By Dr Liyana Azmi
Recently, Malaysia has been recording an increased number of COVID-19 cases categorised by either the Variant of Concern (VOC) or Variant of Interest (VOI). VOCs or VOIs are mutant forms of the COVID virus (SARS-CoV-2), which are more virulent and infectious than its predecessor Wuhan strain. Among the VOCs isolated in Malaysia include the B.1.351 (South African), B.1.617 (India) and B.1.1.7 (England) variant. These VOCs have also been given new names by WHO for better recognition which are Alpha, Beta, Gamma and Delta, respectively. VOIs such as the P.3 (Philippines) and B.1.525 (Nigeria) variants were also detected among the new infection cases in Malaysia. The situation worsens as the Malaysian Ministry of Health detects VOC-infection from every state in Malaysia, along with the current surge of cases. With such findings, it is possible that VOI cases may be spreading in the country.
The increasing VOC and VOI cases in Malaysia is indeed alarming and worrisome as it indicates that a more virulent variant of the virus is infecting the community. According to the Center for Disease Control, VOCs have shown to have:
- higher transmissibility (i.e., can infect a larger population),
- induce a more severe disease (i.e., increased hospitalisations or deaths),
- reduce the effectiveness of treatments and vaccines, and
- may escape diagnostic detection.
On the other hand, VOIs are perceived as ‘less dangerous versions of VOC’. VOIs are mutants of the SARS-CoV-2 virus that:
- cause changes in the receptor-binding-domain (RBD),
- can reduce the effectiveness of treatments and vaccines,
- may induce a more severe disease, and
- may have increased the level of transmissibility.
Essentially, the crucial differences between the original SARS-CoV-2 virus isolated from Wuhan, China and the recent VOCs and VOIs are the changes in the spike protein (S) shape of the virus. The S protein consists of different regions, and one of the most important regions is the receptor-binding-domain (RBD). The RBD is the portion of the S protein which attaches to our lung cells, specifically the angiotensin-converting enzyme 2 (ACE2) cells – which is the enzyme covering the membrane or, the outer layer of our lung cells (Figure 1).
In March 2020, scientists have identified which specific portion of the protein interacts with our ACE2 lung cells. Since the RBD is the point of contact with our ACE2 cells, this discovery has significantly contributed to the development of vaccines. Many vaccination strategies have been focused on interrupting this interaction (SARS-CoV-2 RBD with our ACE2 cells). Studies showed that antibodies generated from the vaccination were successful in interrupting this interaction and caused the neutralisation (or destruction) of the viral proteins.
Comparative genomics and structural characterisation have previously highlighted the differences between these strains. The findings showed that among the differences between these variants, the most significant mutations are the structural changes within the spike proteins (Figure 2). Essentially, coronaviruses have undergone mutations and were able to change the shape of their spike proteins to result in a tighter binding to our ACE2 cells. The result of these mutations has enabled the virus to be more infectious and transmissible.
To illustrate this scenario, we will compare the shape of the spike protein between the original SARS-CoV-2 isolated in Wuhan and the VOCs. In the original SARS-CoV-2 strain, the amount of contact of the RBD to the ACE2 is minimal due to the shape illustrated in Figure 2. Over time, the spike protein evolves and changes its shape. In Figure 2B, the Beta variant (Brazilian variant) has a slightly curved spike protein, thus have more contact points with the ACE2 cells. This mutation results in a tighter bond to the ACE2 cells. The much more infectious Indian variant has evolved further and has a spike protein that is different from both the Brazilian and original SARS-CoV-2 virus. In the Delta variant (Indian variant), the spike protein has more contact points to the ACE2 cells than the Brazilian variant. These mutations explain why the virus can infect a larger population and can induce a more severe disease.
Viruses continue to mutate and will ‘select’ for beneficial mutations, which allow the virus to enhance their infectivity – as seen in the Beta and Delta variant from Figure 2. If the virus continues to infect large populations, this will increase the possibilities of further detrimental mutations. Therefore, vaccinations are crucial and must be given to as many people with utmost urgencies.
The other important take-away message from this situation is that individuals who have been vaccinated are vulnerable to infections from the new variants. This is because the antibody created from the vaccine has a reduced ability to neutralise and fight the variants. Understandably, the public is now concerned that vaccinations will not confer protection against the variants by VOCs and VOIs. Nevertheless, the immune system developed through the current vaccination is still able to significantly reduce the severity of the COVID-19 disease – even against the variants.
Konings, F., Perkins, M.D., Kuhn, J.H. et al. SARS-CoV-2 Variants of Interest and Concern naming scheme conducive for global discourse. Nat Microbiol (2021). https://doi.org/10.1038/s41564-021-00932-w
Lan, J., Ge, J., Yu, J. et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 581, 215–220 (2020). https://doi.org/10.1038/s41586-020-2180-5
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Dr Liyana Azmi is a microbiology lecturer at Universiti Sains Islam Malaysia (USIM). She specialises in structural biology and is interested in protein mutations in bacteria and viruses.