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Charting a Rapid Course Toward Better COVID-19 Tests and Treatments

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Point of care anti
Credit: Quidel; iStock/xavierarnau

It is becoming apparent that our country is entering a new and troubling phase of the pandemic as SARS-CoV-2, the novel coronavirus that causes COVID-19, continues to spread across many states and reaches into both urban and rural communities. This growing community spread is hard to track because up to 40 percent of infected people seem to have no symptoms. They can pass the virus quickly and unsuspectingly to friends and family members who might be more vulnerable to becoming seriously ill. That’s why we should all be wearing masks when we go out of the house—none of us can be sure we’re not that asymptomatic carrier of the virus.

This new phase makes fast, accessible, affordable diagnostic testing a critical first step in helping people and communities. In recognition of this need, NIH’s Rapid Acceleration of Diagnostics (RADx) initiative, just initiated in late April, has issued an urgent call to the nation’s inventors and innovators to develop fast, easy-to-use tests for SARS-CoV-2, the novel coronavirus that causes COVID-19. It brought a tremendous response, and NIH selected about 100 of the best concepts for an intense one-week “shark-tank” technology evaluation process.

Moving ahead at an unprecedented pace, NIH last week announced the first RADx projects to come through the deep dive with flying colors and enter the scale-up process necessary to provide additional rapid testing capacity to the U.S. public. As part of the RADx initiative, seven biomedical technology companies will receive a total of $248.7 million in federal stimulus funding to accelerate their efforts to scale up new lab-based and point-of-care technologies.

Four of these projects will aim to bolster the nation’s lab-based COVID-19 diagnostics capacity by tens of thousands of tests per day as soon as September and by millions by the end of the year. The other three will expand point-of-care testing for COVID-19, making results more rapidly and readily available in doctor’s offices, urgent care clinics, long-term care facilities, schools, child care centers, or even at home.

This is only a start, and we expect that more RADx projects will advance in the coming months and begin scaling up for wide-scale use. In the meantime, here’s an overview of the first seven projects developed through the initiative, which NIH is carrying out in partnership with the Office of the Assistant Secretary of Health, the Biomedical Advanced Research and Development Authority, and the Department of Defense:

Point-of-Care Testing Approaches

Mesa Biotech. Hand-held testing device detects the genetic material of SARS-CoV-2. Results are read from a removable, single-use cartridge in 30 minutes.

Quidel. Test kit detects protein (viral antigen) from SARS-CoV-2. Electronic analyzers provide results within 15 minutes. The U.S. Department of Health and Human Service has identified this technology for possible use in nursing homes.

Talis Biomedical. Compact testing instrument uses a multiplexed cartridge to detect the genetic material of SARS-CoV-2 through isothermal amplification. Optical detection system delivers results in under 30 minutes.

Lab-based Testing Approaches

Ginkgo Bioworks. Automated system uses next-generation sequencing to scan patient samples for SARS-CoV-2’s genetic material. This system will be scaled up to make it possible to process tens of thousands of tests simultaneously and deliver results within one to two days. The company’s goal is to scale up to 50,000 tests per day in September and 100,000 per day by the end of 2020.

Helix OpCo. By combining bulk shipping of test kits and patient samples, automation, and next-generation sequencing of genetic material, the company’s goal is to process up to 50,000 samples per day by the end of September and 100,000 per day by the end of 2020.

Fluidigm. Microfluidics platform with the capacity to process thousands of polymerase chain reaction (PCR) tests for SARS-CoV-2 genetic material per day. The company’s goal is to scale up this platform and deploy advanced integrated fluidic chips to provide tens to hundreds of thousands of new tests per day in the fall of 2020. Most tests will use saliva.

Mammoth Biosciences. System uses innovative CRISPR gene-editing technology to detect key pieces of SARS-CoV-2 genetic material in patient samples. The company’s goal is to provide a multi-fold increase in testing capacity in commercial laboratories.

At the same time, on the treatment front, significant strides continue to be made by a remarkable public-private partnership called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV). Since its formation in May, the partnership, which involves 20 biopharmaceutical companies, academic experts, and multiple federal agencies, has evaluated hundreds of therapeutic agents with potential application for COVID-19 and prioritized the most promising candidates.

Among the most exciting approaches are monoclonal antibodies (mAbs), which are biologic drugs derived from neutralizing antibodies isolated from people who’ve survived COVID-19. This week, the partnership launched two trials (one for COVID-19 inpatients, the other for COVID-19 outpatients) of a mAB called LY-CoV555, which was developed by Eli Lilly and Company, Indianapolis, IN. It was discovered by Lilly’s development partner AbCellera Biologics Inc. Vancouver, Canada, in collaboration with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID). In addition to the support from ACTIV, both of the newly launched studies also receive support for Operation Warp Speed, the government’s multi-agency effort against COVID-19.

LY-CoV555 was derived from the immune cells of one of the very first survivors of COVID-19 in the United States. It targets the spike protein on the surface of SARS-CoV-2, blocking it from attaching to human cells.

The first trial, which will look at both the safety and efficacy of the mAb for treating COVID-19, will involve about 300 individuals with mild to moderate COVID-19 who are hospitalized at facilities that are part of existing clinical trial networks. These volunteers will receive either an intravenous infusion of LY-CoV555 or a placebo solution. Five days later, their condition will be evaluated. If the initial data indicate that LY-CoV555 is safe and effective, the trial will transition immediately—and seamlessly—to enrolling an additional 700 participants with COVID-19, including some who are severely ill.

The second trial, which will evaluate how LY-CoV555 affects the early course of COVID-19, will involve 220 individuals with mild to moderate COVID-19 who don’t need to be hospitalized. In this study, participants will randomly receive either an intravenous infusion of LY-CoV555 or a placebo solution, and will be carefully monitored over the next 28 days. If the data indicate that LY-CoV555 is safe and shortens the course of COVID-19, the trial will then enroll an additional 1,780 outpatient volunteers and transition to a study that will more broadly evaluate its effectiveness.

Both trials are later expected to expand to include other experimental therapies under the same master study protocol. Master protocols allow coordinated and efficient evaluation of multiple investigational agents at multiple sites as the agents become available. These protocols are designed with a flexible, rapidly responsive framework to identify interventions that work, while reducing administrative burden and cost.

In addition, Lilly this week started a separate large-scale safety and efficacy trial to see if LY-CoV555 can be used to prevent COVID-19 in high-risk residents and staff at long-term care facilities. The study isn’t part of ACTIV.

NIH-funded researchers have been extremely busy over the past seven months, pursuing every avenue we can to detect, treat, and, ultimately, end this devasting pandemic. Far more work remains to be done, but as RADx and ACTIV exemplify, we’re making rapid progress through collaboration and a strong, sustained investment in scientific innovation.

Links:

Coronavirus (COVID-19) (NIH)

Rapid Acceleration of Diagnostics (RADx)

Video: NIH RADx Delivering New COVID-19 Testing Technologies to Meet U.S. Demand (YouTube)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)

Explaining Operation Warp Speed (U.S. Department of Health and Human Resources/Washington, D.C.)

NIH delivering new COVID-19 testing technologies to meet U.S. demand,” NIH news release,” July 31, 2020.

NIH launches clinical trial to test antibody treatment in hospitalized COVID-19 patients,” NIH new release, August 4, 2020.

NIH clinical trial to test antibodies and other experimental therapeutics for mild and moderate COVID-19,” NIH news release, August 4, 2020.


Racing to Develop Fast, Affordable, Accessible Tests for COVID-19

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RADx: Innovating Better Tests
Credit: iStock/peshkov

Developing faster, more convenient ways of testing for coronavirus disease 2019 (COVID-19) will be essential to our efforts to end this deadly pandemic. Despite the tremendous strides that have been made in diagnostics over the past seven months, we still need more innovation.

We need reliable, affordable tests for the presence SARS-CoV-2—the novel coronavirus that causes COVID-19—that do not take hours or days to deliver results. We need tests that are more user friendly, and that don’t rely on samples collected by swabs that have to be inserted deep into the nose by someone wearing PPE. We need tests that can be performed at the point-of-care, whether a doctor’s office, urgent care clinic, long-term care facility, or even a home. Ideally, such tests should also be able to integrate with mobile devices to convey results and transmit data seamlessly. Above all, we need tests that are accessible to everyone.

Most current diagnostic tests for SARS-CoV-2 involve detecting viral genetic material using a decades-old technology called the polymerase chain reaction (PCR). If there’s even a tiny bit of viral genetic material in a patient’s sample, PCR can amplify the material millions of times so that it can be readily detected. The problem is that this amplification process is time-consuming and requires a thermal cycling machine that’s generally operated by trained personnel in sophisticated lab settings.

To spur the creation of new approaches that can rapidly expand access to testing, NIH launched the Rapid Acceleration of Diagnostics (RADx) program in late April 2020. This fast-paced, innovative effort, conducted in partnership with the Office of the Assistant Secretary of Health, the Biomedical Advanced Research and Development Authority (BARDA), and the Department of Defense, is supported by $1.5 billion in federal stimulus funding. The goal? To expand diagnostic testing capacity for COVID-19 in the United States to about 6 million tests per day by December. That’s quite a leap forward because our nation’s current testing capacity is currently about 1 million tests per day.

Just yesterday, I joined other NIH leaders in authoring a special report in the New England Journal of Medicine that describes RADx’s main activities, and provides an update on the remarkable progress that’s been made in just three short months [1]. In a nutshell, RADx consists of four components: RADx-tech, RADx Advanced Technology Platforms (RADx-ATP). RADx Radical (RADx-rad), and RADx Underserved Populations (RADx-UP).


Though all parts of RADx are operating on a fast-track, RADx-tech has embraced its rapid timelines in a can-do manner unlike anything that I’ve encountered in my 27 years in government. Here’s how the process, which has been likened to a scientific “shark tank,” works.

Once an applicant submits a test idea to RADx-tech, it’s reviewed within a day by a panel of 30 experts. If approved, the application moves to a highly competitive “shark-tank” in which a team of experts spend about 150 to 200 person-hours with the applicant evaluating the technical, clinical, and commercial strengths and weaknesses of the proposed test.

From there, a detailed proposal is presented to a steering committee, and then sent to NIH. If we at NIH think it’s a great idea, promising early-stage technologies enter what’s called “phase one” development, with considerable financial support and the expectation that the applicant will hit its validation milestones within a month. Technologies that succeed can then go to “phase two”, where support is provided for scale-up of tests for meeting regulatory requirements and supporting manufacture, scale-up, and distribution.

The major focus of RADx-tech is to simplify and speed diagnostic testing for COVID-19. Tests now under development include a variety of mobile devices that can be used at a doctor’s office or other point-of-care settings, and give results in less than an hour. In addition, about half of the tests now under development use saliva or another alternative to samples gathered via nasal swabs.

As Americans think about how to move back safely into schools, workspaces, and other public areas in the era of COVID-19, it is clear that we need to figure out ways to make it easier for everyone to get tested. To attain that goal, RADx has three other components that build on different aspects of this social imperative:

RADx Advanced Technology Platforms (RADx-ATP). This program offers a rapid-response application process for firms with existing point-of-care technologies authorized by the Food and Drug Administration (FDA) for detecting SARS-CoV-2. These technologies are already advanced enough that they don’t need the shark tank. The RADx-ATP program provides support for scaling up production to between 20,000 and 100,000 tests per day by the fall. Another component of this program provides support for expanding automated “mega-labs” to increase testing capacity across the country by another 100,000 to 250,000 tests per day.

RADx Radical (RADx-rad). The program seeks to fuel the development of truly futuristic testing technologies. For example, it supports projects that use biomarkers to detect an infection or predict the severity of disease, including the likelihood of developing COVID-related multisystem inflammatory syndrome in children (MIS-C). Other areas of interest include the use of biosensors to detect the presence of the virus in a person’s breath and the analysis of wastewater to conduct community-based surveillance.

RADx Underserved Populations (RADx-UP). Data collected over the past several months make it clear that Blacks, Latinxs, and American Indians/Alaska Natives are hospitalized and die of COVID-19 at disproportionately higher rates than other groups. RADx-UP aims to engage underserved communities to improve access to testing. Such actions will include closely examining the factors that have led to the disproportionate burden of the pandemic on underserved populations, as well as building infrastructure that can be leveraged to provide optimal access and uptake of SARS-CoV-2 testing in such communities.

At NIH, we have great hopes for what RADx-supported research will do to help bring to an end the greatest public health crisis of our generation. Yet the benefits may not end there. The diagnostic testing technologies developed here will have many other applications moving forward. Long after the COVID-19 pandemic becomes a chapter in history books, I’m convinced the RADx model of rapid innovation will be inspiring future generations of researchers as they look for creative new ways to address other diseases and conditions.

Reference:

[1] Rapid scaling up of COVID-19 diagnostic testing in the United States—The NIH RADx Initiative. Tromberg BJ, Schwetz TA, Perez-Stable E, Hodes RJ. Woychick RP, Bright RA, Fleurence RL, Collins FS. NEJM; 2020 July 16. [Online publication ahead of print]

Links:

Coronavirus (COVID-19) (NIH)

Rapid Acceleration of Diagnostics (RADx)

NIH mobilizes national innovation initiative for COVID-19 diagnostics,” NIH news release, April 29, 2020.


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)


First Molecular Profiles of Severe COVID-19 Infections

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COVID-19 Severity Test
Credit: NIH

To ensure that people with coronavirus disease 2019 (COVID-19) get the care they need, it would help if a simple blood test could predict early on which patients are most likely to progress to severe and life-threatening illness—and which are more likely to recover without much need for medical intervention. Now, researchers have provided some of the first evidence that such a test might be possible.

This tantalizing possibility comes from a study reported recently in the journal Cell. In this study, researchers took blood samples from people with mild to severe COVID-19 and analyzed them for nearly 2,000 proteins and metabolites [1]. Their detailed analyses turned up hundreds of molecular changes in blood that differentiated milder COVID-19 symptoms from more severe illness. What’s more, they found that they could train a computer to use the most informative of the proteins and predict the disease severity with a high degree of accuracy.

The findings come from the lab of Tiannan Guo, Westlake University, Zhejiang Province, China. His team recognized that, while we’ve learned a lot about the clinical symptoms of COVID-19 and the spread of the illness around the world, much less is known about the condition’s underlying molecular features. It also remains mysterious what distinguishes the 80 percent of symptomatic infected people who recover with little to no need for medical care from the other 20 percent, who suffer from much more serious illness, including respiratory distress requiring oxygen or even more significant medical interventions.

In search of clues, Guo and colleagues analyzed hundreds of molecular changes in blood samples collected from 53 healthy people and 46 people with COVID-19, including 21 with severe disease involving respiratory distress and decreased blood-oxygen levels. Their studies turned up more than 470 proteins and metabolites that differed in people with COVID-19 compared to healthy people. Of those, levels of about 300 were associated with disease severity.

Further analysis revealed that the majority of proteins and metabolites on the list are associated with the suppression or dysregulation of one of three biological processes. Two processes are related to the immune system, including early immune responses and the function of particular scavenging immune cells called macrophages. The third relates to the function of platelets, which are sticky, disc-shaped cell fragments that play an essential role in blood clotting. Such biological insights might help pave the way for potentially effective new ways to treat COVID-19 down the road.

Next, the researchers turned to “machine learning” to explore the possibility that such molecular changes also might be used to predict mild versus severe COVID-19. Machine learning involves the use of computers to discern patterns, or molecular signatures, in large data sets that a human being couldn’t readily pick out. In this case, the question was whether the computer could “learn” to tell the difference between mild and severe COVID-19 based on molecular data alone.

Their analyses showed that a computer, once trained, could differentiate mild and severe COVID-19 based on just 22 proteins and 7 metabolites. Their model correctly classified all but one person in the original training set, for an accuracy of about 94 percent. And importantly, in further prospective validation tests, they confirmed that this model accurately identified mild versus severe COVID-19 in most cases.

While these findings are certainly encouraging, there’s much more work to do. It will be important to explore these molecular signatures in many more people. It also will be critical to find out how early in the course of the disease such telltale signatures arise. While we await those answers, I find encouragement in all that we’re learning—and will continue to learn—about COVID-19 each day.

Reference:

[1] Proteomic and metabolomic characterization of COVID-19 patient sera. Shen B et al. Cell. 28 May 2020. [Epub ahead of publication]

Links:

Coronavirus (COVID-19) (NIH)

Blood Tests (National Heart, Lung, and Blood Institute/NIH)

Tiannan Guo Lab (Westlake University, Zhejiang Province, China)


Pop-Up Testing Lab Shows Volunteer Spirit Against Deadly Pandemic

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Caption: Postdoc Jenny Hamilton volunteered to work on coronavirus testing at the Innovative Genomics Institute. Behind her is one of the lab’s liquid-handling systems, which robotically extracts RNA from patient samples before another machine can detect whether that RNA comes from the coronavirus. Credit: Max & Jules Photography.

On March 19, 2020, California became the first U. S. state to issue a stay-at-home order to halt the spread of SARS-CoV-2, the novel coronavirus that causes COVID-19. The order shuttered research labs around the state, and thousands of scientists began sheltering at home and shifting their daily focus to writing papers and grants, analyzing data from past experiments, and catching up on their scientific reading.

That wasn’t the case for everyone. Some considered the order as presenting a perfect opportunity to volunteer, sometimes outside of their fields of expertise, to help their state and communities respond to the pandemic.

One of those willing to pitch in is Jennifer Doudna, University of California, Berkeley (UC Berkeley) and executive director of the school’s Innovative Genomics Institute (IGI), a partnership with the University of California, San Francisco (UC San Francisco). She is also recognized as a pioneer in the development of the popular gene-editing technology called CRISPR.

Doudna, an NIH-supported structural biochemist with no experience in virology or clinical diagnostics, decided that she and her IGI colleagues could establish a pop-up testing lab at their facility. Their job: boost the SARS-CoV-2 testing capacity in her community.

It was a great idea, but a difficult one to execute. The first daunting step was acquiring Clinical Laboratory Improvement Amendments (CLIA) certification. This U. S. certification ensures that quality standards are met for laboratory testing of human blood, body fluid, and other specimens for medical purposes. CLIA certification is required not only to perform such testing in the IGI lab space, but for Doudna’s graduate students, postdocs, and volunteers to process patient samples.

Still, fate was on their side. Doudna and her team partnered with UC Berkeley’s University Health Services to extend the student health center’s existing CLIA certification to the IGI space. And because of the urgency of the pandemic, federal review of the extension request was expedited and granted in a few weeks.

The next challenge was technological. Doudna’s team had to make sure that its diagnostic system was as good or better than those of other SARS-CoV-2 testing platforms. With great care and attention to lab safety, the team began assembling two parallel workstreams: one a semi-manual method to get going right away and the other a faster, automated, robotic method to transition to when ready.

Soon, patient samples began arriving in the lab to be tested for the presence of genetic material (RNA) from SARS-CoV-2, an indication that a person is infected with the virus. The diagnostic system was also soon humming along, with Doudna’s automated workstream having the capacity to process 384 samples in parallel.

The pop-up lab—known formally as the IGI SARS-CoV-2 Diagnostic Testing Laboratory—is funded through philanthropy and staffed by more than 50 volunteers from IGI, UC Berkeley, UC San Francisco, and local data-management companies. Starting on April 6, the lab was fully operational, capable of running hundreds of tests daily with a 24-hour turnaround time for results. A positive test requires that at least two out of three SARS-CoV-2 genomic targets return a positive signal, and the method uses de-identified barcoded sample data to protect patient privacy.

Doudna intends to keep the pop-up lab open as long as her community needs it. So far, they’ve provided testing to UC Berkeley students and staff, first responders (including the entire Berkeley Fire Department), and several members of the city’s homeless population. She says that availability of samples will soon be the rate-limiting step in their sample-analysis pipeline and hopes continued partnerships with local health officials will enable them to work at full capacity to deliver thousands of test results rapidly.

Doudna says she’s been amazed by the team spirit of her lab members and other local colleagues who have come together around a crisis. They’ve gotten the job done by contributing their different skills and resources, including behind-the-scenes efforts by the university’s leadership and staff, philanthropists, city officials, and state government workers.

Although Doudna and her team intend to publish their work to help others follow suit [1], she says the experience has also provided her with many intangible rewards. It has highlighted the value of resilience and adaptation, as well as given her a newfound appreciation for the complexity and precision of operations in the commercial clinical labs that are a routine part of our medical care.

Although the COVID-19 pandemic seems to have thrust all of us into a time warp, in which weeks sometimes feel like months, there is much to do. The amount of work needed to tame this virus is significant and requires an all-hands-on-deck mentality, which NIH and the biomedical research community have embraced fully.

Doudna is not alone. Other labs around the country are engaged in similar efforts. At the NIH’s main campus in Bethesda, MD, staff at the clinical laboratory in the Clinical Center rapidly set up testing for SARS-CoV-2 RNA, and have now tested more than 1,000 NIH staff. Researchers at the Broad Institute of MIT and Harvard partnered with the city of Cambridge, MA, to pilot COVID-19 surveillance in homeless shelters and skilled nursing and assisted living facilities located there.

Hats off to everyone who goes the extra mile to get us through this tough time. I am so gratified when, guided by compassion and dogged determination of the human spirit, science leads the way and provides much needed hope for our future.

Reference:

[1] Blueprint for a Pop-up SARS-CoV-2 Testing Lab. Innovative Genomics Institute SARS-CoV-2 Testing Consortium, Hockemeyer D, Fyodor U, Doudna JA. 2020. medRxiv. Preprint posted on April 12, 2020.

Links:

Coronavirus (COVID-19) (NIH)

CLIA Law & Regulations (Centers for Disease Control and Prevention)

Innovative Genomic Institute (Berkeley, CA)

Doudna Lab (University of California, Berkeley)


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