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NIH’s All of Us Program Joins Fight Against COVID-19

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We’ve learned so much about coronavirus disease 2019 (COVID-19), but there’s still much more that we need to learn in order to defeat this devastating pandemic. Among the critical questions: why do some young people who appear healthy and have no history of chronic disease get very sick from the virus? And why do some people in their 80s or 90s seemingly just shrug off the infection? There’s something going on biologically, but we don’t yet have the answers.

We do, however, have some resources that will enable us to examine lots of data in search of biological clues. One of them is NIH’s All of Us Research Program, which is seeking the help of 1 million people to build one of the most diverse health databases in our nation’s history. Two years after its national launch, the program already has enrolled nearly 350,000 diverse participants from across the United States.

As its name suggests, All of Us is open to all people over age 18 in communities all around the country. An important strength of the effort has been welcoming participants from all backgrounds. Indeed, about 75 percent of people who have volunteered for the program come from groups that have traditionally been underrepresented in medical research. That includes people from many racial and ethnic minority groups, as well as those of many different ages, socioeconomic backgrounds, and geographic locations, including remote and rural areas.

Because of COVID-19 and the need for physical distancing to curb the spread of the potentially deadly virus, All of Us has been forced to halt temporarily all in-person appointments. But program leaders, including Josh Denny, chief executive officer of All of Us, and Kelly Gebo, the program’s chief medical and scientific officer, saw an opportunity to roll up their sleeves and help during this unprecedented public health challenge. In fact, Gebo reports that they’d already been hearing from many of their participant partners that they wanted to be a part of the solution to the COVID-19 pandemic.

To rise to this challenge, the All of Us Research Program has just announced three initiatives to assist the scientific community in seeking new insights into COVID-19. The program will:

• Test blood samples from 10,000 or more participants for the presence of SARS-CoV-2 antibodies, indicating prior infection. The testing will start on samples collected in March 2020 and work backward until positive tests are no longer found. This will show the prevalence of novel coronavirus exposure among All of Us participants from across the country, allowing researchers to sift through the data and assess the varying rates and timing of infections across regions and communities.

• Rapidly collect relevant information from more than 200,000 participants who have shared their electronic health records. A number of those participants have already either been diagnosed with COVID-19 or sought health care for related symptoms. The program is working to standardize this information. It will help researchers look for patterns and learn more about COVID-19 symptoms and associated health problems, as well as the effects of different medicines and treatments.

• Deploy a new online survey to understand better the effects of the COVID-19 pandemic on participants’ physical and mental health. This 20- to 30-minute survey is designed both for participants who have been ill with COVID-19 and those who have not knowingly been infected. Questions will be included on COVID-19 symptoms, stress, social distancing and the economic impacts of the pandemic. Participants are invited to take the survey each month until the pandemic ends, so researchers can study the effects of COVID-19 over time and begin to better understand how and why COVID-19 affects people differently.

As this data becomes available, researchers will look for new leads to inform our efforts to bring greater precision to the diagnosis, treatment, and prevention of COVID-19, including for those communities that have been hit the hardest. Another hope is that what is learned about COVID-19 through All of Us and other NIH-supported research will provide us with the knowledge and tools we need to avert future pandemics,

In case you’re wondering, I happen to be among the thousands of people who’ve already volunteered to take part in All of Us. If you’d like to get involved too, new participants are always welcome to join.

Links:

Coronavirus (COVID-19) (NIH)

All of Us Research Program (NIH)

Join All of Us (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)


Will Warm Weather Slow Spread of Novel Coronavirus?

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Summer gear and a face mask
Credit: Modified from iStock/energyy

With the start of summer coming soon, many are hopeful that the warmer weather will slow the spread of SARS-CoV-2, the novel coronavirus that causes COVID-19. There have been hints from lab experiments that increased temperature and humidity may reduce the viability of SARS-CoV-2. Meanwhile, other coronaviruses that cause less severe diseases, such as the common cold, do spread more slowly among people during the summer.

We’ll obviously have to wait a few months to get the data. But for now, many researchers have their doubts that the COVID-19 pandemic will enter a needed summertime lull. Among them are some experts on infectious disease transmission and climate modeling, who ran a series of sophisticated computer simulations of how the virus will likely spread over the coming months [1]. This research team found that humans’ current lack of immunity to SARS-CoV-2—not the weather—will likely be a primary factor driving the continued, rapid spread of the novel coronavirus this summer and into the fall.

These sobering predictions, published recently in the journal Science, come from studies led by Rachel Baker and Bryan Grenfell at Princeton Environmental Institute, Princeton, NJ. The Grenfell lab has long studied the dynamics of infectious illnesses, including seasonal influenza and respiratory syncytial virus (RSV). Last year, they published one of the first studies to look at how our warming climate might influence those dynamics in the coming years [2].

Those earlier studies focused on well-known human infectious diseases. Less clear is how seasonal variations in the weather might modulate the spread of a new virus that the vast majority of people and their immune systems have yet to encounter.

In the new study, the researchers developed a mathematical model to simulate how seasonal changes in temperature might influence the trajectory of COVID-19 in cities around the world. Of course, because the virus emerged on the scene only recently, we don’t know very much about how it will respond to warming conditions. So, the researchers ran three different scenarios based on what’s known about the role of climate in the spread of other viruses, including two coronaviruses, called OC43 and HKU1, that are known to cause common colds in people.

In all three scenarios, their models showed that climate only would become an important seasonal factor in controlling COVID-19 once a large proportion of people within a given community are immune or resistant to infection. In fact, the team found that, even if one assumes that SARS-CoV-2 is as sensitive to climate as other seasonal viruses, summer heat still would not be enough of a mitigator right now to slow its initial, rapid spread through the human population. That’s also clear from the rapid spread of COVID-19 that’s currently occurring in Brazil, Ecuador, and some other tropical nations.

Over the longer term, as more people develop immunity, the researchers suggest that COVID-19 may likely fall into a seasonal pattern similar to those seen with diseases caused by other coronaviruses. Long before then, NIH is working intensively with partners from all sectors to make sure that safe, effective treatments and vaccines will be available to help prevent the tragic, heavy loss of life that we’re seeing now.

Of course, climate is just one key factor to consider in evaluating the course of this disease. And, there is a glimmer of hope in one of the group’s models. The researchers incorporated the effects of control measures, such as physical distancing, with climate. It appears from this model that such measures, in combination with warm temperatures, actually might combine well to help slow the spread of this devastating virus. It’s a reminder that physical distancing will remain our best weapon into the summer to slow or prevent the spread of COVID-19. So, keep wearing those masks and staying 6 feet or more apart!

References:

[1] Susceptible supply limits the role of climate in the early SARS-CoV-2 pandemic. Baker RE, Yang W, Vecchi GA, Metcalf CJE, Grenfell BT. Science. 2020 May 18. [Online ahead of print.]

[2] Epidemic dynamics of respiratory syncytial virus in current and future climates. Baker RE, Mahmud AS, Wagner CE, Yang W, Pitzer VE, Viboud C, Vecchi GA, Metcalf CJE, Grenfell BT.Nat Commun. 2019 Dec 4;10(1):5512.

Links:

Coronavirus (COVID-19) (NIH)

Bryan Grenfell (Princeton University, Princeton, NJ)

Rachel Baker (Princeton University, Princeton, NJ)


3D Printing the Novel Coronavirus

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Credit: 3D Print Exchange, NIAID, NIH

The coronavirus disease 2019 (COVID-19) pandemic has truly been an all-hands-on-deck moment for the nation. Among the responders are many with NIH affiliations, who are lending their expertise to deploy new and emerging technologies to address myriad research challenges. That’s certainly the case for the dedicated team from the National Institute of Allergy and Infectious Diseases (NIAID) at the NIH 3D Print Exchange (3DPX), Rockville, MD.

A remarkable example of the team’s work is this 3D-printed physical model of SARS-CoV-2, the novel coronavirus that causes COVID-19. This model shows the viral surface (blue) and the spike proteins studded proportionally to the right size and shape. These proteins are essential for SARS-CoV-2 to attach to human cells and infect them. Here, the spike proteins are represented in their open, active form (orange) that’s capable of attaching to a human cell, as well as in their closed, inactive form (red).

The model is about 5 inches in diameter. It takes more than 5 hours to print using an “ink” of thin layers of a gypsum plaster-based powder fused with a colored binder solution. When completed, the plaster model is coated in epoxy for strength and a glossy, ceramic-like finish. For these models, NIAID uses commercial-grade, full-color 3D printers. However, the same 3D files can be used in any type of 3D printer, including “desktop” models available on the consumer market.

Darrell Hurt and Meghan McCarthy lead the 3DPX team. Kristen Browne, Phil Cruz, and Victor Starr Kramer, the team members who helped to produce this remarkable model, created it as part of a collaboration with the imaging team at NIAID’s Rocky Mountain Laboratories (RML), Hamilton, MT.

The RML’s Electron Microscopy Unit captured the microscopic 3D images of the virus, which was cultured from one of the first COVID-19 patients in the country. The unit handed off these and other data to its in-house visual specialist to convert into a preliminary 3D model. The model was then forwarded to the 3DPX team in Maryland to colorize and optimize in preparation for 3D printing.

This model is especially unique because it’s based exclusively on SARS-CoV-2 data. For example, the model is assembled from data showing that the virus is frequently oval, not perfectly round. The spike proteins also aren’t evenly spaced, but pop up more randomly from the surface. Another nice feature of 3D printing is the models can be constantly updated to incorporate the latest structural discoveries.

That’s why 3D models are such an excellent teaching tools to share among scientists and the public. Folks can hold the plaster virus and closely examine its structure. In fact, the team recently printed out a model and delivered it to me for exactly this educational purpose.

In addition to this complete model, the researchers also are populating the online 3D print exchange with atomic-level structures of the various SARS-CoV-2 proteins that have been deposited by researchers around the world into protein and electron microscopy databanks. The number of these structures and plans currently stands at well over 100—and counting.

As impressive as this modeling work is, 3DPX has found yet another essential way to aid in the COVID-19 fight. In March, the Food and Drug Administration (FDA) announced a public-private partnership with the NIH 3D Print Exchange, Department of Veterans Affairs (VA) Innovation Ecosystem, and the non-profit America Makes, Youngstown, OH [1]. The partnership will develop a curated collection of designs for 3D-printable personal protective equipment (PPE), as well as other necessary medical devices that are in short supply due to the COVID-19 pandemic.

You can explore the partnership’s growing collection of COVID-19-related medical supplies online. And, if you happen to have a 3D printer handy, you could even try making them for yourself.

Reference:

[1] FDA Efforts to Connect Manufacturers and Health Care Entities: The FDA, Department of Veterans Affairs, National Institutes of Health, and America Makes Form a COVID-19 response Public-Private Partnership (Food and Drug Administration)

Links:

Coronavirus (COVID-19) (NIH)

NIH 3D Print Exchange (National Institute of Allergy and Infectious Diseases/NIH, Rockville, MD)

Rocky Mountain Laboratories (NIAID/NIH, Hamilton, MT)

Department of Veterans Affairs (VA) Innovation Ecosystem (Washington, D.C.)

America Makes (Youngstown, OH)

NIH Support: National Institute of Allergy and Infectious Diseases


Enlisting Monoclonal Antibodies in the Fight Against COVID-19

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B38 Antibody and SARS-CoV-2 wtih ACE2 Receptor
Caption: Antibody Binding to SARS-CoV-2. Structural illustration of B38 antibody (cyan, green) attached to receptor-binding domain of the coronavirus SARS-CoV-2 (magenta). B38 blocks SARS-CoV-2 from binding to the ACE2 receptor (light pink) of a human cell, ACE2 is what the virus uses to infect cells. Credit: Y. Wu et a. Science, 2020

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


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