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Antibody Points to Possible Weak Spot on Novel Coronavirus

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Credit: Meng Yuan and Nicholas Wu, Wilson Lab, The Scripps Research Institute, La Jolla, CA

Researchers are working hard to produce precise, 3D molecular maps to guide the development of safe, effective ways of combating the coronavirus disease 2019 (COVID-19) pandemic. While there’s been a lot of excitement surrounding the promise of antibody-based tests and treatments, this map you see above highlights another important use of antibodies: to inform efforts to design a vaccine.

This image shows the crystal structure of a human antibody (heavy chain in orange, light chain in yellow), which is a blood protein our immune systems produce to attack viruses and other foreign invaders. This particular antibody, called CR3022, is bound to a key surface protein of the novel coronavirus (white).

The CR3022 antibody actually doesn’t come from someone who has recovered from COVID-19. Instead, it was obtained from a person who, nearly two decades ago, survived a bout of severe acute respiratory syndrome (SARS). The SARS virus, which disappeared in 2004 after a brief outbreak in humans, is closely related to the novel coronavirus that causes COVID-19.

In a recent paper in the journal Science, the NIH-funded lab of Ian Wilson, The Scripps Research Institute, La Jolla, CA, along with colleagues at The University of Hong Kong, sought to understand how the human immune system interacts with and neutralizes this highly infectious virus [1]. The lab did so by employing high-resolution X-ray crystallography tools [2]. They captured the atomic structure of this antibody bound to its target by shooting X-rays through its crystallized form. (An antibody measures about 10 nanometers; a nanometer is 1 billionth of a meter.)

Other researchers had shown previously that CR3022 cross-reacts with the novel coronavirus, although the antibody doesn’t bind tightly enough to neutralize and stop it from infecting cells. So, Wilson’s team went to work to learn precisely where the antibody attaches to the novel virus. Those sites are of special interest because they highlight spots on a virus that are vulnerable to attack—and, as such, potentially good targets for vaccine designers.

A key finding in the new paper is that the antibody binds a highly similar site on both the SARS and novel coronaviruses. Those sites differ in each virus by just four amino acids, the building blocks of a protein.

This is particularly interesting because the antibody pictured above is bound to a spike protein, which is the appendage on both the SARS and novel coronavirus that enables them to bind to a key receptor protein on the surface of human cells, called ACE2. This binding activity marks the first step for these viruses in gaining entry into human cells and infecting them.

The human antibody shown in this image locks onto the virus’s spike protein at a different location than where the human ACE2 protein binds to the novel coronavirus. Intriguingly, the antibody binds to a spot on the novel coronavirus that is usually hidden, except for when virus shapeshifts its structure in order to infect a cell.

The findings suggest that a successful vaccine may be one that elicits antibodies that targets this same spot, but binds more tightly than the one seen above, thereby protecting human cells against the virus that causes COVID-19. However, Wilson notes that this study has just uncovered one potential vulnerability of the novel coronavirus, and it is likely the virus likely has many more that could be revealed with further study.

To continue in this quest to design a safe and effective vaccine, Wilson and his colleagues are now gathering blood samples to collect antibodies from people who’ve recovered from COVID-19. So, we can look forward to seeing some even more revealing images soon.

References:

[1] A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV. Yuan M, Wu NC, Zhu X, Lee CD, So RTY, Lv H, Mok CKP, Wilson IA. Science. 2020 Apr 3.

[2] 100 Years Later: Celebrating the Contributions of X-ray Crystallography to Allergy and Clinical Immunology. Pomés A, Chruszcz M, Gustchina A, Minor W, Mueller GA, Pedersen LC, Wlodawer A, Chapman MD. J Allergy Clin Immunol. 2015 Jul;136(1):29-37.

Links:

Coronaviruses (National Institute of Allergy and Infectious Diseases/NIH)

Coronavirus (COVID-19) (NIH)

Ian Wilson (The Scripps Research Institute, La Jolla, CA)

NIH Support: National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Institute of General Medical Sciences


Genomic Study Points to Natural Origin of COVID-19

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COVID-19 Update

No matter where you go online these days, there’s bound to be discussion of coronavirus disease 2019 (COVID-19). Some folks are even making outrageous claims that the new coronavirus causing the pandemic was engineered in a lab and deliberately released to make people sick. A new study debunks such claims by providing scientific evidence that this novel coronavirus arose naturally.

The reassuring findings are the result of genomic analyses conducted by an international research team, partly supported by NIH. In their study in the journal Nature Medicine, Kristian Andersen, Scripps Research Institute, La Jolla, CA; Robert Garry, Tulane University School of Medicine, New Orleans; and their colleagues used sophisticated bioinformatic tools to compare publicly available genomic data from several coronaviruses, including the new one that causes COVID-19.

The researchers began by homing in on the parts of the coronavirus genomes that encode the spike proteins that give this family of viruses their distinctive crown-like appearance. (By the way, “corona” is Latin for “crown.”) All coronaviruses rely on spike proteins to infect other cells. But, over time, each coronavirus has fashioned these proteins a little differently, and the evolutionary clues about these modifications are spelled out in their genomes.

The genomic data of the new coronavirus responsible for COVID-19 show that its spike protein contains some unique adaptations. One of these adaptations provides special ability of this coronavirus to bind to a specific protein on human cells called angiotensin converting enzyme (ACE2). A related coronavirus that causes severe acute respiratory syndrome (SARS) in humans also seeks out ACE2.

Existing computer models predicted that the new coronavirus would not bind to ACE2 as well as the SARS virus. However, to their surprise, the researchers found that the spike protein of the new coronavirus actually bound far better than computer predictions, likely because of natural selection on ACE2 that enabled the virus to take advantage of a previously unidentified alternate binding site. Researchers said this provides strong evidence that that new virus was not the product of purposeful manipulation in a lab. In fact, any bioengineer trying to design a coronavirus that threatened human health probably would never have chosen this particular conformation for a spike protein.

The researchers went on to analyze genomic data related to the overall molecular structure, or backbone, of the new coronavirus. Their analysis showed that the backbone of the new coronavirus’s genome most closely resembles that of a bat coronavirus discovered after the COVID-19 pandemic began. However, the region that binds ACE2 resembles a novel virus found in pangolins, a strange-looking animal sometimes called a scaly anteater. This provides additional evidence that the coronavirus that causes COVID-19 almost certainly originated in nature. If the new coronavirus had been manufactured in a lab, scientists most likely would have used the backbones of coronaviruses already known to cause serious diseases in humans.

So, what is the natural origin of the novel coronavirus responsible for the COVID-19 pandemic? The researchers don’t yet have a precise answer. But they do offer two possible scenarios.

In the first scenario, as the new coronavirus evolved in its natural hosts, possibly bats or pangolins, its spike proteins mutated to bind to molecules similar in structure to the human ACE2 protein, thereby enabling it to infect human cells. This scenario seems to fit other recent outbreaks of coronavirus-caused disease in humans, such as SARS, which arose from cat-like civets; and Middle East respiratory syndrome (MERS), which arose from camels.

The second scenario is that the new coronavirus crossed from animals into humans before it became capable of causing human disease. Then, as a result of gradual evolutionary changes over years or perhaps decades, the virus eventually gained the ability to spread from human-to-human and cause serious, often life-threatening disease.

Either way, this study leaves little room to refute a natural origin for COVID-19. And that’s a good thing because it helps us keep focused on what really matters: observing good hygiene, practicing social distancing, and supporting the efforts of all the dedicated health-care professionals and researchers who are working so hard to address this major public health challenge.

Finally, next time you come across something about COVID-19 online that disturbs or puzzles you, I suggest going to FEMA’s new Coronavirus Rumor Control web site. It may not have all the answers to your questions, but it’s definitely a step in the right direction in helping to distinguish rumors from facts.

Reference:
[1] The proximal origin of SARS-CoV-2. Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. Nat Med, 17 March 2020. [Epub ahead of publication]

Links:

Coronavirus (COVID-19) (NIH)

COVID-19, MERS & SARS (National Institute of Allergy and Infectious Diseases/NIH)

Andersen Lab (Scripps Research Institute, La Jolla, CA)

Robert Garry (Tulane University School of Medicine, New Orleans)

Coronavirus Rumor Control (FEMA)

NIH Support: National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute


To Beat COVID-19, Social Distancing is a Must

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Teleworking with family at home
gettyimages/SDI Productions

Even in less challenging times, many of us try to avoid close contact with someone who is sneezing, coughing, or running a fever to avoid getting sick ourselves. Our attention to such issues has now been dramatically heightened by the emergence of a novel coronavirus causing a pandemic of an illness known as COVID-19.

Many have wondered if we couldn’t simply protect ourselves by avoiding people with symptoms of respiratory illness. Unfortunately, the answer is no. A new study shows that simply avoiding symptomatic people will not go far enough to curb the COVID-19 pandemic. That’s because researchers have discovered that many individuals can carry the novel coronavirus without showing any of the typical symptoms of COVID-19: fever, dry cough, and shortness of breath. But these asymptomatic or only mildly ill individuals can still shed virus and infect others.

This conclusion adds further weight to the recent guidance from U.S. public health experts: what we need most right now to slow the stealthy spread of this new coronavirus is a full implementation of social distancing. What exactly does social distancing mean? Well, for starters, it is recommended that people stay at home as much as possible, going out only for critical needs like groceries and medicines, or to exercise and enjoy the outdoors in wide open spaces. Other recommendations include avoiding gatherings of more than 10 people, no handshakes, regular handwashing, and, when encountering someone outside of your immediate household, trying to remain at least 6 feet apart.

These may sound like extreme measures. But the new study by NIH-funded researchers, published in the journal Science, documents why social distancing may be our best hope to slow the spread of COVID-19 [1]. Here are a few highlights of the paper, which looks back to January 2020 and mathematically models the spread of the coronavirus within China:

• For every confirmed case of COVID-19, there are likely another five to 10 people with undetected infections.
• Although they are thought to be only about half as infectious as individuals with confirmed COVID-19, individuals with undetected infections were so prevalent in China that they apparently were the infection source for 86 percent of confirmed cases.
• After China established travel restrictions and social distancing, the spread of COVID-19 slowed considerably.

The findings come from a small international research team that included NIH grantee Jeffrey Shaman, Columbia University Mailman School of Public Health, New York. The team developed a computer model that enabled researchers to simulate the time and place of infections in a grid of 375 Chinese cities. The researchers did so by combining existing data on the spread of COVID-19 in China with mobility information collected by a location-based service during the country’s popular 40-day Spring Festival, when travel is widespread.

As these new findings clearly demonstrate, each of us must take social distancing seriously in our daily lives. Social distancing helped blunt the pandemic in China, and it will work in other nations, including the United States. While many Americans will likely spend weeks working and studying from home and practicing other social distancing measures, the stakes remain high. If this pandemic isn’t contained, this novel coronavirus could well circulate around the globe for years to come, at great peril to us and our loved ones.

As we commit ourselves to spending more time at home, progress continues to be made in using the power of biomedical research to combat this novel coronavirus. A notable step this week was the launch of an early-stage human clinical trial of an investigational vaccine, called mRNA-1273, to protect against COVID-19 [2]. The vaccine candidate was developed by researchers at NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and their collaborators at the biotechnology company Moderna, Inc., Cambridge, MA.

This Phase 1 NIAID-supported trial will look at the safety of the vaccine—which cannot cause infection because it is made of RNA, not the whole coronavirus—in 45 healthy adults. The first volunteer was injected this past Monday at Kaiser Permanente Washington Health Research Institute, Seattle. If all goes well and larger follow-up clinical studies establish the vaccine’s safety and efficacy, it will then be necessary to scale up production to make millions of doses. While initiating this trial in record time is reason for hope, it is important to be realistic about all of the steps that still remain. If the vaccine candidate proves safe and effective, it will likely take at least 12–18 months before it would be widely available.

In the meantime, social distancing remains one of the best weapons we have to slow the silent spread of this virus and flatten the curve of the COVID-19 pandemic. This will give our health-care professionals, hospitals, and other institutions more valuable time to prepare, protect themselves, and aid the many people whose lives may be on the line from this coronavirus.

Importantly, saving lives from COVID-19 requires all of us—young, old and in-between—to take part. Healthy young people, whose risk of dying from coronavirus is not zero but quite low, might argue that they shouldn’t be constrained by social distancing. However, the research highlighted here demonstrates that such individuals are often the unwitting vector for a dangerous virus that can do great harm—and even take the lives of older and more vulnerable people. Think about your grandparents. Then skip the big gathering. We are all in this together

References:

[1] Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2). Li R, Pei S, Chen B, Song Y, Zhang T, Yang W, Shaman J. Science. 16 March 2020. [Preprint ahead of publication]

[2] NIH clinical trial of investigational vaccine for COVID-19 begins. NIH News Release, March 16, 2020.

Links:

Coronavirus (COVID-19) (NIH)

COVID-19, MERS & SARS (National Institute of Allergy and Infectious Diseases/NIH)

Coronavirus (COVID-19) (Centers for Disease Control and Prevention, Atlanta)

NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences


Structural Biology Points Way to Coronavirus Vaccine

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Spike Protein on Novel Coronavirus
Caption: Atomic-level structure of the spike protein of the virus that causes COVID-19.
Credit: McLellan Lab, University of Texas at Austin

The recent COVID-19 outbreak of a novel type of coronavirus that began in China has prompted a massive global effort to contain and slow its spread. Despite those efforts, over the last month the virus has begun circulating outside of China in multiple countries and territories.

Cases have now appeared in the United States involving some affected individuals who haven’t traveled recently outside the country. They also have had no known contact with others who have recently arrived from China or other countries where the virus is spreading. The NIH and other U.S. public health agencies stand on high alert and have mobilized needed resources to help not only in its containment, but in the development of life-saving interventions.

On the treatment and prevention front, some encouraging news was recently reported. In record time, an NIH-funded team of researchers has created the first atomic-scale map of a promising protein target for vaccine development [1]. This is the so-called spike protein on the new coronavirus that causes COVID-19. As shown above, a portion of this spiky surface appendage (green) allows the virus to bind a receptor on human cells, causing other portions of the spike to fuse the viral and human cell membranes. This process is needed for the virus to gain entry into cells and infect them.

Preclinical studies in mice of a candidate vaccine based on this spike protein are already underway at NIH’s Vaccine Research Center (VRC), part of the National Institute of Allergy and Infectious Diseases (NIAID). An early-stage phase I clinical trial of this vaccine in people is expected to begin within weeks. But there will be many more steps after that to test safety and efficacy, and then to scale up to produce millions of doses. Even though this timetable will potentially break all previous speed records, a safe and effective vaccine will take at least another year to be ready for widespread deployment.

Coronaviruses are a large family of viruses, including some that cause “the common cold” in healthy humans. In fact, these viruses are found throughout the world and account for up to 30 percent of upper respiratory tract infections in adults.

This outbreak of COVID-19 marks the third time in recent years that a coronavirus has emerged to cause severe disease and death in some people. Earlier coronavirus outbreaks included SARS (severe acute respiratory syndrome), which emerged in late 2002 and disappeared two years later, and MERS (Middle East respiratory syndrome), which emerged in 2012 and continues to affect people in small numbers.

Soon after COVID-19 emerged, the new coronavirus, which is closely related to SARS, was recognized as its cause. NIH-funded researchers including Jason McLellan, an alumnus of the VRC and now at The University of Texas at Austin, were ready. They’d been studying coronaviruses in collaboration with NIAID investigators for years, with special attention to the spike proteins.

Just two weeks after Chinese scientists reported the first genome sequence of the virus [2], McLellan and his colleagues designed and produced samples of its spike protein. Importantly, his team had earlier developed a method to lock coronavirus spike proteins into a shape that makes them both easier to analyze structurally via the high-resolution imaging tool cryo-electron microscopy and to use in vaccine development efforts.

After locking the spike protein in the shape it takes before fusing with a human cell to infect it, the researchers reconstructed its atomic-scale 3D structural map in just 12 days. Their results, published in Science, confirm that the spike protein on the virus that causes COVID-19 is quite similar to that of its close relative, the SARS virus. It also appears to bind human cells more tightly than the SARS virus, which may help to explain why the new coronavirus appears to spread more easily from person to person, mainly by respiratory transmission.

McLellan’s team and his NIAID VRC counterparts also plan to use the stabilized spike protein as a probe to isolate naturally produced antibodies from people who’ve recovered from COVID-19. Such antibodies might form the basis of a treatment for people who’ve been exposed to the virus, such as health care workers.

The NIAID is now working with the biotechnology company Moderna, Cambridge, MA, to use the latest findings to develop a vaccine candidate using messenger RNA (mRNA), molecules that serve as templates for making proteins. The goal is to direct the body to produce a spike protein in such a way to elicit an immune response and the production of antibodies. An early clinical trial of the vaccine in people is expected to begin in the coming weeks. Other vaccine candidates are also in preclinical development.

Meanwhile, the first clinical trial in the U.S. to evaluate an experimental treatment for COVID-19 is already underway at the University of Nebraska Medical Center’s biocontainment unit [3]. The NIH-sponsored trial will evaluate the safety and efficacy of the experimental antiviral drug remdesivir in hospitalized adults diagnosed with COVID-19. The first participant is an American who was repatriated after being quarantined on the Diamond Princess cruise ship in Japan.

As noted, the risk of contracting COVID-19 in the United States is currently low, but the situation is changing rapidly. One of the features that makes the virus so challenging to stay in front of is its long latency period before the characteristic flu-like fever, cough, and shortness of breath manifest. In fact, people infected with the virus may not show any symptoms for up to two weeks, allowing them to pass it on to others in the meantime. You can track the reported cases in the United States on the Centers for Disease Control and Prevention’s website.

As the outbreak continues over the coming weeks and months, you can be certain that NIH and other U.S. public health organizations are working at full speed to understand this virus and to develop better diagnostics, treatments, and vaccines.

References:

[1] Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, Graham BS, McLellan JS. Science. 2020 Feb 19.

[2] A new coronavirus associated with human respiratory disease in China. Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, Hu Y, Tao ZW, Tian JH, Pei YY, Yuan ML, Zhang YL, Dai FH, Liu Y, Wang QM, Zheng JJ, Xu L, Holmes EC, Zhang YZ. Nature. 2020 Feb 3.

[3] NIH clinical trial of remdesivir to treat COVID-19 begins. NIH News Release. Feb 25, 2020.

Links:

Coronaviruses (National Institute of Allergy and Infectious Diseases/NIH)

Coronavirus (COVID-19) (NIAID)

Coronavirus Disease 2019 (Centers for Disease Control and Prevention, Atlanta)

NIH Support: National Institute of Allergy and Infectious Diseases


Promising Treatment for New Human Coronavirus

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In Fall 2012 a new coronavirus appeared on the global public health radar. The virus has caused 17 cases of severe respiratory disease in the Middle East and Europe, and 11 of these people died. This new virus attracted immediate attention because of the high fatality rate—and because it was in the same family as the virus that caused the global outbreak of severe acute respiratory syndrome (SARS) in 2003, which sickened more than 8,000 people.