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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

76 Comments

  • C says:

    Is it possible that the virus mutates and could also be transmitted for example by animals, insects, in water and so on?
    Or could it mutate and get resistent against certain medications?
    And if so does the risk of mutation increase the more people get infected?

    • Bill Hutchins says:

      Viruses mutate all the time. This blog lists three small early stage attempts at SARS-Cov-2 research.

      • Eunice Afonso says:

        Human cells differ from individual to individual. Maybe the virus reacts differently depending on the human host. But it surprized me that specially individuals with Cancers or under cancer treatments can acquire this virus. Most Cancers are aggressive and do not like other viruses to interfere. As well humans under cancer treatment, usually take prescriptions that improve human immune system, in order to fight the cancer. IDK I am just a 58 old lady, that worked with the Public for 30 years. I till now, can say I don’t get the Flu, nor the vaccines. However, this “sea spiky” looking Virus seems more aggressive them the Flu Virus.

  • anna zinonos says:

    the cases of people who didnt meet a carrier could mean many surfaces in public building were contaminated

    Is there any progress in medicines research? medicines maybe could be produced faster than a vaccine that would inhibit the virus from becoming terminal for the patients?

    • Bill Hutchins says:

      Remdesevir is a medicine, Anna. Commonly touched surfaces should be cleaned very often. Especially now, since institutes like the NIH need a lot of money to even start saving lives, let alone improve outcomes or reduce infectivity.

  • Douglas Mitchell says:

    Excellent! Serine. Acidifying endocytic P.H.?.LJ001. lipid solvent Sugar!

  • Aaron Gill says:

    Test Ciclesonide inhaler seems to stop RNA replication and provide relief.

  • Wesley Bonacini says:

    Is possible to use nk3 to kill the cycle of the vírus? Maybe working to another virus too? Or NKT for exemple…? Something with the (CeA) … Protein K3.

    • Yonis says:

      If the virus is not resistant to antibacterial gels, soaps and other substances, why you do not evaluate the composition of said bactericides and create something that can be administered intravenously to attack covid19 from inside the body without causing harm considered for the administration of said bactericides. See what bactericides the human body could resist if small, non-lethal doses are used to see how the virus reacts.

      Of course, first you have to see the behavior of the covid19 from the outside, testing antibacterials without combining or just using all components, and if there is a positive response, then try them on animals or people who want to risk such treatment. Use the antibacterial ingredients separately to see which one reacts with or not.

      On the other hand. I don’t know if I’m a little bit suspicious or paranoid, but there is a game that’s on Playstore called PLAGUE INC. that came out long before the creation of this virus, becoming a pandemic or possible endemic. … Perhaps it may or may not be related, or perhaps the person who created the virus got the game’s ideas. Really apologize for stealing your time but it doesn’t hurt to have support even if it’s not great but it will do some good…

      • Eunice Afonso says:

        The chemicals in antibacterial soaps, only attack the virus when on surfaces and on skin surface. This is before it enters the human body. So the eradicating agents on soaps might not be the idea when Virus attaches to protons protein cells. Or whatever. Guess I’m a roocky

  • Prashant Kumar says:

    Is the virus protein being made in lab as antigen for vaccine development? I think spike glycoprotein and membrane glycoprotein are 2 good candidates for vaccine development. Any thoughts.

  • Prashant Kumar says:

    How about any protease inhibitors as possible drug for treating covid-19 infection? This will possibly prevent viral coat protein to assemble and hence reduces viral load. This is ultimately cleared off by body defense system.

  • S. Gongola says:

    [non-scientist here]
    Have they (are they) collecting data — on people who’ve tested positive for virus and had a resulting mild vs. serious illness — relative to the environment they were in when they most likely became infected (e.g. contact with infected individual)? Data such as inside/outside, size of space/room (or type of weather), proximity, duration & type(s) of contact with infected individual, time of day (AM vs. late evening/near bedtime), temp. & humidity, physical exertion/deep inhalation by either party, …etc.

    and/or is data being collected that may identify if any level of correlation exists between those diagnosed with nasal allergies (or other respiratory related autoimmune disease) and the resulting level (mild vs. serious) of covid-19 illness?

  • Henry A. says:

    Dear researchers for a vaccine for the coronavirus.
    If you take the view that it’s the trees trying to protect themselves from too much exposure to deadly UV radiation, as we all know now, sunlight on the leaves of trees produces oxygen O2, but if you look at the number of oxygen molecules in chlorophyll, it’s 5, so 2 for oxygen; 3 for ozone O3.

    The trees are suffering because of the depleted ozone layer, so wouldn’t it be the natural thing in their crowns or coronas in stepping up ozone production trying to rebuild the protective ozone layer for themselves. If you look at the effect of ozone on human lungs it bears a remarkable resemblance to the effects of the corona virus.

    If you look at the atoms in the RNA of the virus , there seems to be only 4 oxygen atoms, whilst chlorophyll has 5, so it could be the virus is unleashed to step up the tree’s search for another atom of oxygen to make more O2 for oxygen and more O3 for ozone for the trees protection against Ultraviolet radiation.

    Coronaviruses (CoVs), enveloped positive-sense RNA viruses, are characterized by club-like spikes that project from their surface, an unusually large RNA genome, and a unique replication strategy.
    RNA

    adenine  C5 H5 N5.
    cytosine C4 H5 N3 O 
    guanine C5 H5 N5 O
    uracil C4 H4 N2 O2

    TOTAL OXYGEN ATOMS = 4

    CHLOROPHYLL C55 H72 Mg N4 O5

    TOTAL OXYGEN ATOMS = 5

    Could you make a vaccine out of bonding another oxygen atom to the RNA protein in the virus? Just a thought. Hope of some help.

    • Bill Hutchins says:

      Social distancing is currently advised! Not a vaccine but effective!! Stay home if you are sick or have a cold, fever or cough. Once people start infecting less than one other individual the epidemic slows.

  • Rabeeca Sam Harris says:

    There are things you can do to help stop germs like coronavirus spreading:
    Always carry tissues with you and use them to catch your cough or sneeze. Then bin the tissue, and wash your hands, or use a sanitiser gel
    Wash your hands more often than usual, for 20 seconds each time with soap and water or hand sanitiser, especially when you:
    • get home or into work
    • blow your nose, sneeze or cough
    • eat or handle food
    Avoid touching your eyes, nose and mouth with unwashed hands
    Avoid close contact with people who are unwell

    • Bill Hutchins says:

      That’s right Rabeeca. People only worry about not getting infected. How about not infecting others? Get health staff protective gear. They are at risk of becoming super spreaders. If you see a super spreader (red nostrils, breathing tense) stop them. Send them home.

  • R.S. says:

    … Just came across your blog and found it quite interesting, can’t wait to see your post. You’ve been sharing really insightful posts and I’m an avid reader of your posts. Keep sharing the knowledge and adding value to our lives.

  • Julie says:

    I’m a mom, no doctor. I hope an open minded doctor sees this and tries this. But, as a mom I have noticed over the years that many times they tell me it’s a upper resp. Virus and antibiotics don’t work for my children. It always ends up worse after 10 days and I end up back for antibiotics then it starts clearing it up same day antibiotics. How is that possible if it’s viral – dr. Tells me it ends up bacterial every time. Give me a break.

    I know there is a concern for antibiotic resistance, but I’m talking a couple of times year for the upper respiratory issues that can cause more dangerous issues like pneumonia. I think this happens more often then necessary because they tell families just go home and wait 10-12 day it’s a virus. When I was young I remember getting antiobics often for various issues, upper resp., ear, sinus and have no issues. Why are they taking these risks. I asked the doctor why can’t they test for bacterial and not guess that it’s viral, he said too expensive. Please take a chance on these people to see if they can save these people. I’m so upset and sadden for these people and families.

    Now, I watched an Asian forensic dr. Who is doing autopsies on people who had corona virus and he noticed that all the victims have very thick mucus on and in their lungs that he believes this is blocking oxygen and that’s why the respirators are not working as well on these people as their lungs are getting blocked! Why not give them antibiotics and strong expectorant to see if it helps along with the other viral treatments – what do they have to lose? Please hope this reaches someone who can make a difference.

    Xo, a mom who cares

    • Philip LoGerfo says:

      It is true that the ultimate cause of death for many Covid19 patients is from bacterial spread, especially for those who have weak immune systems that cannot fight off the initial viral infection. Eventually, all the cell death caused by viral infection leads to a feeding ground for bacteria. I believe that many patients in critical care are given antibiotics, such as Azithromycin. However, the symptoms and causes of death vary tremendously for CoVid patients, and so much has yet to be understood.
      Here is an excellent video that gives a clear description of how CoVid viral infection eventually leads to bacterial infection, among other things.
      https://www.youtube.com/watch?v=BtN-goy9VOY&feature=youtu.be

      Hope this helps!

  • James Rust says:

    good work ladies and gentleman. Is this an engineered virus.

  • MD says:

    I am curious, if SARS was a virus being studied for over a decade, and in a scientific journal from 2018 it was published that even with over 10 years of studying this version of the coronavirus vaccines were still not available due to concerns with liver damage in some samples, and issues with attenuation in others, wouldn’t we say the time frame for this new virus to already be undergoing human testing is highly questionable?

  • D.M.H. says:

    A novel non viral treatment would be an adjunct treatment that negates the ability of the virus to evade the human immune system. This type of treatment would work on present and future corona viruses as the treatment is not aimed at the virus itself.

  • Philip LoGerfo says:

    Recombinant ACE2 therapy seems like a clear method to neutralize the virus, as discussed in the referenced paper below. However, a small molecule that mimics the ACE2 interaction with the Spike protein, would be far less expensive to produce, and much easier to distribute, store, and administer, than recombinant ACE2.

    The challenge lies in identifying a handful of effective small molecules with binding properties analogous to ACE2 binding site. However, a clear strategy, from in silico -> in vitro -> in vivo could be executed in time for the next cold season.

    “Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target”
    https://link.springer.com/article/10.1007/s00134-020-05985-9

  • C.S. says:

    Hi, good information is given.

  • Shahenaz says:

    I’m a third-year mbbs student… M from india
    But according to my knowledge we can make corona vaccine by antibody produced in laboratory & give passive immunization to patient
    Let’s say we extracted healthy blood b lymphocyte & give spike proteins antigen which present on covid19 surface protein
    And also we Cpg dna strand which required for b cell in to plasama cell to make antibody against specific antigen…
    After antibody form we make it hybridoma cell to continue production of monoclonal antibody…
    Then give this passive immunization to rat or rabbit which partially infected with covid 19 so if animal are cure, then trial on human

    I hope its work……

  • pedro says:

    with all the deaths around the world today .March 28 2020
    and the compassionate use of Remdevisir taken away …. its seems more than cruel as so many where being saved as last resort by this drug?
    why can’t we approve it and continue the trials at the same time in this time of crisis like we did with AZT during the Aids outbreak ?

    so many stories of the drug saving people
    and its been proven safe from its phase 1 trials… ? lots of drugs have side affects including Tylenol , statins, bp drugs and most cancer drugs…. just to name a few
    what is the FDA waiting for??

  • Jennifer D. says:

    I have these immune boosting items on hand: colloidal silver, vitamin C, Neem leaf capsules, Pau D’Arco caps, L-Lysine, Mushroom complex caps, L-Arginine, Primrose oil caps, a blend of herbals for respiratory health, teas & essential oils. (Of course hand washing & sanitizing) I have noticed though that one of the main protocols for those with symptoms is to be given an immuno-suppressant. If I became infected, would taking these supplements cause the virus to have a more aggressive reaction? Are the international health community trying any of these items in battling this? I know Europe uses much more natural health methods including essential oils & vibrational frequency treatments but, I am curious if they are trying to use them or not.

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