sharpless is an expert on antibody testing for COVID-19. You might wonder how NCI got involved in COVID-19 testing. Well, you’re going to find out. Our conversation took place while videoconferencing, with him connecting from North Carolina and me linking in from my home in Maryland. Here’s a condensed transcript of our chat:
Collins: Ned, thanks for joining me. Maybe we should start with the basics. What are antibodies anyway?
Sharpless: Antibodies are proteins that your body makes as part of the learned immune system. It’s the immunity that responds to a bacterium or a virus. In general, if you draw someone’s blood after an infection and test it for the presence of these antibodies, you can often know whether they’ve been infected. Antibodies can hang around for quite a while. How long exactly is a topic of great interest, especially in terms of the COVID-19 pandemic. But we think most people infected with coronavirus will make antibodies at a reasonably high level, or titer, in their peripheral blood within a couple of weeks of the infection.
Collins: What do antibodies tell us about exposure to a virus?
Sharpless: A lot of people with coronavirus are infected without ever knowing it. You can use these antibody assays to try and tell how many people in an area have been infected, that is, you can do a so-called seroprevalence survey.
You could also potentially use these antibody assays to predict someone’s resistance to future infection. If you cleared the infection and established immunity to it, you might be resistant to future infection. That might be very useful information. Maybe you could make a decision about how to go out in the community. So, that part is of intense interest as well, although less scientifically sound at the moment.
Collins: I have a 3D-printed model of SARS-CoV-2 on my desk. It’s sort of a spherical virus that has spike proteins on its surface. Do the antibodies interact with the virus in some specific ways?
Sharpless: Yes, antibodies are shaped like the letter Y. They have two binding domains at the head of each Y that will recognize something about the virus. We find antibodies in the peripheral blood that recognize either the virus nucleocapsid, which is the structural protein on the inside; or the spikes, which stick out and give coronavirus its name. We know now that about 99 percent of people who get infected with the virus will develop antibodies eventually. Most of those antibodies that you can detect to the spike proteins will be neutralizing, which means they can kill the virus in a laboratory experiment. We know from other viruses that, generally, having neutralizing antibodies is a promising sign if you want to be immune to that virus in the future.
Collins: Are COVID-19 antibodies protective? Are there reports of people who’ve gotten better, but then were re-exposed and got sick again?
Sharpless: It’s controversial. People can shed the virus’s nucleic acid [genetic material], for weeks or even more than a month after they get better. So, if they have another nucleic acid test it could be positive, even though they feel better. Often, those people aren’t making a lot of live virus, so it may be that they never stopped shedding the virus. Or it may be that they got re-infected. It’s hard to understand what that means exactly. If you think about how many people worldwide have had COVID-19, the number of legitimate possible reinfection cases is in the order of a handful. So, it’s a pretty rare event, if it happens at all.
Collins: For somebody who does have the antibodies, who apparently was previously infected, do they need to stop worrying about getting exposed? Can they can do whatever they want and stop worrying about distancing and wearing masks?
Sharpless: No, not yet. To use antibodies to predict who’s likely to be immune, you’ve got to know two things.
First: can the tests actually measure antibodies reliably? I think there are assays available to the public that are sufficiently good for asking this question, with an important caveat. If you’re trying to detect something that’s really rare in a population, then any test is going to have limitations. But if you’re trying to detect something that’s more common, as the virus was during the recent outbreak in Manhattan, I think the tests are up to the task.
Second: does the appearance of an antibody in the peripheral blood mean that you’re actually immune or you’re just less likely to get the virus? We don’t know the answer to that yet.
Collins: Let’s be optimistic, because it sounds like there’s some evidence to support the idea that people who develop these antibodies are protected against infection. It also sounds like the tests, at least some of them, are pretty good. But if there is protection, how long would you expect it to last? Is this one of those things where you’re all set for life? Or is this going to be something where somebody’s had it and might get it again two or three years from now, because the immunity faded away?
Sharpless: Since we have no direct experience with this virus over time, it’s hard to answer. The potential for this cell-based humoral immunity to last for a while is there. For some viruses, you have a long-lasting antibody protection after infection; for other viruses, not so much.
So that’s the unknown thing. Is immunity going to last for a while? Of course, if one were to bring up the topic of vaccines, that’s very important to know, because you would want to know how often one would have to give that vaccine, even under optimal circumstances.
Collins: Yes, our conversation about immunity is really relevant to the vaccines we’re trying to develop right now. Will these vaccines be protective for long periods of time? We sure hope so, but we’ve got to look carefully at the issue. Let’s come back, though, to the actual performance of the tests. The NCI has been right in the middle of trying to do this kind of validation. How did that happen, and how did that experience go?
Sharpless: Yes, I think one might ask: why is the National Cancer Institute testing antibody kits for the FDA? It is unusual, but certainly not unheard of, for NCI to take up problems like this during a time of a national emergency. During the HIV era, NCI scientists, along with others, identified the virus and did one of the first successful compound screens to find the drug AZT, one of the first effective anti-HIV therapies.
NCI’s Frederick National Lab also has a really good serology lab that had been predominantly working on human papillomavirus (HPV). When the need arose for serologic testing a few months ago, we pivoted that lab to a coronavirus serology lab. It took us a little while, but eventually we rounded up everything you needed to create positive and negative reference panels for antibody testing.
At that time, the FDA had about 200 manufacturers making serology tests that hoped for approval to sell. The FDA wanted some performance testing of those assays by a dispassionate third party. The Frederick National Lab seemed like the ideal place, and the manufacturers started sending us kits. I think we’ve probably tested on the order of 20 so far. We give those data back to the FDA for regulatory decision making. They’re putting all the data online.
Collins: How did it look? Are these all good tests or were there some clunkers?
Sharpless: There were some clunkers. But we were pleased to see that some of the tests appear to be really good, both in our hands and those of other groups, and have been used in thousands of patients.
There are a few tests that have sensitivities that are pretty high and specificities well over 99 percent. The Roche assay has a 99.8 percent specificity claimed on thousands of patients, and for the Mt. Sinai assay developed and tested by our academic collaborators in a panel of maybe 4,000 patients, they’re not sure they’ve ever had a false positive. So, there are some assays out there that are good.
Collins: There’s been talk about how there will soon be monoclonal antibodies directed against SARS-CoV-2. How are those derived?
Sharpless: They’re picked, generally, for appearing to have neutralizing activity. When a person makes antibodies, they don’t make one antibody to a pathogen. They make a whole family of them. And those can be individually isolated, so you can know which antibodies made by a convalescent individual really have virus-neutralizing capacity. That portion of the antibody that recognizes the virus can be engineered into a manufacturing platform to make monoclonal antibodies. Monoclonal means one kind of antibody. That approach has worked for other infectious diseases and is an interesting idea here too.
Collins: I can say a bit about that, because we are engaged in a partnership with industry and FDA called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV). One of the hottest ideas right now is monoclonal antibodies, and we’re in the process of devising a master protocol, one for outpatients and one for inpatients.
Janet Woodcock of Operation Warp Speed tells me 21 companies are developing monoclonal antibodies. While doing these trials, we’d love to do comparisons, which is why it’s good to have an organization like ACTIV to bring everybody together, making sure you’re using the same endpoints and the same laboratory measures. I think that, maybe even by late summer, we might have some results. For people who are looking at what’s the next most-hopeful therapeutic option for people who are really sick with COVID-19, so far we have remdesivir. It helps, but it’s not a home run. Maybe monoclonal antibodies will be the next thing that really gives a big boost in survival. That would be the hope.
Ned, let me ask you one final question about herd, or group, immunity. One hears a bit about that in terms of how we are all going to get past this COVID-19 pandemic. What’s that all about?
Sharpless: Herd immunity is when a significant portion of the population is immune to a pathogen, then that pathogen will die out in the population. There just aren’t enough susceptible people left to infect. What the threshold is for herd immunity depends on how infectious the virus is. For a highly infectious virus, like measles, maybe up to 90 percent of the population must be immune to get herd immunity. Whereas for other less-infectious viruses, it may only be 50 percent of the population that needs to be immune to get herd immunity. It’s a theoretical thing that makes some assumptions, such as that everybody’s health status is the same and the population mixes perfectly every day. Neither of those are true.
How well that actual predictive number will work for coronavirus is unknown. The other thing that’s interesting is a lot of that work has been based on vaccines, such as what percentage do you have to vaccinate to get herd immunity? But if you get to herd immunity by having people get infected, so-called natural herd immunity, that may be different. You would imagine the most susceptible people get infected soonest, and so the heterogeneity of the population might change the threshold calculation.
The short answer is nobody wants to find out. No one wants to get to herd immunity for COVID-19 through natural herd immunity. The way you’d like to get there is with a vaccine that you then could apply to a large portion of the population, and have them acquire immunity in a more safe and controlled manner. Should we have an efficacious vaccine, this question will loom large: how many people do we need to vaccinate to really try and protect vulnerable populations?
Collins: That’s going to be a really critical question for the coming months, as the first large-scale vaccine trials get underway in July, and we start to see how they work and how successful and safe they are. But I’m also worried seeing some reports that 1 out of 5 Americans say they wouldn’t take a vaccine. It would be truly a tragedy if we have a safe and effective vaccine, but we don’t get enough uptake to achieve herd immunity. So, we’ve got some work to do on all fronts, that’s for sure.
Ned, I want to thank you for sharing all this information about antibodies and serologies and other things, as well as thank you for your hard work with all your amazing NCI colleagues.
Sharpless: Thanks for having me.
Reference:
[1] SARS-CoV-2 IgG Antibody Responses in New York City. Reifer J, Hayum N, Heszkel B, Klagsbald I, Streva VA. medRxiv. Preprint posted May 26, 2020.
Links:
Coronavirus (COVID-19) (NIH)
At NCI, A Robust and Rapid Response to the COVID-19 Pandemic. Norman E. Sharpless. Cancer Currents Blog. April 17, 2020 (National Cancer Institute/NIH)
Serological Testing for SARS-CoV-2 Antibodies (American Medical Association, Chicago)
COVID-19 Antibody Testing Primer (Infectious Diseases Society of America, Arlington, VA)
Accelerating COVID-19 Therapeutic Interventions and Vaccines (NIH)
Enlisting Monoclonal Antibodies in the Fight Against COVID-19
Posted on by Dr. Francis Collins
We now know that the immune system of nearly everyone who recovers from COVID-19 produces antibodies against SARS-CoV-2, the novel coronavirus that causes this easily transmitted respiratory disease [1]. The presence of such antibodies has spurred hope that people exposed to SARS-CoV-2 may be protected, at least for a time, from getting COVID-19 again. But, in this post, I want to examine another potential use of antibodies: their promise for being developed as therapeutics for people who are sick with COVID-19.
In a recent paper in the journal Science, researchers used blood drawn from a COVID-19 survivor to identify a pair of previously unknown antibodies that specifically block SARS-CoV-2 from attaching to human cells [2]. Because each antibody locks onto a slightly different place on SARS-CoV-2, the vision is to use these antibodies in combination to block the virus from entering cells, thereby curbing COVID-19’s destructive spread throughout the lungs and other parts of the body.
The research team, led by Yan Wu, Capital Medical University, Beijing, first isolated the pair of antibodies in the laboratory, starting with white blood cells from the patient. They were then able to produce many identical copies of each antibody, referred to as monoclonal antibodies. Next, these monoclonal antibodies were simultaneously infused into a mouse model that had been infected with SARS-CoV-2. Just one infusion of this combination antibody therapy lowered the amount of viral genetic material in the animals’ lungs by as much as 30 percent compared to the amount in untreated animals.
Monoclonal antibodies are currently used to treat a variety of conditions, including asthma, cancer, Crohn’s disease, and rheumatoid arthritis. One advantage of this class of therapeutics is that the timelines for their development, testing, and approval are typically shorter than those for drugs made of chemical compounds, called small molecules. Because of these and other factors, many experts think antibody-based therapies may offer one of the best near-term options for developing safe, effective treatments for COVID-19.
So, what exactly led up to this latest scientific achievement? The researchers started out with a snippet of SARS-CoV-2’s receptor binding domain (RBD), a vital part of the spike protein that protrudes from the virus’s surface and serves to dock the virus onto an ACE2 receptor on a human cell. In laboratory experiments, the researchers used the RBD snippet as “bait” to attract antibody-producing B cells in a blood sample obtained from the COVID-19 survivor. Altogether, the researchers identified four unique antibodies, but two, which they called B38 and H4, displayed a synergistic action in binding to the RBD that made them stand out for purposes of therapeutic development and further testing.
To complement their lab and animal experiments, the researchers used a particle accelerator called a synchrotron to map, at near-atomic resolution, the way in which the B38 antibody locks onto its viral target. This structural information helps to clarify the precise biochemistry of the complex interaction between SARS-CoV-2 and the antibody, providing a much-needed guide for the rational design of targeted drugs and vaccines. While more research is needed before this or other monoclonal antibody therapies can be used in humans suffering from COVID-19, the new work represents yet another example of how basic science is expanding fundamental knowledge to advance therapeutic discovery for a wide range of health concerns.
Meanwhile, there’s been other impressive recent progress towards the development of monoclonal antibody therapies for COVID-19. In work described in the journal Nature, an international research team started with a set of neutralizing antibodies previously identified in a blood sample from a person who’d recovered from a different coronavirus-caused disease, called severe acute respiratory syndrome (SARS), in 2003 [3]. Through laboratory and structural imaging studies, the researchers found that one of these antibodies, called S309, proved particularly effective at neutralizing the coronavirus that causes COVID-19, SARS-CoV-2, because of its potent ability to target the spike protein that enables the virus to enter cells. The team, which includes NIH grantees David Veesler, University of Washington, Seattle, and Davide Corti, Humabs Biomed, a subsidiary of Vir Biotechnology, has indicated that S309 is already on an accelerated development path toward clinical trials.
In the U.S. and Europe, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership, which has brought together public and private sector COVID-19 therapeutic and vaccine efforts, is intensely pursuing the development and testing of therapeutic monoclonal antibodies for COVID-19 [4]. Stay tuned for more information about these potentially significant advances in the next few months.
References:
[1] Humoral immune response and prolonged PCR positivity in a cohort of 1343 SARS-CoV 2 patients in the New York City region. Wajnberg A , Mansour M, Leven E, Bouvier NM, Patel G, Firpo A, Mendu R, Jhang J, Arinsburg S, Gitman M, Houldsworth J, Baine I, Simon V, Aberg J, Krammer F, Reich D, Cordon-Cardo C. medRxiv. Preprint Posted May 5, 2020.
[2] A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2. Wu Y. et al., Science. 13 May 2020 [Epub ahead of publication]
[3] Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Pinto D, Park YJ, Beltramello M, Veesler D, Cortil D, et al. Nature. 18 May 2020 [Epub ahead of print]
[4] Accelerating COVID-19 therapeutic interventions and vaccines (ACTIV): An unprecedented partnership for unprecedented times. Collins FS, Stoffels P. JAMA. 2020 May 18.
Links:
Coronavirus (COVID-19) (NIH)
Monoclonal Antibodies (National Cancer Institute/NIH)
Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)
NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences
COVID-19 Brings Health Disparities Research to the Forefront
Posted on by Dr. Francis Collins
The coronavirus 2019 (COVD-19) pandemic has brought into sharp focus many of the troubling things that we already knew about health disparities in the United States but have failed to address. With the bright light now shining on this important issue, it is time to talk about the role research can play in reducing the disproportionate burden of COVID-19, as well as improving the health of all people in our great nation.
In recent weeks, we’ve seen a growing list of disturbing statistics about how blacks, Hispanics, tribal communities, and some other racial, ethnic, and disadvantaged socioeconomic groups are bearing the brunt of COVID-19. One of the latest studies comes from a research team that analyzed county-by-county data gathered about a month ago. Their findings? The 22 percent of U.S. counties that are disproportionately black accounted for 52 percent of our nation’s COVID-19 cases and 58 percent of COVID-19 deaths. In a paper awaiting peer review, the team, led by Emory University, Atlanta, and amfAR, the Foundation for AIDS Research, Washington, DC., noted that neither the size of the county nor whether it was urban or rural mattered [1].
Recently, I had an opportunity to discuss the disparate burden of COVID-19 with Dr. Eliseo Pérez-Stable, Director of NIH’s National Institute on Minority Health and Health Disparities (NIMHD). Besides leading an institute, Dr. Pérez-Stable is a widely recognized researcher who studies various factors that contribute to health disparities. Our conversation took place via videoconferencing, with him linking in from his home in Washington, D.C., and me from my home in nearby Maryland. Here’s a condensed transcript of our chat:
Collins: Eliseo, you and I recently had a chance to have a pretty intense discussion with the Congressional Black Caucus about health disparities and the COVID-19 pandemic. So, could you start off with a little bit about what populations are being hit hardest?
Pérez-Stable: Collecting data about disease incidence and mortality on the basis of race and ethnicity and other important demographic factors, like socioeconomic status, had really been absent in this pandemic until recently.
Part of that I think is entirely understandable. Hospitals were pressed with a surge of very sick patients, and there was a certain amount of fear and panic in the community. So, people were not completing all these forms that usually get turned in to the health departments and then forwarded to the CDC. If you go back in history, similar things happened in the early 1980s with the HIV epidemic. We weren’t collecting data on race and other sociodemographic variables initially. But, with time, we did complete these data and a picture emerged.
With the COVID-19 pandemic, obviously, the outcomes are much faster, with over 60,000 deaths in just a matter of three months. And we started to see reports, initially out of Connecticut, Milwaukee, Chicago, and New Orleans, that African Americans were dying at a disproportionate rate.
Now, the initial—and I think still the most likely—explanation for this higher mortality relates to two factors. The first is a higher rate of co-morbidities. We know that if you have cardiovascular disease, more than mild obesity, or diabetes, you’re more likely to get severe COVID-19 and potentially die from it. So, we could have just said, “Aha! It’s obvious why this population, and others with higher rates of co-morbidities might be expected to have higher rates of severe disease and higher mortality.”
But there is a second factor that relates to getting infected, for which we have much-less clear data. There was recently a map in The Washington Post showing the distribution of the rate of COVID-19 infections in Washington, D.C., by ward. The highest rates are in the wards that are east of the Anacostia River, which are about 90 percent African American. So, there is an appearance of a correlation between the proportion of African Americans in the community and the rate of Covid-19 infection. Now why could that be?
Collins: Yes, what explains that?
Pérez-Stable: Well, I think crowding is part of it, certainly in this neighborhood. A second option would be multiple families living under one roof.
Collins: So, you can’t exactly practice physical distancing very well in that situation.
Pérez-Stable: Absolutely. You and I can go into our respective rooms, probably have our respective bathrooms, and socially and physically isolate from the rest of the household if need be. Many people can’t do that. They have three generations in one small apartment, all using one bathroom, maybe two bedrooms for six or eight people.
So, we do face different conditions by which one casual infection can lead to much more community transmission. But much information still needs to be ascertained and there does seem to be some regional variance. For example, in Chicago, Milwaukee, and Atlanta, the reports, at least initially, are worse than they are in Connecticut or Florida. Also, New York City, which has been the epicenter of the U.S. for this pandemic, has an increased rate of infections and mortality among Latino-Hispanic populations as well. So, it isn’t isolated to an African-American issue.
Collins: What about access to healthcare?
Pérez-Stable: Again, we can postulate based on a little bit of anecdote and a little bit of data. I’m a general internist by background, and I can see the enormous impact this pandemic has had on healthcare settings.
First, elective ambulatory visits and elective admissions to the hospital have been postponed, delayed, or cancelled. About 90 percent of ambulatory care is occurring through telemedicine or telephone connections, so in-person visits are occurring only for really urgent matters or suspected COVID-19.
If you have health insurance and can use systems, you can probably, through telephone triage with a nurse, get either approval or nonapproval for being tested [for COVID-19], drive to a place, get tested by someone wearing protective equipment, and never actually have to visit with anyone. And you’ll get your result now back as soon as one day, depending on the system. Now, if you’re insured, but don’t really know how to use systems, navigating all these things can be a huge challenge. So, that could be a factor.
People are also afraid to come to clinic, they’re afraid to show up at the emergency room, because they’re afraid to get infected. So, they’re worried about going in, unless they get very sick. And when they get very sick, they may be coming in with more advanced cases [of COVID-19].
So, telephone triage, advice from clinicians on the phone, is critical. We are seeing some doctors base their decisions on whether a person is able to breathe okay on the phone, able to say a whole sentence without catching their breath. These kinds of basic things that we learned in clinical medicine training are coming into play in a big way now, because we just cannot provide the kind of care, even in the best of circumstances, that people may need.
Of course, uninsured patients will have even more barriers, although everyone in the healthcare system is trying their best to help patients when they need to be helped, rather than depend on insurance triage.
Collins: A big part of trying to keep the disease from spreading has been access to testing so that people, even those with mild symptoms, can find out if they have this virus and, if so, quarantine and enable public health workers to check out their contacts. I’m guessing, from what you said, that testing has been happening a lot less in urban communities that are heavily populated by African Americans and that further propagates the spread of the disease. Am I right?
Pérez-Stable: So far, most testing has been conducted on the basis of symptoms. So, if you have enough symptoms that you may potentially need to be hospitalized, then you get tested. Also, if you’re a healthcare worker who had contact with a COVID-19 patient, you might be tested, or if there’s someone you’ve been very close to that was infected, you may be tested. So, I don’t think so much it’s a matter of disproportionate access to testing by one group or another, as much as that the overall triage and selection criteria for testing have been rather narrow. Up until now, it has not been a simple process to get tested for COVID-19. As we scale up and get better point-of-care tests and much easier access to getting tested, I think you’ll see dissemination across the board.
Collins: It’s interesting we’re talking about this, because this is an area that Congress recently came to NIH and said, “We want you to do something about the testing by encouraging more technology, particularly technology that can be distributed to the point-of-care, and that is out in the community.”
Everyone wants a test that gives you a quick turnaround, an answer within an hour, instead of maybe a day or two. A big part of what NIH is trying to do is to make sure that if we’re going to develop these new testing technologies, they get deployed in places that otherwise might not have much access to testing—maybe by working through the community health centers. So, we’re hoping we might be able to make a contribution there.
Pérez-Stable: The economic factors in this pandemic are also huge. A significant proportion of the population that we’re referring to—the disparity population, the minorities, the poor people—work in service jobs where they’re on the front line. They were the restaurant servers and people in the kitchen, they’re still the bus drivers and the Uber drivers, and those who are working in pharmacies and supermarkets.
On the one hand, they are at higher risk for getting infected because they’re in more contact with people. On the other hand, they’re really dependent on this income to maintain their household. So, if they test positive or get exposed to COVID-19, we really do have a challenge when we ask them to quarantine and not go to work. They’re not in a position where they have sick leave, and they may be putting themselves at risk for being laid off.
Collins: Eliseo, you’ve been studying health disparities pretty much your whole research career. You come from a community where health disparities are a reality, having been born in Cuba and being part of the Latino community. Did you expect that COVID-19 would be this dramatic in the ways in which it has so disproportionately affected certain groups?
Pérez-Stable: I can’t say that I did. My first thought as a physician was to ask: “Is there any reason to think that an infectious agent like COVID-19 would disproportionally infect or impact any population?” My gut answer was “No.” Infectious diseases usually seem to affect all people; sort of equal opportunity invaders. There are some data that would say that influenza and pneumonia are not any worse among African Americans or Latinos than among whites. There are some slight differences in some regions, but not much.
Yet I know this a question that NIH-funded scientists are interested in addressing. We need to make sure that there aren’t any particular susceptibility factors, possibly related to genetics or the lung epithelium, that lead to such different COVID-19 outcomes in different individuals. Clearly, something must be going on, but we don’t know what that is. Maybe one of those factors tracks through race or ethnicity because of what those social constructs represent.
I recently listened to a presentation by Rob Califf, former FDA Commissioner, who spoke about how the pandemic has created a spotlight on our disparities-creating system. I think much of the time this disparities-creating system is in the background; it doesn’t really affect most people’s daily lives. Now, we’re suddenly hit with a bucket of cold water called COVID-19, and we’re saying what is going on and what can we do about it to make a difference. I hope that, once we begin to emerge from this acute crisis, we take the opportunity to address these fundamental issues in our society.
Collins: Indeed. Let’s talk about what you’re doing at NIMHD to support research to try to dig into both the causes of health disparities and the interventions that might help.
Pérez-Stable: Prompted by your motivation, we started talking about how minority health and health disparities research could respond to this pandemic. In the short-term, we thought along the lines of how can we communicate mitigation interventions, such as physical distancing, in a more effective way to our communities? We also asked what we could do to enhance access to healthcare for our populations, both to manage chronic conditions and for diagnosis and treatment of acute COVID-19.
We also considered in the mid- and long-term effects of economic disruption—this surge of unemployment, loss of jobs, loss of insurance, loss of income—on people’s health. Worries include excess use of alcohol and other substances, and worsening of mental and emotional well-being, particularly due to severe depression and chronic mental disorders not being well controlled. Intimate partner violence has already been noted to increase in some countries, including France, Spain, and the United States, that have gone on physical distancing interventions. Similarly, child abuse can be exacerbated under these circumstances. Just think of 24/7 togetherness as a test of how people can hold it together all the time. I think that that can bring out some fragility. So, interventions to address these, that really activate our community networks and community-based organizations, are real strengths. They build on the resilience of the community to highlight how we can get through this difficult period of time.
I feel optimistic that science will bring answers, in the form of both therapies and vaccines. But in the meantime, we have a way to go and we a lot to do.
Collins: You mentioned the promise of vaccines. The NIH is working intensively on this, particularly through a partnership called ACTIV, Accelerating Covid-19 Therapeutic Interventions and Vaccines. We hope that in several more months, we’ll be in a position to begin testing these vaccines on a large scale, after having some assurances about their safety and efficacy. From our conversation, it sounds like we should be trying to get early access to those vaccines to people at highest risk, including those in communities with the heaviest burden. But how will that be received? There hasn’t always been an easy relationship between researchers, particularly government researchers, and the African-American community.
Pérez-Stable: I think we have learned from our historical experiences that mistrust of the system is real. To try to pretend that it isn’t there is a big mistake. Address these concerns upfront, obtain support from thought leaders in the community, and really work hard to be inclusive. In addition to vaccines, we need participation in any clinical trials that are coming up for therapeutics.
We also need research on how optimally to communicate this with all the different segments of the population. This includes not just explaining what it means to be eligible for vaccine trials or therapeutic trials, but also discussing the consequences of, say, getting tested, whether it be a viral or antibody test. What does the information mean for them?
Most people just want to know “Am I clear of the virus or not?” That certainly could be part of the answer, but many may require more nuanced responses. Then there’s behavior. If I’m infected and I recover, am I safe to go back out and do things that other people shouldn’t do? We’d love to be able to inform the population about that. But, as you know, we don’t really have the answers to that just yet.
Collins: Good points. How do we make sure, when we’re trying to reach out to populations that have shouldered such a heavy burden, that we’re actually providing information in a fashion that is readily understood?
Pérez-Stable: One thing to keep in mind is the issue of language. About 5 to 10 percent of U.S. adults don’t speak English well. So, we really have to address the language barrier. I also want to highlight the challenge that some tribal nations are facing. Navajo country has had particular challenges with COVID-19 infections in a setting of minimal medical infrastructure. In fact, there are communities that have to go and get their water for the day at a distant site, so they don’t have modern plumbing. How can we recommend frequent hand washing to someone who doesn’t even have running water at home? These are just a few examples of the diversity of our country that need to be addressed as we deal with this pandemic.
Collins: Eliseo, you’ve given us a lot to think about in an obviously very serious situation. Anything you’d like to add?
Pérez-Stable: In analyzing health outcomes, researchers often think about responses related to a metabolic pathway or to a gene or to a response to a particular drug. But as we use the power of science to understand and contain the COVID-19 pandemic, I’d like to re-emphasize the importance of considering race, ethnicity, socioeconomic status, the built environment, the social environment, and systems. Much of the time these factors may only play secondary roles, but, as in all science related to humans, I think they have to be considered. This experience should be a lesson for us to learn more about that.
Collins: Thank you for those wonderful, inspiring words. It was good to have this conversation, Eliseo, because we are the National Institutes of Health, but that has to be health for everybody. With COVID-19, we have an example where that has not turned out to be the case. We need to do everything we can going forward to identify ways to change that.
Reference:
[1] Assessing Differential Impacts of COVID-19 on Black Communities. Millet GA et al. MedRxiv. Preprint posted on May 8, 2020.
Links:
Video: Francis Collins and Eliseo Pérez-Stable on COVID-19 Health Disparities (NIH)
Coronavirus (COVID-19) (NIH)
Director’s Corner (National Institute on Minority Health and Disparities/NIH)
COVID-19 and Racial/Ethnic Disparities. Webb Hooper M, Nápoles AM, Pérez-Stable EJ.JAMA. 2020 May 11.
amfAR Study Shows Disproportionate Impact of COVID-19 on Black Americans, amfAR News Release, May 5, 2020.
Rising to the COVID-19 Challenge: Rapid Acceleration of Diagnostics (RADx)
Posted on by Dr. Francis Collins
Step into any major medical center, and you will see the amazing power of technology at work. From X-rays to functional MRIs, blood typing to DNA sequencing, heart-lung machines to robotic surgery, the progress that biomedical technology has made over the past century or so stands as a testament to human ingenuity—and its ability to rise to the all-important challenge of saving lives and improving health.
Today, our nation is in the midst of trying to contain a most formidable health threat: the global coronavirus disease 2019 (COVID-19) pandemic. I’m convinced that biomedical technology has a vital role to play in this urgent effort, which is why the NIH today launched the Rapid Acceleration of Diagnostics (RADx) Initiative.
Fueled by a bold $1.5 billion investment made possible by federal stimulus funding, RADx is an urgent call for science and engineering’s most inventive and visionary minds—from the basement to the board room—to develop rapid, easy-to-use testing technologies for SARS-CoV-2, the novel coronavirus that causes COVID-19. To achieve this, NIH will work closely with our colleagues at the Biomedical Advanced Research and Development Authority, the Centers for Disease Control and Prevention, and the Food and Drug Administration.
If all goes well, RADx aims to support innovative technologies that will make millions more rapid SARS-CoV-2 tests available to Americans by late summer or fall. Such widespread testing, which will facilitate the speedy identification and quarantine of infected individuals and their contacts, will likely be a critical component of making it possible for Americans to get safely back into public spaces, including returning to work and school.
For history buffs and tech geeks, the RADx acronym might ring a bell. During the World War II era, it was the brainstorming of MIT’s “Rad Lab” that gave birth to radar—a groundbreaking technology that, for the first time, enabled humans to use radio waves to “see” planes, storm systems, and many other things. Radar played such a valuable role in finding bombing targets, directing gunfire, and locating enemy aircraft, ships, and artillery that some have argued that this technology actually won the war for the U.S. and its Allies.
As for NIH’s RADx, our aim is to speed the development and commercialization of tests that can rapidly “see” if people have been infected with SARS-CoV-2 with very high sensitivity and specificity, meaning there would be few false negatives and false positives. A key part of this effort, which started today, will be a national technology development competition that’s open to all comers. In this competition, which begins a bit like a “shark tank,” participants will vie for an ultimate share of an approximately $500 million fund that will be awarded to help advance the most-promising testing technologies.
The proposals will undergo an initial review for technical, clinical, commercial, and regulatory issues. For example, could the testing technology be easily scaled up? Would it provide clear advantages over existing approaches? And would the U.S. health-care system realistically be able to adopt the technology rapidly? If selected, the proposals will then enter a three-phase process that will run into summer. Each development team will receive its own initial budget, deadlines, and set of deliverables. Competitors must also work collaboratively with an assigned expert and utilize associated web-based tools.
As you see in the graphic above, each phase will whittle down the competition. Those testing technologies that succeed in making it to Phase 2 will receive an appropriate budget to enable full clinical deployment on an accelerated timeline. They will also be matched with technical, business, and manufacturing experts to boost their chances of success.
Of course, not all technologies will enter the competition at the same stages of development. Those that are already relatively far along will be “fast tracked” to a phase that corresponds with their place in the commercialization process. Our hope is that the winning technologies will feature patient- and user-friendly designs, mobile-device integration, affordable cost, and increased accessibility, for use at the point of care (or even at home).
To assist competitors in their efforts to accomplish these bold goals, RADx will expand the Point-of-Care Technologies Research Network, which was established several years ago by NIH’s National Institute of Biomedical Imaging and Bioengineering (NIBIB). The network supports hundreds of investigators through five technology hubs at: Emory University/Georgia Institute of Technology, Atlanta; Johns Hopkins University, Baltimore; Northwestern University, Evanston, IL; University of Massachusetts Medical School, Worcester; and the Consortia for Improving Medicine with Innovation & Technology at Harvard Medical School/Massachusetts General Hospital, Boston.
RADx is focused on diagnostic testing, but NIH is also intensely engaged in developing safe, effective therapies and vaccines for COVID-19. One innovative effort, called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), is a public-private partnership that aims to speed the development of ways to treat and prevent this disease that’s caused so much suffering and death around the globe.
So, to the U.S. science and engineering community, I have these words: Let’s get going—our nation has never needed your skills more!
Links:
Coronavirus (COVID-19) (NIH)
NIH mobilizes national innovation initiative for COVID-19 diagnostics, NIH news release, April 29, 2020
Point-of-Care Technologies Research Network (National Institute of Biomedical Imaging and Biotechnology/NIH)
NIH to launch public-private partnership to speed COVID-19 vaccine and treatment options, NIH news release, April 17, 2020.
We Need More COVID-19 Tests. We Propose a ‘Shark Tank’ to Get There, Lamar Alexander, Roy Blunt. Washington Post, April 20, 2020.
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