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Human Antibodies Target Many Parts of Coronavirus Spike Protein

Posted on by Dr. Francis Collins

Viral spike with labels Receptor-binding domain (RBD) antibody, N-terminal domain (NTD) antibody, S2 subunit antibody
Caption: People who recovered from mild COVID-19 infections produced antibodies circulating in their blood that target three different parts of the coronavirus’s spike protein (gray). Credit: University of Texas at Austin

For many people who’ve had COVID-19, the infections were thankfully mild and relatively brief. But these individuals’ immune systems still hold onto enduring clues about how best to neutralize SARS-CoV-2, the coronavirus that causes COVID-19. Discovering these clues could point the way for researchers to design highly targeted treatments that could help to save the lives of folks with more severe infections.

An NIH-funded study, published recently in the journal Science, offers the most-detailed picture yet of the array of antibodies against SARS-CoV-2 found in people who’ve fully recovered from mild cases of COVID-19. This picture suggests that an effective neutralizing immune response targets a wider swath of the virus’ now-infamous spike protein than previously recognized.

To date, most studies of natural antibodies that block SARS-CoV-2 have zeroed in on those that target a specific portion of the spike protein known as the receptor-binding domain (RBD)—and with good reason. The RBD is the portion of the spike that attaches directly to human cells. As a result, antibodies specifically targeting the RBD were an excellent place to begin the search for antibodies capable of fending off SARS-CoV-2.

The new study, led by Gregory Ippolito and Jason Lavinder, The University of Texas at Austin, took a different approach. Rather than narrowing the search, Ippolito, Lavinder, and colleagues analyzed the complete repertoire of antibodies against the spike protein from four people soon after their recoveries from mild COVID-19.

What the researchers found was a bit of a surprise: the vast majority of antibodies—about 84 percent—targeted other portions of the spike protein than the RBD. This suggests a successful immune response doesn’t concentrate on the RBD. It involves production of antibodies capable of covering areas across the entire spike.

The researchers liken the spike protein to an umbrella, with the RBD at the tip of the “canopy.” While some antibodies do bind RBD at the tip, many others apparently target the protein’s canopy, known as the N-terminal domain (NTD).

Further study in cell culture showed that NTD-directed antibodies do indeed neutralize the virus. They also prevented a lethal mouse-adapted version of the coronavirus from infecting mice.

One reason these findings are particularly noteworthy is that the NTD is one part of the viral spike protein that has mutated frequently, especially in several emerging variants of concern, including the B.1.1.7 “U.K. variant” and the B.1.351 “South African variant.” It suggests that one reason these variants are so effective at evading our immune systems to cause breakthrough infections, or re-infections, is that they’ve mutated their way around some of the human antibodies that had been most successful in combating the original coronavirus variant.

Also noteworthy, about 40 percent of the circulating antibodies target yet another portion of the spike called the S2 subunit. This finding is especially encouraging because this portion of SARS-CoV-2 does not seem as mutable as the NTD segment, suggesting that S2-directed antibodies might offer a layer of protection against a wider array of variants. What’s more, the S2 subunit may make an ideal target for a possible pan-coronavirus vaccine since this portion of the spike is widely conserved in SARS-CoV-2 and related coronaviruses.

Taken together, these findings will prove useful for designing COVID-19 vaccine booster shots or future vaccines tailored to combat SARS-COV-2 variants of concern. The findings also drive home the conclusion that the more we learn about SARS-CoV-2 and the immune system’s response to neutralize it, the better position we all will be in to thwart this novel coronavirus and any others that might emerge in the future.


[1] Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes. Voss WN, Hou YJ, Johnson NV, Delidakis G, Kim JE, Javanmardi K, Horton AP, Bartzoka F, Paresi CJ, Tanno Y, Chou CW, Abbasi SA, Pickens W, George K, Boutz DR, Towers DM, McDaniel JR, Billick D, Goike J, Rowe L, Batra D, Pohl J, Lee J, Gangappa S, Sambhara S, Gadush M, Wang N, Person MD, Iverson BL, Gollihar JD, Dye J, Herbert A, Finkelstein IJ, Baric RS, McLellan JS, Georgiou G, Lavinder JJ, Ippolito GC. Science. 2021 May 4:eabg5268.


COVID-19 Research (NIH)

Gregory Ippolito (University of Texas at Austin)

NIH Support: National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Institute of General Medical Sciences; National Center for Advancing Translational Sciences


  • Lisa Phillip Rimland says:

    This is an amazing study, thank you for posting Dr. Collins, I have been wondering about the possible beneficial immunological effects of having had mild Covid. This study gives us a bigger picture regarding the body’s response to Covid, and possibly more insights regarding the design of vaccines and boosters, and gives us hope for the future.

    • Africa so says:

      It looks like from his finding that obtaining an immunity from actually acquiring the Covid 19 infection is better because the antibodies produced target all parts of the spike protein rathr that the targeted RBD portion by the vaccine. With the vaccine, herd immunity will never be achieved because the NTD portion will allow the virus to continue mutating.

      • Joshua says:

        That’s the opposite of what Dr. Collins said. He explicitly says that the NTD is a poor target for antibodies because it mutates quickly, and that one of the reasons that mutants have been so successful at spreading is because they evade human antibodies that target the NTD.

        • JohnWest says:

          Thanks for that.. I was wondering where previous poster was coming from. Natural immunity seems to be less reliable than one(s) that target the RBD. Would wonder why we have ACE ports in our airways. Are there any “naturally occurring” things that have the same shape as the Covid viruses RBD segment? WHat does ACE port do? Can it be plugged?

  • Andrew Goldstein says:

    Has SARS-CoV-2 antibody cross reactivity been observed with either other viral epitopes or with host antigens? I ask this because the former could be beneficial and the latter detrimental, causing harmful autoimmune reactions. Autoimmune diseases can be triggered by other viral infections or genetic predisposition.

  • Gary S. says:

    How long do the anti-bodies continue once the covid illness is diminished after contracting it? I don’t think I need the vaccine since I had the virus in November ’20.

    • Debra Smallwood says:

      I had mild covid March 1st of this year. How long do these antibodies protect you from getting covid again?

  • John Hasty BS, MT(ASCP) Retired says:

    The antibodies to the Coronavirus “Target” many antigenic sites including those of the Spike Protein. Everyone is pushing information about the Spike Protein because that the antigen used in the current vaccines. I see only a unified narrow minded point of view and wonder why.

  • Dr. Imtiyaz says:

    The reduction in infection and development of antibodies in response to mild COVID infection in patients with single jab of 20 to 30 days is evident with various amounts of symptomatic relief and recovery.

  • LA Smith says:

    My question is why does big pharma always go for megadollar super cures without adequately exploring chemical entities shelved in years past? I am aware that some effort was made, but not enough. In an emerging crisis, shouldn’t quicker, cheaper cures the public can access in a drug store be looked at? Big pharma will always attempt to maximize profits while the public is left hanging. Do we really have to lose 600,000 people before somebody says “We need something inexpensive, already in existence, & easier to get out there.” Example: the rebirth of Vancomycin.

    • camilo Colaco says:

      aspirin, given coagulopathy?

    • Dan S says:

      To LA Smith,
      When you say example, are you meaning that they should investigate Vancomycin as a drug to treat Covid? If so, then you should go read up about how covid and vancomycin would work together. Vancomycin is a broad spectrum antibiotic used primarily to treat bacterial infections, and covid is a viral infection. Viruses typically are not affected by antibiotics, rather antivirals. Antivirals are usually created with a certain virus in mind, which would make it almost impossible to use a random anti-viral to target covid. To my knowledge, there are not any broad spectrum anti-virals that you could just prescribe to someone with a random viral infection. Also, vanco doesn’t need a rebirth as I see it used quite often in a hospital setting for bacterial infections.

      To camilo Colaco,
      since there are plenty of resources proving that covid is destroying veins and is not actually a clot-producing virus, this method would also produce poor results (if any). In comments below, there is a great discussion about using ozone to destroy the glycans in an attempt to “open up” the virus so that the body’s immune system can destroy it. There are plenty of medicines being researched, but the ultra cheap, commonly used medicines that we currently have (or have stored away) will not work to destroy the virus, sadly.

      • JohnWest says:

        Could try to trigger the virus to dump it’s payload without docking, or issue a short term plug to seal up ACE ports for a short period as something to slow down the replication?

  • Claudio Romulo Siqueira Filho says:

    One of my students asked me why is it so difficult to make an effective vaccine for the novel coronavirus. My answer was: Imagine that I introduced to you five members of my family. Do you think that you can say that you really know my family? I’m saying this because a few years ago, I had many papers showing that a good vaccine product takes time to be “really well done.” For Covid we had less than one year. I think we have a lot to learn about how long it takes to make a good vaccine against the Coronavirus family.

    • Tim says:

      Cornavirus pandemics have been around since 2003 and there have been plenty of publications regarding it not necessarily in the US.

  • Gwen G. says:

    I am immunocompromised. I have been on Prednisone every day for about 10 years for dx of lupus and RA. I have had both Moderna vaccine doses with the last being given 4/11/21. Additionally, I am a pancreatic cancer pt; Whipple 12/5/19 and last chemo 7/28/20 with regular scans for follow up. I got a sore arm after my first vaccine injection but no side effects with the second. Is there a test to see if I have antibodies for COVID 19? I feel I need to know this before I can relax into the new CDC guidelines. Thank you for your prompt reply in advance.

  • Jean Bosco Sahaha says:

    It sounds interesting.

  • Gianni Zuccheri says:

    I would like to express a hypothesis starting from what is exposed in several articles. To simplify, I will mention :
    — The article “Dynamic View of Spike Protein Reveals Prime Targets for COVID-19 Treatments” reports:

    ” ..They are sugar molecules called glycans that are thought to shield the spike protein by sweeping away antibodies. Also notice areas (purple) that the simulation identified as the most-attractive targets for antibodies, based on their apparent lack of protection by those glycans…”

    . . . Ozone is a strong oxidant. The spike protein is rich in cysteine residues, permanently oxidized by ozone. If the denaturation of viral structures occurs during treatment with Ozone therapy (it consists in the administration of a mixture of ozone and oxygen, called medical ozone, by autohemotherapy), their original conformation will be altered. The immune-system will face the viral structures, both in their original and altered conformation, thus producing two different lines of antibodies.

    I will use walnut as a comparison. Most often antibodies are produced (from vaccine or during illness) against what the shell represents. By means of ozone this shell is shattered and thus a content is exposed to which the antibody production would no longer be forced to chase the enemy’s changes. Therefore, it does not matter if the shell changes, the kernel is unchanged and finally we can have some fixed points, both in the development of monoclonal therapies and in the study of vaccines.

    It would also be interesting to assess whether there is a different rate of reinfection between O3-treated patients and those who are not.

    • Bioman says:

      I think your idea of ozone treatment is very novel. I guess the key is getting rid of these glycans all over the surface of the spike protein. I challenge you with the concept if you cant beat them join them. In the directors last article did you notice that the N-terminal domain is exposed as a binding site. The N-terminal domain has a special spot called the galectin fold. If a carbohydrate drug binds to this site it neutralizes the spike protein. You might be thinking wow this is a great theory but it is not a theory. This was already done in human clinical trials.

      See, carbohydrate drugs seem to neutralize the spike protein. So love all the the talk about theory here by the director but I would like to explain to him that the ideal site (Galectin Fold on the N-terminal domain) already has been found and is in clinical trials with great results . . . Too bad this technology is apparently going overseas . . . So while I love this theoretical discussion why aren’t we talking about human clinical trials that have validated a target on the spike protein that neutralizes the virus with a cheap-to-produce carbohydrate instead of a monoclonal antibody?

      • Gianni Zuccheri says:

        I believe that every good idea is an opportunity to search for solutions, combining it with the knowledge already acquired: productive synergy.
        Thank you for drawing my attention to the Galectin Fold on the N-terminal domain: considering it important, it is my intention to deepen.

  • Don L says:

    I find your blog posts to be informative, interesting, and written in a style that allows a layperson to understand them. Thank you for taking time to write these posts. Looking forward to reading and learning more.

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