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COVID-19

Testifying on COVID-19 Vaccine Development

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Testifying on Vaccine Development for COVID-19
It was an honor to testify before the U.S. Senate Appropriations Subcommittee on Labor, Health and Human Services, Education, and Related Agencies on July 2. The topic of the hearing was the President’s plan to develop and distribute a COVID-19 vaccine. Also testifying were Robert Redfield, director of the Centers for Disease Control and Prevention, and Gary Disbrow, acting director of Biomedical Advanced Research and Development Authority (BARDA). The nearly three-hour hearing allowed a productive exchange of information on this critical topic and many of NIH’s high-priority efforts to develop vaccines and therapeutics for COVID-19. Credit: C-Span.


Finding Antibodies that Neutralize SARS-CoV-2

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Neutralizing Antibodies
Caption: Model of three neutralizing antibodies (blue, purple and orange) bound to the spike protein, which allows SARS-CoV-2 attach to our cells. Credit: Christopher Barnes and Pamela Bjorkman, California Institute of Technology, Pasadena.

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


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)


Public Health Policies Have Prevented Hundreds of Millions of Coronavirus Infections

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Touchless carryout
Credit: Stock photo/Juanmonino

The alarming spread of coronavirus disease 2019 (COVID-19) last winter presented a profound threat to nations around the world. Many government leaders responded by shutting down all non-essential activities, implementing policies that public health officials were hopeful could slow the highly infectious SARS-CoV-2, the novel coronavirus that causes COVID-19.

But the shutdown has come at a heavy cost for the U.S. and global economies. It’s also taken a heavy personal toll on many of us, disrupting our daily routines—getting children off to school, commuting to the office or lab, getting together with friends and family, meeting face to face to plan projects, eating out, going to the gym—and causing lots of uncertainty and frustration.

As difficult as the shutdowns have been, new research shows that without these public health measures, things would have been much, much worse. According to a study published recently in Nature [1], the implementation of containment and mitigation strategies across the globe prevented or delayed about 530 million coronavirus infections across six countries—China, South Korea, Iran, Italy, France, and the United States. Take a moment to absorb that number—530 million. Right now, there are 8.8 million cases documented across the globe.

Estimates of the benefits of anti-contagion policies have drawn from epidemiological models that simulate the spread of COVID-19 in various ways, depending on assumptions built into each model. But models are sophisticated ways of guessing. Back when decisions about staying at home had to be made, no one knew for sure if, or how well, such approaches to limit physical contact would work. What’s more, the only real historical precedent was the 1918 Spanish flu pandemic in a very different, much-less interconnected world.

That made it essential to evaluate the pros and cons of these public health strategies within a society. As many people have rightfully asked: are the health benefits really worth the pain?

Recognizing a pressing need to answer this question, an international team of scientists dropped everything that they were doing to find out. Led by Solomon Hsiang, director of the University of California, Berkeley’s Global Policy Laboratory and Chancellor’s Professor at the Goldman School of Public Policy, a research group of 15 researchers from China, France, South Korea, New Zealand, Singapore, and the United States evaluated 1,717 policies implemented in all six countries between January 2020, when the virus began its global rise, and April 6, 2020.

The team relied on econometric methods that use statistics and math to uncover meaningful patterns hiding in mountains of data. As the name implies, these techniques are used routinely by economists to understand, in a before-and-after way, how certain events affect economic growth.

In this look-back study, scientists compare observations before and after an event they couldn’t control, such as a natural disaster or disease outbreak. In the case of COVID-19, these researchers compared public health datasets in multiple localities (e.g., states or cities) within each of the six countries before and several weeks after lockdowns. For each data sample from a given locality, the time period right before a policy deployment was the experimental “control” for the same locality several weeks after it received one or more shutdown policy “treatments.”

Hsiang and his colleagues measured the effects of all the different policies put into place at local, regional, and national levels. These included travel restrictions, business and school closures, shelter-in-place orders, and other actions that didn’t involve any type of medical treatment for COVID-19.

Because SARS-CoV-2 is a new virus, the researchers knew that early in the pandemic, everyone was susceptible, and the outbreak would grow exponentially. The scientists could then use a statistical method designed to estimate how the daily growth rate of infections changed over time within a location after different combinations of large-scale policies were put into place.

The result? Early in the pandemic, coronavirus infection rates grew 38 percent each day, on average, across the six countries: translating to a two-day doubling time. Applying all policies at once slowed the daily COVID-19 infection rate by 31 percentage points! Policies having the clearest benefit were business closures and lockdowns, whereas travel restrictions and bans on social gatherings had mixed results. Without more data, the analysis can’t specify why, but the way different countries enacted those policies might be one reason.

As we continue to try to understand and thwart this new virus and its damage to so many aspects of our personal and professional lives, these new findings add context, comfort, and guidance about the present circumstances. They tell us that individual sacrifices from staying home and canceled events contributed collectively to a huge, positive impact on the world.

Now, as various communities start cautiously to open up, we should continue to practice social distancing, mask wearing, and handwashing. This is not the time to say that the risk has passed. We are all tired of the virus and its consequences for our personal lives, but the virus doesn’t care. It’s still out there. Stay safe, everyone!

Reference:

[1] The effect of large-scale anti-contagion policies on the COVID-19 pandemic. Hsiang S, Allen D, Annan-Phan S, et al. Nature. 2020 June 8 [published online ahead of print].

Links:

Coronavirus (NIH)

Global Policy Lab: Effect of Anti-Contagion Policies (University of California, Berkeley)

Video: How much have policies to slow COVID-19 worked? (UC Berkeley)

Hsiang Lab (UC Berkeley)

Global Policy Lab Rallies for COVID-19 Research,” COVID-19 News, Goldman School of Public Policy, June 5, 2020.


Genes, Blood Type Tied to Risk of Severe COVID-19

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SARS-CoV-2 virus particles
Caption: Micrograph of SARS-CoV-2 virus particles isolated from a patient.
Credit: National Institute of Allergy and Infectious Diseases, NIH

Many people who contract COVID-19 have only a mild illness, or sometimes no symptoms at all. But others develop respiratory failure that requires oxygen support or even a ventilator to help them recover [1]. It’s clear that this happens more often in men than in women, as well as in people who are older or who have chronic health conditions. But why does respiratory failure also sometimes occur in people who are young and seemingly healthy?

A new study suggests that part of the answer to this question may be found in the genes that each one of us carries [2]. While more research is needed to pinpoint the precise underlying genes and mechanisms responsible, a recent genome-wide association (GWAS) study, just published in the New England Journal of Medicine, finds that gene variants in two regions of the human genome are associated with severe COVID-19 and correspondingly carry a greater risk of COVID-19-related death.

The two stretches of DNA implicated as harboring risks for severe COVID-19 are known to carry some intriguing genes, including one that determines blood type and others that play various roles in the immune system. In fact, the findings suggest that people with blood type A face a 50 percent greater risk of needing oxygen support or a ventilator should they become infected with the novel coronavirus. In contrast, people with blood type O appear to have about a 50 percent reduced risk of severe COVID-19.

These new findings—the first to identify statistically significant susceptibility genes for the severity of COVID-19—come from a large research effort led by Andre Franke, a scientist at Christian-Albrecht-University, Kiel, Germany, along with Tom Karlsen, Oslo University Hospital Rikshospitalet, Norway. Their study included 1,980 people undergoing treatment for severe COVID-19 and respiratory failure at seven medical centers in Italy and Spain.

In search of gene variants that might play a role in the severe illness, the team analyzed patient genome data for more than 8.5 million so-called single-nucleotide polymorphisms, or SNPs. The vast majority of these single “letter” nucleotide substitutions found all across the genome are of no health significance, but they can help to pinpoint the locations of gene variants that turn up more often in association with particular traits or conditions—in this case, COVID-19-related respiratory failure. To find them, the researchers compared SNPs in people with severe COVID-19 to those in more than 1,200 healthy blood donors from the same population groups.

The analysis identified two places that turned up significantly more often in the individuals with severe COVID-19 than in the healthy folks. One of them is found on chromosome 3 and covers a cluster of six genes with potentially relevant functions. For instance, this portion of the genome encodes a transporter protein known to interact with angiotensin converting enzyme 2 (ACE2), the surface receptor that allows the novel coronavirus that causes COVID-19, SARS-CoV-2, to bind to and infect human cells. It also encodes a collection of chemokine receptors, which play a role in the immune response in the airways of our lungs.

The other association signal popped up on chromosome 9, right over the area of the genome that determines blood type. Whether you are classified as an A, B, AB, or O blood type, depends on how your genes instruct your blood cells to produce (or not produce) a certain set of proteins. The researchers did find evidence suggesting a relationship between blood type and COVID-19 risk. They noted that this area also includes a genetic variant associated with increased levels of interleukin-6, which plays a role in inflammation and may have implications for COVID-19 as well.

These findings, completed in two months under very difficult clinical conditions, clearly warrant further study to understand the implications more fully. Indeed, Franke, Karlsen, and many of their colleagues are part of the COVID-19 Host Genetics Initiative, an ongoing international collaborative effort to learn the genetic determinants of COVID-19 susceptibility, severity, and outcomes. Some NIH research groups are taking part in the initiative, and they recently launched a study to look for informative gene variants in 5,000 COVID-19 patients in the United States and Canada.

The hope is that these and other findings yet to come will point the way to a more thorough understanding of the biology of COVID-19. They also suggest that a genetic test and a person’s blood type might provide useful tools for identifying those who may be at greater risk of serious illness.

References:

[1] Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. Wu Z, McGoogan JM, et. al. 2020 Feb 24. [published online ahead of print]

[2] Genomewide association study of severe Covid-19 with respiratory failure. Ellinghaus D, Degenhardt F, et. a. NEJM. June 17, 2020.

Links:

The COVID-19 Host Genetics Initiative

Andre Franke (Christian-Albrechts-University of Kiel, Germany)

Tom Karlsen (Oslo University Hospital Rikshospitalet, Norway)


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