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COVID-19: What you need to know about SARS-CoV-2 variants
Mutations are a part of life. Every time a virus replicates, there is a chance that its genetic code won’t be copied accurately. These typos travel inside new virus particles as they leave one body and move on to infect the next. Some of these mutations die out; others survive and circulate widely. Some mutations are harmless; others increase infectivity or allow a virus to better escape the immune system—that’s when public health bodies might deem that strain a variant of concern.
Swaps or deletions of single amino acids can change the shapes of different proteins. Mutations can happen in any of the proteins of SARS-CoV-2, and these may change the virus’s properties. Many of the worrisome mutations are found on the spike protein, as it is the target of antibody treatments and is mimicked by the currently authorized COVID-19 vaccines. Researchers are especially troubled when typos occur in two parts of the spike protein—the N-terminal domain, which is at the beginning of the protein and which some antibodies target, and the receptor-binding domain (RBD), which grabs hold of ACE2 receptors on human cells and starts the process of infection.
To understand how specific mutations affect the structure and function of the spike protein and what those changes mean for treatments and vaccines, C&EN talked to Priyamvada Acharya, Rory Henderson, and Sophie Gobeil at Duke University. With colleagues, these researchers have combined biochemical assays, cryo-electron microscopy, and modeling to show how the mutations seen in the variants of concern work together to change the stability of the spike protein. The spike is a trimer of three identical protein strands folded and interwoven together. Before the virus has infected a cell, the spike takes on two conformations: a down state, in which the RBD is hidden, and an up state, in which the RBD faces out, ready to bind to ACE2. The team found that different mutations can increase binding in different ways. This process, in which similar features are arrived at independently, is called convergent evolution.
Here are the variants of concern as designated by either the US Centers for Disease Control and Prevention or the World Health Organization, followed by emerging variants that the world is closely watching.
First detected United Kingdom
Status Variant of concern
Key mutations Fifteen amino acid swaps and three amino acid deletions in the proteins of the virus. Nine of the mutations are in the spike protein including N501Y, a swap of an asparagine to a tyrosine in the receptor-binding domain, and deletions of the 69th, 70th, and 144th amino acids in the N-terminal domain.
Biological impact The mutations in the spike work together to make binding to ACE2 more likely, and they help the protein hold on to ACE2 more tightly. Studies suggest the virus is about 50–70% more infectious.
What that means for our arsenal Data from countries such as Israel suggest that authorized vaccines continue to offer robust protection. Therapeutic antibodies that target the receptor-binding domain still work well, but those targeting the N-terminal domain show weaker binding in some assays.
First detected South Africa
Status Variant of concern
Key mutations Twelve amino acid swaps in proteins of the virus. Nine of those swaps are in the spike protein, with three occurring in the receptor-binding domain: N501Y, the same swap observed in B.1.1.7 (Alpha); K417N, a swap of a lysine to an asparagine; and E484K, a switch of a glutamic acid to a lysine.
Biological impact The changes in the spike protein seem to make the form of the spike with the receptor binding domain in the up position more likely, but via a different mechanism from the one used by the B.1.1.7 (Alpha) variant. Researchers found that in South Africa, B.1.351 (Beta) is up to 50% more infectious than the original virus.
What that means for our arsenal Therapeutic antibodies show weaker binding to this variant of the spike, and clinical trials have found multiple vaccines are less effective against this variant. For example, South Africa, where this variant was widespread, has halted the use of AstraZeneca’s adenoviral vector vaccine because of worries that it is not as protective against this variant. mRNA vaccines seem to overcome the reduction in neutralization and Moderna has launched a trial of a modified vaccine to tackle this variant.
B.1.427 and B.1.429 (Epsilon)
First detected US (California)
Status No longer monitored
Key mutations Six different amino acid swaps in viral proteins. The spike protein contains four of those, including L452R, a swap of a leucine for an arginine in the receptor-binding domain.
Biological impact Scientists think that L452R can make the spike bind more strongly to ACE2. Early evidence showed that this variant is about 20% more infectious, but it now seems to be dying out.
What that means for our arsenal Some therapeutic antibodies have weaker binding to these variants of the spike. There is also some evidence that vaccines are slightly less effective against it.
First detected Brazil
Status Variant of concern
Key mutations Seventeen amino acid swaps and one deletion in various viral proteins. Eleven mutations occur in the spike protein, including three in the receptor-binding domain: the N501Y and E484K swaps seen in other variants, and K417T, a swap of a lysine to a threonine.
Biological impact The changes in the spike protein destabilize the form of the spike with all the RBDs in the down position. This favors the form with RBDs in the up position, increasing binding to the ACE2 receptor.
What that means for our arsenal Therapeutic antibodies that target the receptor-binding domain show weaker binding to this variant of the spike, and lab studies suggest that vaccines might not be as protective.
First detected India
Status Variant of concern
Key mutations Around 15 amino acid swaps and deletions in different viral proteins. These changes include a swap of a leucine to an arginine (L452R) in the receptor-binding domain and a swap of a proline to an arginine (P681R) in the furin cleavage site, which is key for the virus to get into cells.
An additional swap of a lysine to an asparagine (K417N) has led to what some have dubbed "Delta with K417N" or “Delta Plus.” India’s health ministry has described this as a new and distinct variant of concern, but the WHO currently considers this part of the Delta variant.
Biological impact Lab experiments have shown that this variant gets into cells more easily and replicates more effectively once there. Epidemiological studies have found that it is more transmissible than Alpha and, as a consequence, Delta has become the dominant variant in many countries.
What that means for our arsenal Lab-based studies suggest that some antibody therapies offer less protection, but Regeneron Pharmaceuticals’ casirivimab-imdevimab cocktail and GlaxoSmithKline and Vir Biotechnology’s sotrovimab are still effective against Delta. Early analyses of cases in multiple countries show that both messenger RNA- and DNA-based vaccines still offer protection against symptomatic infection and hospital admission, but at a slightly reduced level. Pfizer and its partner BioNTech have announced they are conducting early tests to determine whether a third dose of its mRNA vaccine could boost protection. The companies are also developing a modified vaccine tailored to the Delta variant.