As of now, we’re all more than ready for the pandemic to be over. In many countries, the infection numbers combined with vaccinations may soon reach herd immunity. Yet, we are hearing more and more about new SARS-CoV2 variants.
The news about these variants, skyrocketing case numbers, and terminologies like “variants of concern” may have led to another wave of fear and lockdowns.
In this article, we will explain the biochemical details of these variants and what they mean for infectivity, disease severity, and vaccine effectiveness.
What are COVID-19 Variants and How Do They Arise?
SARS-CoV2 variants or strains are new versions of the virus that have some differences in their genetic sequences RNA. They arise when the virus’s RNA polymerase enzyme makes a mistake as it copies the viral genome inside human cells.
Generally, RNA polymerases make more mistakes than DNA-polymerases, so new RNA virus variants emerge more frequently than DNA viruses. The human DNA polymerase makes mistakes at around 1–2 in a million because it has a proofreader that reduces the error rates by orders of magnitude.
Coronaviruses also have an enzyme that corrects errors made by the RNA polymerase, but the enzyme isn’t very good. The enzyme makes mistakes at around 1 in 135,000–1 in 34,000,1 which is about 7.4–58.8 times the rate of DNA polymerase.
The errors from RNA polymerase that change the genetic sequence are called mutations. There are three types of mutations:
- Substitutions: When one or more RNA bases are replaced by a different one
- Deletions: When one or more RNA bases are eliminated
- Insertions: When one or more extra bases are inserted into the RNA molecule
The more times the virus replicates, the higher the chance these mistakes will occur. Therefore, the more people it has infected, the more likely there will be new mutations.
Each mutation refers to a mistake or a single change in the amino acid, whereas each variant or strain can be a combination of multiple mutations.
In most cases, the new variants do nothing or are detrimental to the virus, such as by impairing viral replication or entry into the cells. In such cases, the new variants will not thrive and you’ll most likely never hear about them.
In rare cases, the mutations somehow increase the virus’ evolutionary fitness, such as by speeding up viral replication, enhancing entry into the host cells, or evading pre-existing immune protection. As a result, the variants will likely spread and infect more people.
Why Most Discovered Variants are in the Spike Protein
Although these mutations can occur in any protein of the virus, most discovered (ones that thrived) mutations occur on the spike protein. The spike protein’s receptor binding domain (RBD) binds to ACE2 like lock and key before the viral and cell membranes fuse and the virus enters the cells.
The D614G variant in the RBD helps it bind to ACE2 more tightly, making it a winning combination (from the virus point of view, of course!). First appeared at the beginning of 2020, it is now almost universal because it increases viral infectivity. It seems to be responsible for the loss of smell symptom.2
D614G replaced the amino acid aspartate (D) at the position 614 of the protein with a glycine (G). The glycine on that position facilitates the recognition of spike by ACE2.3
Although the virus has an enzyme that prevents mutations, the number of infected people with COVID-19 worldwide is so high that we now see a huge number of different mutations and variants. Some have already emerged and are now extinct, such as the Cluster V variant from Denmark.
What are COVID-19 Variant Classifications?
The US CDC classifies COVID-19 variants into three groups based on the quality of evidence available.3 Although constantly evolving, the classification is aimed to guide public health measures.
Variants of Interest
- evidence of increased disease severity in animals
- changes in receptor binding
- reduced effectiveness of pre-existing immunity from prior infections or vaccination
- reduced efficacy of treatments
- increased false negative rates in RT-PCR tests
- predicted increased transmissibility or disease severity
Variants of Concern
- evidence of increased transmissibility
- more severe disease, e.g. increased hospitalization and deaths
- significant reduction in effectiveness of prior antibodies
- reduced effectiveness of existing treatments or vaccines
- diagnostic detection failures
Variants of High Consequence
For these variants, there is clear evidence that current preventive or countermeasures are significantly less effective than other preexisting variants, which could be the following:
- failure of current tests to detect the infections
- significantly reduced effectiveness of vaccines and treatments
- more severe diseases and increased hospitalizations
Fortunately, there are currently no variants of high consequence.
All the variants of interest and concern acquired mutations that made them enter host cells more easily than the original virus, and are thus more transmissible.
The variants of concern include the following:
The UK Variant (B.1.1.7)
It has eight specific amino acid mutations in the spike protein. Among them, deletion of amino acids on positions 69 and 70 (termed Δ69,70) stands out.4 Another important mutation is N501Y, on the surface of the RBD.
No evidence exists for change in symptoms or duration of the disease, but mortality is increased by 35%.5,6
The South Africa Variant (B.1.351)
Its signature is the triplet K417N, E484K, N501Y. The first two are located at the RBD of spike. K417N decreases affinity for the ACE2, but the other two increase it. Overall, the three mutations increase spike affinity for ACE2 by five-fold.7 The variant is 1.5-fold more transmissible.8 However, there is no evidence of increased disease severity.
The Brazil Variant (P.1)
This is characterized by 10 mutations in the spike protein, including the triplet of the South Africa variant (K417N, E484K, N501Y). These three mutations occurred independently and prevailed because the virus benefitted so much from them.9 Despite concern over increased numbers of hospitalizations and deaths, there is no reported evidence for higher severity of the disease.10
The India Variant (B.1.617)
In May 2021, the WHO added this to its list of variants of concern. For the CDC, this was still a variant of interest. In fact, this is a lineage with already three sublineages (B.1.167.1, B.1.167.2, and B.1.167.3).11
The characteristic signature is G142D, L452R, E484Q, P681R, although not all the mutations are present in the three sublineages. L452R and E484Q are located at the RBD. P681R is at a segment of the spike protein that is cleaved by ACE2 during viral entry into the cell. Most probably, P681R accelerates the fusion of the viral and the human cell membranes.12
Although being transmitted faster, these viruses do not seem to increase death rates.13
The California Variants (B.1.427 and B.1.429)
Due to the specific US situation, the CDC also classifies these two as variants of concern. They were initially described as a single lineage with two sublineages.
B.1.427 contains L452R and D614G, whereas B.1.429 contains S13I, W152C, L452R, D614G. L452R is located at the RBD and probably promotes the interaction with ACE2.
It transmits faster than the original virus but not as fast as variants of concern B.1.1.7, B.1.351, and P.1.14
Do These Variants Evade Antibodies From Original COVID-19 Infections and Current Vaccines?
In the blood of convalescent people, the antibodies against the RBD of spike are a minority but account for 90% of neutralization activity!15
Most current vaccines are designed to induce antibody response against the spike protein. Eventually, a variant might emerge that evades the original antibodies if the new spike variant differs enough.
Whether one vaccine is efficient or not against one variant has to be tested case by case.
Two types of tests have been done. One is by collecting sera from vaccinated people, mixing it with the virus, and measuring neutralization in vitro. The other is by vaccinating a very large number of people in areas where the variant is present and following up with them for months.
The following is the summary of current studies from these tests.
Sera from people vaccinated with Comirnaty (Pfizer/Biontech), mRNA-1273 (Moderna), or Covaxin (Bharat Biotech) can all neutralize this variant in the test tube.16,17
South Africa Variant
Sera from people vaccinated with Comiranty or mRNA-1273 can neutralize this variant virus.18 Also the mRNA-1273 vaccine produces sera with lower but still significant neutralization.19
In contrast, the ChadOx nCov-19 (AstraZeneca) was inefficient both in vitro and in a clinical assay: It prevented mild to moderate disease with only 10% efficacy.20 Other vaccines, still not in use, have shown efficacy against this variant, including the Novavax vaccine, BBIBP-CorV (Sinopharm), and RBD-Dimer (Anhui Zhifei Longcom).21,22
Both Comiranty and ChadOx nCov-19 vaccines induce antibodies in sera with neutralization activity in vitro against this variant.23
Sera from people vaccinated with the mRNA-1273, Comirnaty, or Covaxin all neutralize this variant, the first two with reduced efficacy compared to with the original virus.24,25
How Do the Tests Work to Distinguish Between the Variants?
The current COVID-19 tests only determine whether the virus is present in the sample. The RT-PCR can also be semi-quantitative or help to estimate the viral load. Therefore, to distinguish new variants, the lab may need to determine the full viral RNA sequence, which can be laborious and time-consuming. Sequencing the spike gene is a good alternative, although not always feasible.
So, the most-used technique is a variant-specific PCR test. The variant-specific PCR test is simply a COVID-19 diagnostic PCR test adapted to detect one or more variants.
PCR tests kits come with primers and probes. A primer is a small DNA molecule designed to bind to one specific region of the virus RNA. If the region is there, it amplifies. The amplified region then binds to a specific probe, and the probe fluoresces.
In fact, the tests use different primers and probes of different colors, to recognize more than one RNA region to minimize the risk of false negatives.
Because the primers for nucleic acid tests of SARS-CoV2 are sequence-specific, some mutations may interfere with the tests.
A while ago, when running routine diagnostic tests, researchers noted that the TaqPath PCR test (Thermo Fisher Scientific) failed to detect the spike gene region in some samples. But it still succeeded in detecting the other regions. It happened that in those samples the virus contained the Δ69,70 mutation. It was the UK variant. The test failed because one primer was designed to bind the spike gene right on the mutated region. This feature was helpful though because it guided researchers to target the UK variant.26,27
The FDA is attentive to cases like this and regularly updates information on the impact of mutations on the diagnostic tests.28
At the moment, several PCR tests from several suppliers distinguish different variants in one run, using a combination of multiple primers. Each primer detects one specific region. One primer may detect the Δ69,70 only, and another may detect the same region but only if unmutated. Combining these with primers for the signature mutations of different variants allows for rapidly distinguishing between variants.
So, What Can You Do?
Aside from following local public health guidelines, it has become more important now than ever to take care of your physical and mental health.
Some variants may reduce the effectiveness of specific treatments such as COVID-19 vaccines and convalescent sera. However, measures to support your immune system, such as with sleep, nutrition, and stress management are still effective.
It is also important to keep in mind that although the uncertainties can be scary, the variants have not undone over a year’s worth of scientific advances. We still know a lot more about the virus, the treatments, and prevention than we did in the beginning of the pandemic. The mRNA vaccine, for example, can be quickly updated should a new variant render the pre-existing ones ineffective.
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