When SARS-CoV-2 mutates and gives rise to new variants, they sometimes bind better to receptors in our lung cells. This may confer a fitness advantage that enables them to outcompete earlier variants and perhaps also cause more severe illness. New research shows how this happens.
SARS-CoV-2 has many names: “Wuhan” (the original SARS-CoV-2), the “British” variant (B.1.1.7, Alpha), the “South African” variant (B.1.351, Beta), the “Brazilian” variant (P.1, Gamma), the “mink” variant (Cluster 5), the “Indian” variant (B.1.617.2, Delta) and now Omicron (B.1.1.529).
The variants develop in different directions, and some become better at transmitting among people.
Now several studies show what happens biochemically when SARS-CoV-2 binds to the human target receptor, improving its transmissibility and probably also leading to more severe COVID-19.
The results have been published in Frontiers in Immunology, the Journal of Immunology, the Journal of Biological Chemistry and eLIFE.
“SARS-CoV-2 is constantly trying to optimise its ability to enter our cells while evading immune recognition at the same time. It does this by mutating, which leads to new variants. But this also means that we will probably have to decide to change the sequence of the mRNA vaccines designed to protect us from infection. The current vaccines are based on the genetic code of the original SARS-CoV-2 variant. If this changes markedly, vaccine development must also be able to keep up. In this context, knowing how SARS-CoV-2 evolves to survive in a situation in which the population has increasing immunity is important,” explains a researcher behind the study, Mikkel-Ole Skjødt, Associate Professor, Department of Immunology and Microbiology, University of Copenhagen and the Laboratory of Molecular Medicine, Rigshospitalet, Copenhagen.
Part of a larger project
The research is part of several studies in which the researchers investigated functional differences of the emerging SARS-CoV-2 variants.
As a starting-point, they investigated whether people infected with the original SARS-CoV-2 variant would have difficulties in antibody neutralisation of the Cluster 5 mink variant. The results did not show this but demonstrated mutations in the spike receptor binding domain bound to the human ACE-2 (angiotensin-converting enzyme 2) target receptor four to five times stronger than that of the original variant.
The researchers also examined the link between the development of antibodies and the COVID-19 disease, finding that the level of virus-specific antibodies is directly correlated with the severity of COVID-19.
“This study indicated that treating people during a severe COVID-19 course with plasma-derived antibodies from individuals who have recovered from COVID-19 is not necessarily a good idea,” says Mikkel-Ole Skjødt.
Alpha variant binds 10 times more strongly to human cells
In two of the new studies, the researchers investigated how effective the Alpha, Beta and Gamma variants bound to the ACE2 target receptor on the surface of our lung cells.
These variants are World Health Organization variants of concern and outcompeted the existing variants shortly after they emerged because they were more transmissible.
The researchers wanted to determine how.
They specifically examined the interaction between the receptor-binding domain in the spike protein from SARS-CoV-2 and the ACE2 receptor biophysically and by studying transgenic mice with the human ACE2 gene inserted into their genome.
Mice are not normally infected by SARS-CoV-2 in the same way as humans, nor do they develop the same type of disease. However, the researchers showed that mice with the human ACE2 gene were severely infected and that the mice infected with the Alpha variant developed more severe disease than when infected with the original variant.
Furthermore, the research showed that Alpha had optimised the binding to the ACE2 receptor with 10-fold higher affinity but did not evade antibody neutralisation to any great extent. In contrast, both the Beta and Gamma variants showed intermediate binding optimisation (3–4 times stronger binding to ACE2 compared with the original variant) but markedly improved ability to evade neutralisation by our antibodies.
”This probably explains why these variants took over at some point. Biochemically, they bind better to our cells than the original variant lines, and some also evade the immune response. This enabled the gradual outcompetition of existing variants,” explains Mikkel-Ole Skjødt.
SARS-CoV-2 has mutated to become a highly optimised virus
Mikkel-Ole Skjødt explains that one specific region, the receptor-binding domain, on the spike protein crucially influences the ability of SARS-CoV-2 to bind to target cells, transmit and cause illness. This region is in direct contact with the ACE2 receptor on the surface of our lung cells.
Mutations have occurred in the receptor-binding domain in the variants of SARS-CoV-2, improving its ability to bind to ACE2.
The researchers also found by examining all the variants broadly that SARS-CoV-2 might not be that prone to change.
“Although SARS-CoV-2 is constantly mutating, I would still describe it as a relatively conservative RNA virus that already is quite optimised in its ability to bind to our cells. Thus, we could expect new variants to evolve primarily to evade the immune response instead of strengthening the receptor binding. SARS-CoV-2 has evolved slowly so far, but we risk facing an ever-increasing problem,” says Mikkel-Ole Skjødt.
Vaccines need updating
Mikkel-Ole Skjødt explains that the small changes in the spike protein that improve its ability to infect people and the improved ability to evade vaccine induced immune responses calls for a revision of the current vaccines that might not be longer fully suited for the current challenge. The vaccines should therefore be modified to ensure that they follow the emerging new variants and this should be relatively easy to implement for the mRNA type vaccines.
The recent identification of yet another variant, Omicron (B.1.1.529), with an unprecedented number of mutations in the spike protein, highlights the need to act along these lines.
In addition, Mikkel-Ole Skjødt suggests focusing on vaccine strategies that specifically target the receptor-binding domain only.
Mikkel-Ole Skjødt and the Laboratory of Molecular Medicine at Rigshospitalet has developed and tested two vaccine prototypes and compared the effectiveness of targeting the entire spike protein or just the receptor-binding domain. Experiments on mice showed that the mice receiving a vaccine focused only on the receptor-binding domain developed a more efficient SARS-CoV-2-neutralizing antibody response than those receiving a vaccine that included the entire spike protein.
“However, remember that the current vaccines still offer really good protection against severe disease and death. Many vaccinated individuals get infected now and do not progress to severe illness, but it may still be a good idea to continually refine and optimise the vaccines to keep up with new emerging SARS-CoV-2 variants. Some vaccines could be further developed to focus on the binding site in the spike protein where certain key mutations occurs,” concludes Mikkel-Ole Skjødt.
