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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


Zika Virus: An Emerging Health Threat

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Credit: Kraemer et al. eLife 2015;4:e08347

For decades, the mosquito-transmitted Zika virus was mainly seen in equatorial regions of Africa and Asia, where it caused a mild, flu-like illness and rash in some people. About 10 years ago, the picture began to expand with the appearance of Zika outbreaks in the Pacific islands. Then, last spring, Zika popped up in South America, where it has so far infected more than 1 million Brazilians and been tentatively linked to a steep increase in the number of babies born with microcephaly, a very serious condition characterized by a small head and brain [1]. And Zika’s disturbing march may not stop there.

In a new study in the journal The Lancet, infectious disease modelers calculate that Zika virus has the potential to spread across warmer and wetter parts of the Western Hemisphere as local mosquitoes pick up the virus from infected travelers and then spread the virus to other people [2]. The study suggests that Zika virus could eventually reach regions of the United States in which 60 percent of our population lives. This highlights the need for NIH and its partners in the public and private sectors to intensify research on Zika virus and to look for new ways to treat the disease and prevent its spread.


How Influenza Pandemics Occur

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Credit: National Institute of Allergy and Infectious Diseases, NIH

Flu season is upon us! Check out this NIH video to see how these pandemics emerge and spread new flu viruses around the globe.


The Diabetes Threat

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The number of Americans diagnosed with type 2 diabetes rose from 1.5 million in 1958 to 18.8 million in 2010. That’s an increase of epidemic proportions. Even more disturbing, another 7 million Americans have type 2 diabetes, but don’t know it and, consequently, can’t take steps to control the disease. Altogether, over 8% of the U.S. population now has this potentially deadly metabolic condition.

  • Type 2 diabetes wreaks havoc on the body by raising the levels of glucose in the blood, increasing the risk of blindness, heart disease, kidney failure, nerve damage, and even Alzheimer’s disease.
  • Pre-diabetes is a condition in which blood glucose levels are higher than normal, but not high enough to be called diabetes. 79 million U.S. adults age 20 and older have pre-diabetes.
  • NIH studies have shown that losing just 6–7% of body weight and increasing physical activity can prevent or delay pre-diabetes from progressing to diabetes. 85% of people with diabetes are overweight.

Photo of a pair of sneakers with the text "November is National Diabetes Month -  Be Active - Make a plan to live well."


A View of the U.S. Obesity Epidemic

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Map showing Percent of Obese (BMI > 30) in U.S. Adults in 1985

 

Map showing Percent of Obese (BMI > 30) in U.S. Adults in 1995 by state

 

Map showing Percent of Obese (BMI > 30) in U.S. Adults in 2005 by state

 

Map showing Percent of Obese (BMI > 30) in U.S. Adults in 2010 by state

These snapshots reveal a very disturbing trend: the rise in obesity in the US from 1985 to 2010. Today one third of adults in the US are obese, another third are overweight.

Because obesity has risen to epidemic levels—causing devastating and costly health problems, reducing life expectancy, and provoking stigma and discrimination—the NIH has established the NIH Obesity Research Task Force to accelerate progress in obesity research. For example, why are some individuals more susceptible to obesity? Can knowledge of biology and behavior be leveraged to develop better intervention strategies? What strategies work? For whom? Can these approaches be scaled up?