It has long been known that the new Sars-CoV-2 coronavirus binds to our cells with part of its crown-like spike protein. At the same time, our immune system also reacts to this protein and produces antibodies that dock at the binding site and thus deactivate it – at least that is how it was previously thought. But now researchers have discovered an antibody that docks at an unexpected location on the spike protein. This antibody was originally isolated from a patient infected with the closely related Sars-1 virus. Because the binding site of this antibody appears to remain relatively the same for all corona viruses, this could open up the possibility of a general corona vaccination, the researchers said.
The “crowns”, which stand out from the shell of the Sars-CoV-2 coronavirus, are crucial for both the virus and our immune system. Because at these spike proteins sits the binding site with which Sars-CoV-2 docks to the ACE2 receptor on our respiratory and lung cells. However, there is one special feature: In normal conditions, the binding site of the spike protein is protected and inaccessible to external attacks. It is only shortly before the coronavirus binds to the cell that it changes the configuration of the protein, opens it and thus brings it into a form that is suitable for the cell receptor. This configuration change makes it more difficult for the immune system to attack the binding site of the virus as soon as it enters the body and to produce suitable antibodies. Previous studies on the spike protein of Sars-CoV-2 had also shown that the binding site of other, closely related coronaviruses such as Mers and Sars are similar but not identical. This suggested that drugs and vaccines against these predecessor viruses are unlikely to work against the new coronavirus.
Sars antibody also fits on Sars-CoV-2
But there is another aspect that could be decisive for the development of new vaccines and remedies for the coronavirus: You have to know exactly where the antibodies produced by the body against Sars-CoV-2 dock with the virus protein. “Our goal is therefore to obtain structural information about the antibodies and their binding sites and then use this to advance vaccine development against Sars-CoV-2,” explains Nicholas Wu of the Scripps Research Institute in La Jolla, California, who works with his colleague Meng Yuan is the lead author of the study. To obtain this information, Wu and his team used an antibody that had been isolated from a patient previously infected with the virus after the Sars epidemic in 2006. The starting point for this was a report by Chinese researchers who observed a reaction of this antibody, called CR3022, to the new Sars-CoV-2 earlier this year. In order to clarify how this is possible despite the existing differences between the two viruses, Wu and his colleagues have decoded the interaction of this antibody with the spike protein of Sars-CoV-2 for the first time with an atomic resolution.
The crystallographic analyzes revealed surprising results. Because the antibody does not dock as expected at the site of the spike protein used for cell binding. “Interestingly, there is no overlap between the antibody’s epitope and the protein’s ACE2 binding site,” the researchers report. This means that this antibody behaves differently than most previously known against Sars. Instead, CR3022 binds to another part of the viral protein, which apparently only differs in four amino acids between Sars and Sars-CoV-2. This could explain why there is this cross-reaction of the antibody in both related viruses. Apparently, the part of the protein to which this antibody is adapted is so important for the coronaviruses that it hardly changes even with new virus forms. “Our study thus provides new insights into how Sars-CoV-2 can be attacked by the antibody immune response and reveals a hidden epitope that Sars and Sars-CoV-2 have in common,” the researchers report.
Opportunity for a universal coronavirus vaccine?
The fact that the new corona virus does have a site similar to the old Sars virus could now offer new sites for a vaccine or medication. Because tests prove that CR3022 prevents infection of human cells, at least with the old Sars virus. In such in-vitro experiments with the new corona virus, however, this does not seem to work, as Wu and his team now found. One of the reasons for this seems to be that the antibody binding site is only exposed if the spike protein opens in the body as part of a normal infection. As the researchers explain, for some viruses this process can only be insufficiently understood in vitro. “There are examples of antibodies that show no neutralization activity in vitro, but still protect in vivo, for the influenza virus, the herpes virus, the cytomegalovirus and also the dengue virus,” report Wu and his colleagues.
They therefore consider it entirely possible that the CR3022 antibody can also protect against infection with Sars-CoV2, although this did not work in cell cultures. “We therefore need suitable animal models for further studies,” says the researchers. However, if their suspicions are confirmed, antibodies and other active substances that attach to the binding site of CR3022 could help Covid-19 patients and also at least temporarily protect people exposed to the virus from infection with Sars-CoV-2. In addition, the discovery of a part of the spike protein that has apparently hardly been changed opens up the opportunity to perhaps develop a vaccine that acts broadly against many or perhaps all coronaviruses: “Although such a more universal coronavirus vaccine is not the most urgent goal at the moment, it is it is definitely worthwhile for future work, ”said Wu and his colleagues. “Because then we could be better prepared for the next outbreak of a new corona virus.”
Source: Meng Yuan (Scripps Research Institute, La Jolla) et al., Science, doi: 10.1126 / science.abb7269