As it comes up to 5 years since the original strand of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is still a lot that the scientific community doesn't fully understand. One of the biggest dilemmas that was faced during the pandemic is the consistent mutations that led to numerous variants throughout 2020 and 2021 especially. To help identify variants that have a higher health risk, the WHO described 2 major types of viral variants: variants of concern (VOC) and variants of interest (VOI). The WHO placed variants in these groups based on their function changes that happened because of mutations; how severe the disease was that it caused; and how easily it was able to avoid being destroyed by the immune system and the available vaccines. [1] There were many different variants that were named by the WHO using the Greek alphabet. Some of the most notorious being Alpha, Beta, Delta and Omicron.
The coronavirus is made up of many components which make it capable of invading human host cells, one of which is the transmembrane spike glycoprotein. The spike is made up two sections called subunits:
S1 - has an amino-terminal domain and a receptor-binding domain (RBD). It is responsible for binding to a receptor on the human host cell called ACE2. This starts the process of infection in the body. Defines pathogenicity
S2 - has the trimeric core of the protein and is responsible for membrane fusion [2]
The spike protein works by it being able to go between an open confirmation and closed confirmation where a hinge-like movement reveals the the RBD which means it can then bind to ACE2 which makes the spike protein become an even more open structure until it becomes fully open. That in turn creates a three-ACE2-bound structure which initiates S2 membrane fusion. [2]
Evolution of COVID-19 from December 2019 to October 2020 was equivalent to approximately 2 mutations a month in the global population. Scientists discovered that the spike mutation in particular was were the majority of mutations in the genome of the virus was taking place. This was possibly due to the spike protein was the main way that the virus invaded host cells. [2]
Mutations are often seen as when an amino acid change happens in a sequence of the DNA. This can be crucial because even though some amino acid changes will still result in the same codes for proteins being created, one change can mean the protein being created by a sequence can change completely leading to a change in protein size, function or in some cases, the protein being completely deleted.
There still isn't a completely clear understanding of the functional consequences of mutations in the spike protein, however focus has remain mainly on amino acid changes in the sequence coding for the spike protein. An example of a mutation to note is N439K, first noticed in Scotland in March 2020, and later emerged again in Europe. It enhances binding affinity to ACE2 receptor and reduces the ability of neutralisation by monoclonal antibodies.[2] What this means is that viruses with this mutation is better adapted to enter human host cells through easier binding of the S1 subunit to ACE2 and immune cells in the body are less able to prevent this from happening. Another mutation with similar consequences was Y453F.
How the virus acts within a host cell is said to be determined by the spike protein--ACE2 binding affinities. When scientists looked at SARS-CoV in comparison to SARS-CoV-2, they found that spike protein and ACE2 binding affinity is correlated with a higher disease severity in SARS-CoV infections, with SARS-CoV-2 seeing similar and stronger results in comparison to the SARS-CoV RBD. But, there is said to be am equal or lower binding affinity of the whole SARS-CoV-2 S protein to ACE2 compared to SARS-CoV, suggesting a less exposed RBD. [3]
When this key process was discovered it became the main target for vaccines and treatments throughout the pandemic. Due to the constant mutations located in thee genome of the spike protein, the specificity of a vaccine to a certain variant often came at a disadvantage, especially for variants such as Omicron.
References:
1 – SARS-CoV-2: evolution and emergence of new viral variants Flores-Vega et al
2 – SARS-CoV-2 variants, spike mutations and immune and immune escape Harvey et al
3 – Coronavirus biology and replication: implications for SARS-CoV-2 V’kovski et al Assessed and Endorsed by the Medreport Medical Review Board