This article has been reviewed by Dr. Zachary Benet, one of our subject matter experts.
The paper that will be demystified today can be found here.
- The exterior of coronaviruses are studded with spikes that are important for infecting human cells.
- Antibodies are immune molecules designed to bind a very specific bacterium or virus, targeting it for removal. An antibody called CR3022 was found previously found to bind the spikes of the 2003 SARS coronavirus.
- It turns out that antibody CR3022 can also bind the spikes of the novel SARS-CoV-2 virus. This ability to bind multiple targets is known as cross-reactivity.
- The therapeutic value of CR3022 is unknown, but further research into cross-reactive antibodies may one day lead to antibody therapies that can target, for instance, multiple types of coronaviruses.
Our immune systems make use of a variety of cells and molecules to thwart infections. Among these are Y-shaped molecules called antibodies. Produced one to two weeks following the beginning of an infection, antibodies are tailored by our immune system to target a specific component of a certain bacterium or virion (virus particle). The antibody and its target are like two jigsaw pieces that fit just right, in a puzzle of a billion pieces. When an antibody binds to the surface of a pathogen (i.e. bacterium and virus), this signals to the immune system that an offender has been found, and that microbe is promptly degraded through one of three mechanisms outlined below1.
Certain viruses, such as influenza and coronaviruses, are studded with spikes that help mediate entry into cells2. Since viral spikes are highly exposed, they are popular targets for antibody binding. After an infection has run its course, remaining antibodies can continue to circulate in the bodies of recovered individuals, providing immunity from months to years to come. Through a century-old, Nobel prize-winning treatment known as passive antibody therapy, the antibody-enriched blood of these recovered individuals can be transferred into new patients. Since antibody generation can be time-consuming and ineffective in new patients, passive antibody therapy speeds up the immune system’s clock, offering a head start to the new patient (an unfair one from the virus’s point of view). This technique was recently administered to five critically-ill COVID-19 patients and reported to improve the health of four of the patients3.
In contrast to clinics that treat with an assortment of antibodies, researchers study antibodies on a case-by-case basis. One such antibody, extracted from the blood of a recovered SARS patient in the mid-2000s, is CR3022. Although CR3022 was designed by the immune system to target the spike of SARS virions (the virus responsible for the 2003 SARS epidemic), two independent studies have found that this antibody can also recognize and bind the spikes of the novel SARS-CoV-2 virus4,5 (the virus that causes COVID-19). This result is surprising because antibodies are very picky in terms of what they are able to bind. The physical make-up of their counterparts have to match with the antibodies just so, like lock and key. CR3022’s ability to bind the SARS-CoV-2 spike is best attributed to the high degree of similarity (86%) between the targeted regions of SARS and SARS-CoV-2 spikes.
That being said, it turns out that CR3022 does not bind the SARS-CoV-2 spike in all situations. For instance, CR3022 binds isolated SARS-CoV-2 spike proteins in a test tube very well. When, however, the researchers mix full SARS-CoV-2 virions (with the spike proteins sticking out of it) with CR3022, the antibody is not able to bind. It appears then that CR3022 cannot detect SARS-CoV-2 virions. To not disappoint, the authors of the study cite cases among other viruses, such as influenza and dengue, where antibodies fail to bind virions in the lab setting, but successfully bind and neutralize virions in the body.
Another unusual feature of CR3022 lies in its binding position on the spike protein. As previously mentioned, many viruses use their spikes as keys to enter human cells and commence infection. Hence, the most effectively neutralizing antibodies bind spikes at the tip that contacts human cells, diminishing their infectivity. CR3022 though is an exception that targets the spike protein outside of this region. While this strategy would be less effective at directly blocking viral entry into cells, the authors of the study suggest that CR3022 binding creates opportunity for CR3022 to work together with other antibodies, amplifying the immune response against SARS-CoV-2. This enhanced response would not harm the patient, unlike the dangerous immune overdrive commonly known as a cytokine storm.
Antibody CR3022 is by no means a silver bullet against the SARS-CoV-2. Despite the strong interactions observed between CR3022 and free-floating spike proteins, CR3022 has yet to demonstrate any therapeutic value against the novel coronavirus. Yet, the discovery that antibodies generated specifically for the SARS virus may be cross-reactive with the SARS-CoV-2 virus is promising. It may stimulate the discovery of other antibodies of similar cross-reactivities, and focus research towards harnessing these natural tools for the clinic. The discovery of antibodies that can bind both SARS and SARS-CoV-2 virions would steer the search for broadly neutralizing antibodies against future coronaviruses.
- By Lumen Learning, available at https://courses.lumenlearning.com/wm-biology2/chapter/antibody-functions/ under a Creative Commons Attribution 4.0.
- Li, F. (2016) Structure, Function, and Evolution of Coronavirus Spike Proteins. Annual Review of Virology, 3(1): 237–261. doi:10.1146/annurev-virology-110615-042301
- Shen C, Wang Z, Zhao F, et al. (2020) Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA, 323(16): 1582–1589. doi:10.1001/jama.2020.4783
- Yuan, M. et al. (2020) A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV. Science, doi:10.1126/science.abb7269
- Tian, X. et al., (2020) Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody, Emerg Microbes Infect, 9(1): 382-385, doi:10.1080/22221751.2020.1729069
“Annoj is a research technician working at a biotech startup in Toronto. Having completed a Bachelor’s degree in Immunology and Master’s in Biochemistry, his research interests span both fields and everything in between. Outside of the lab, he serves as the editor of a community newspaper and enjoys playing retro video games.”