Mutations Observed in Coronavirus “Spike” Caution
By Vidya Kunnathully, Ph.D.
While lockdowns start to ease in some parts of the world, others continue to extend it, fearing a fresh wave of infections. Nevertheless, the one question that has plagued all our minds alike is—when will social distancing end?
The world’s hope for a return to normalcy is now pinned on a vaccine. Currently, over 100 COVID-19 vaccines are under pre-clinical evaluations, of which 8 have already entered trials1. A popular strategy to design these vaccines is to inject coronavirus proteins directly into the body, and most have focused on the Spike (S) protein. As the worldwide race for a vaccine continues, scientists express caution over recent mutations identified in the S protein-encoding gene.
What Makes the Spike Protein a Prime Target?
The Spike protein is a trimeric fusion protein composed of two functional subunits. These two subunits facilitate viral attachment and fusion to the host cellular membranes, an essential first step in viral replication that permits the virus to deliver its RNA into the cell2,3. Typically, the human immune system can detect amino acid sequences on foreign proteins, like the S protein, and invoke an immune reaction to defend itself. However, Professor Rob Woods, a scientist at UGA’s Complex Carbohydrate Research Center, explains that things may be trickier in reality. “If a pathogen puts a sugar on the protein’s surface, it can mask the amino acids,” he said. “One sugar can mask a whole cluster of amino acids so our antibodies can’t see them. Many viruses do this—influenza and hepatitis C, for example”4.
Furthermore, a recent study led by Professor Max Crispin at Southampton University reveals the extent to which the virus disguises itself to enter human cells undetected5. Professor Crispin said, “By coating themselves in sugars, viruses are like a wolf in sheep’s clothing”6. Their results demonstrate that the Spike protein is extensively decorated with host-derived sugars or glycans with each trimer displaying 66 N-linked glycosylation sites. While all the above factors undoubtedly make the S protein an attractive target in vaccine design efforts, the big question looming over us now is—how efficacious will these vaccines be if the Spike protein continues to evolve?
Spike Protein Mutations: Slow But Dangerous
Since most vaccines target the Spike protein, there is an urgent need to map the mutations it has been accumulating. Although the mutation rate of SARS-CoV-2 is lower than that of the seasonal flu virus, its rapid global spread could enable the virus to accumulate rare but favorable mutations. One such example is the non-silent (Aspartate to Glycine: D614G) mutation at position 614 of the Spike protein. This dominant subtype has rapidly outcompeted other preexisting subtypes, including the ancestral one, allowing its explosive spread, especially across Europe and North America7,8. Its spread has been so explosive that in ten weeks (between February and March 2020), over 60% of people were infected as compared to only 2% for the index strain9.
One explanation for this preferential spread across Europe and North America is a commonly found deletion in the serine protease-encoding TMPRSS2 gene. This variant TMPRSS2 gene encodes increased amounts of the serine protease that primes the S protein, enabling an even easier entry of the D614G mutant into the host cells9. To make matters worse, the D614G mutation arose just before the virus spread to Europe, so this lineage could have simply ended up being the version that spread to the west8. Data shows that European travelers eventually seeded some outbreaks in the US10.
In another study comparing virus strains from thirty countries across the globe, Professor M. Radhakrishna Pillai and colleagues reported over fifty-four non-synonymous mutations in the S-protein encoding gene. Most importantly, four of these mutations are on the receptor binding domain of the Spike protein and may have direct implications on the infectivity of SARS-CoV-211. This is particularly concerning because most vaccine design efforts are focused on the receptor binding region of the Spike protein.
What Do These Mutations Mean for Us?
Since current immunogens and testing reagents are mostly based on the Spike protein sequence from the index strain from Wuhan, the impact these newly identified mutations could have is not entirely clear. Though we lack the specific details, most vaccine candidates are based on the receptor binding region of the Spike protein. The good news is that the D614G mutation is not on that part of the Spike protein. While the mutations could still have some allosteric long-range effects, according to Dr. Derek Lowe, “it’s difficult-to-impossible to try to model such things”12.
On the bright side, the Global Initiative on Sharing All Influenza Data or GISAID initiative is promoting the rapid sharing of data from all influenza viruses and the COVID-19 causing coronavirus13. Most researchers contribute their data to the GISAID. Therefore, vaccine testers would be alerted if broad community changes are observed in the frequency of mutations. Interestingly, not all regions of the Spike protein have been mutating. Professor Crispin claims that there were no observed mutations to N-linked glycosylation sites5. Considering that these regions act as a protective “glycan shield” for the virus, this is one “sweet spot” we wish had mutated.
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