vaccine design
Human Antibodies Target Many Parts of Coronavirus Spike Protein
Posted on by Dr. Francis Collins
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.
Reference:
[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.
Links:
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
Antibody Points to Possible Weak Spot on Novel Coronavirus
Posted on by Dr. Francis Collins
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
