Is the new variant of SARS-CoV-2 dangerous?

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Is the new variant of SARS-CoV-2
dangerous?
Have new mutant Variant reached Pakistan?
Mulazim Hussain Bukhari1, Shahzadi Zain2

The B.1.1.7. Virus that originated in England, is not a new virus but a modified form of SARS-CoV-V2. It is infecting people and people are recovering from it. The 501 / V2 (N501Y.V2) variant was also reported in Africa independently. The virus may inactivate monoclonal antibodies. Real-time PCR may fail to detect the virus, but the mRNA vaccine will still be effective because this variant consist of only a slight modification of the spike protein.

A new variant of the coronavirus accounting for more than 60% of the cases in London, is spreading rapidly in UK and raising concerns about rapid transmission and possibility of more severe illness, internationally. This new variant, named “SARS-CoV-2 VOC 202012/01” or “B.1.1.7.”, is the first variant of concern, reported in 2020. This variant consists of a mutation in the receptor binding domain (RBD) of the spike protein S2 at position 501, where amino acid asparagine (N) is replaced with another amino acid tyrosine (Y). Hence, the name N501Y, the same variant reported in South Africa completely independently. The virus is mutating slowly and almost changed from its grandfather originating from Wuhan. The main mutation seen in Sweden in minks to South Africa (SA) and then UK and now in Nigeria. The spread is towards other countries like countries are Australia, Denmark, Netherlands, South Africa and The United Kingdom. The new name of the variant is N501Y.V2 was first detected in the Nelson Mandela Bay of SA.1-5


Prof. Mulazim Hussain Bukhari

 How to Survive This Pandemic?

As daily we are hearing the news of new mutations and new variations, no matter where we are living, we must wear a face mask, keep social distance, avoid large crowds and gatherings, Avoid hotels, bars, jims, wash your hands with practicing a good hand hygiene, take good diet, better sleep, few minutes exercise, get vaccinated when it becomes available to you, and to protect your life and the lives of others, don’t visit any of the where to catch COVID.

What are the mutations noted?
There are over three thousands proteins in SARS-Cov-2 and eight of these proteins have shown changes in this variant. Two of these eight proteins are more important. That is why it was renamed B.1.1.7 and N501Y. The new variant contains several mutations especially at binding motifs that allows it to attach more easily to human cells through ACE-2 receptors, because of three mutations in the receptor-binding domain (RBD) in the spike glycoprotein of the virus.

In South African (SA) variant N501Y (a change from asparagine (N) to tyrosine (Y) in amino-acid position 501), K417N, and E484K. Two of these mutations (E484K and N501Y) are within the receptor-binding motif (RBM) of the receptor-binding domain (RBD). Receptor binding motif in the spike protein of SARS-CoV-2, N501Y, RBM, K417N and E484K, increased the affinity to bind with ACE2 receptors. Unusual for a new variant to contain several mutations about 3 in 
RBD incl. It is more transmissible and it appears to have mutated further than the new variant that has been discovered in the U.K. N501Y is being reported in other countries (0.2%) e.g.UK but there was “no evidence” so far to suggest that the infection caused by this variant is more severe (Fig.1).5

Why we are politics, media is nervous?
The WHO and CDC has declared that they are keenly watching the outcome of these new viruses, but in a statement said that yet there was “no evidence” so far to suggest that the infection caused by this variant is more severe.

South Africa has recorded 931,000 cases of Covid-19, with almost 25,000 deaths, according to official statistics. Excess mortality studies suggest a death toll of more than 56,000. Shedding is more and causing more people to be infected. But not increasing the death rate. In technical term if the virus spreads rapid is less lethal But we don’t know because there still less data about it. Let’s see with the data is available we will let you know.

Is this virus lethal?
This new variant is infecting people rapidly and people are getting sick more quickly. The sick people either are confined to their homes, or hospitalized, or die which automatically reduce the spread of this virus to general population. It is a general rule that if the infection cause mild illness, infected people continue to mingle with non-infected people and pathogen spreads more quickly and vice versa. Another factor that may affect the spread of infection are the super-spreaders who do not exercise caution.3

The new variant is spreading rapidly and looks sever, but still there is no data available, so it is to early to tell. Early signs that the new variant is spreading fast, and faster than 1st wave viruses. It is widespread – probably across most of SA by now. The date shows that the new variant is more transmissible but not lethal and more infecting the young age group 25-49 Years old. (Table-I-II)1

Gene mutation in SARS-CoV-2 and its consequences

Gene modification or mutation is a regular phenomenon in Viruses. SARS-CoV-2 mutates regularly, as expected, acquiring about one new mutation every two weeks. Many of these mutations are silent as they cause no change in the structure of the proteins but some mutations may change the genome in a way that leads to modification in protein structure. The potential consequences of some of these mutations may include rapid transmission in humans, ability to cause more severe illness, ability to evade detection by rtPCR, reduced effectiveness of therapeutic agents, or ability to evade vaccine-induced immunity.1-2

How and where did this change take place?
The RNA of this SARS CoV-2 has 30,000 base papers. Its RNA is made up of 30,000 bricks. Each of its genes has a specific function. If you start from the five end, about thirty of its proteins are very important. The first protein is called protease, which bites and mixes the fragments of the virus and makes proteins for it when it enters the human body. Then there are replicating enzymes called replicas, Then there are helicase that capture the human ATP and use the virus to open the RNA of the SARS CoV-2 through their reverse transcripts and help carry it into the human DNA. At the end of the SARS CoV-2 RNA, are spikes proteins based on S1 and S2 and the receptor binding domain RBD. It consists of a total of 3821, base pairs, starting from 21,563 and going up to 25,384. In other words, it is made up of a total of four thousand bricks, but in new mutations only few bricks have been changed and happened in the mutated SARS CoV-2, with S1, S2 and RBD all change a little bit. So this is not strain of SARS CoV-2 but are its variants.

Why do these mutations occur in the new virus?
Whenever SARS V2 to SARS-Cov-2 enters human cells, its proteins and other enzymes make copies of the new virus. And every time a copy is made and small changes are made to each new virus because there are no proofreaders. In the same way, if hidden, it is called a modified manuscript. Thus, even inside the virus, there are no proof-readers and the proof-reading system of human DNA has been compromised. This virus has proof readers but it is a very long virus which contains about thirty thousand proteins so some bricks go wrong. This is called mutation.

How many changes can a virus make?
There are some mutations that cause the virus to lose its ability and become disabled. In this case, the spread of the virus is completely stopped. Some changes are very minor, which can be called drift. If one or two amino acids change, the pathogenicity does not change much. The virus is still contagious but not lethal. The third change is called shift when the virus changes too much and its pathogenicity changes. The virus is lethal but this feature will reduce the viral spread. The same thing happened with the SARS- CoV-2

How and where did this change take place?
SARS CoV-2 is a RNA virus. With 30,000 genetic bases, it has the largest genomes of all RNA viruses. Each of its genes have a specific function. If you start from 5’ end, the first protein is called protease, which bites and mixes the fragments of the virus and synthesize proteins for it when it enters the human body. Then there are replicating enzymes called replicase. There are helicase that capture the human ATP and open the RNA of the SARS CoV-2 and help carry it into the human DNA. At the end of the SARS CoV-2 RNA, are spikes proteins with subunits S1 and S2 and the Receptor Binding Domain (RBD). This spike protein consists of a total of 3821 base pairs, starting from 21,563 and going up to 25,384 (a total of four thousand bricks), but in new variant, a few bricks have been changed. As a result, S1, S2 and RBD all change a little bit. So it is not a new strain of SARS CoV-2 but a variant!

Why do these mutations occur to make new variants?
Whenever SARS-Cov-2 enters human cells, it replicates itself to make copies of new viruses. Viruses use human machinery to replicate. Every time a copy is made, there is a possibility of a slight change in nucleotides sequence which may result in addition, deletion or replacement of an amino acid, leading to a small change in protein structure. It is called mutation.2

How much a virus can mutate?
There are some mutations that cause the virus to lose its ability to replicate, hence, virus does not propagate further. In this case, the spread of the virus is completely stopped. Some changes are very minor, does not affect protein structure or function and are called “Drift”. If one or two amino acids change, the pathogenicity does not change much. The virus is still contagious but not lethal. Last but not the least, “Shift” happen when the virus mutates too much and its pathogenicity changes. This virus may become lethal but this feature will reduce the viral spread as explained earlier.

How did this new variant B.1.1.7. Virus come into being?
Historically, viral variants have emerged and disappeared on their own! If the mutation is favourable for viral spread and survival, the variant stays and propagate further. If the mutation is unfavourable for viral spread, the variant disappears on its own. When SARS CoV-2 enters in a normal human, human immune system tries to fight it, but if the immune system is compromised or suppressed, human body cannot control replication of the virus, resulting in millions of copies, including some new mutations. If these mutations are favourable, virus can be transmitted to other people and continue to spread and survive in community.

B.1.1.7. consists of many mutation. Some of these include P681H, 69/70 and ORF8. P681H deletion is near the S1/S2 subunit cleavage site. This mutation has emerged spontaneously many times in the past. 69/70 is a double deletion that can likely leads to a change in the shape of the spike protein and has also occurred spontaneously many times. This caused monoclonal antibodies to fail to recognize the epitope, a phenomenon described as monoclonal antibody escape. ORF8 stop codon (Q27stop) deletion is not in the spike protein. It occurred in the past, in Singapore, where it emerged and disappeared on its own.2-5

Have we seen this variant in Pakistan?
B.1.1.7. has not been identified in the Pakistan yet. Possibility of finding this variant in Pakistan still exist either because of independent mutation or through a carrier from UK or elsewhere in world where this variant has or will be isolated next.

What are the consequences of B.1.1.7. variant?
One of the mutation, D614G, in B.1.17., has the property to spread more quickly. this variant bind more tightly to the human angiotensin-converting enzyme 2 (ACE2) receptor. This tighter binding may translates into significant epidemiological or clinical concerns. However, there is no evidence that B.1.1.7. will produces more severe illness than other SARS-CoV-2 variants. Most of the commercial diagnostic tests have multiple targets to detect the virus. The rtPCR that use good kits, can detect at least three zones of the virus and will be able to detect the virus even if there is a mutation in one of these zones.2

This new variant may have reduced susceptibility for monoclonal antibodies but convoluted plasma taken from patient recovering from the new virus will still be useful. The mRNA vaccines approved by FDA have more than one target and will be effective for this variant.2

Will the current vaccine work against this new variant?
Hope it will work but currently, Still there is no data available, so it is to early to tell. 
May these new variants beat vaccine or Monocloncal antibodies if these have been built against these targeted sites. PCR may be beaten if their detection power is limited and against few channels. The only concern is they are increasing the viral load because they are rapidly attaching the human cells and entering in it with rapid replication in side

The most important protein in SARS-CoV-2 is spike protein with subunits S1 and S2 and consists of 3821 base pairs of nucleotides. Three base pairs combine to code one amino acid, that means Spike protein has 1273 amino acids. Around 5 to 6 amino acids come together to form an epitope. The mRNA vaccine stimulate human body to make “antibodies” against roughly 212 epitopes of spike protein S in the SARS-CoV-2, with significant overlap. If SARS-CoV-2 mutates, and these antibodies do not work against the modified part of this protein, rest of the Spike protein is still susceptible to these antibodies. In the current variant B.1.1.7., the first variant of concern so far, only eight amino acids have been changed, rest of the 1265 amino acids are still the same as original SARS-CoV-2 so the current mRNA or viral vector vaccine will still work sufficiently.

What is the fine balance between virus and host?
Viruses usually evolve to become more transmissible & less severe (less pathogenic or less lethal). Mostly within humans in response to immune pressure. Sometimes when they pass through another species 
. SARS-CoV-2 relatively stable in 1st wave, SA recorded about 35 lineages (most were the more transmissible D614G variant from Europe with minor variations). The 2nd wave now in all provinces with some early signs of it spreading faster than 1st wave. Not clear if 2nd wave has more or less deaths (severity unclear). Preliminary results. 
501.V2 variant associated with higher viral load Speculate the following: Higher viral load in swabs may translate to higher efficiency of transmission ie. Higher transmissibility. This may translate into a higher R0. While other viruses are transmitting, this variant is transmitting faster. This may translate into a 2nd wave that will have many more cases than 1st wave. (Fig.5)

Is it re-infecting people who got infected in the 1st wave.?
There may be chance but still there is no data available, so it is to early to tell. 
Still no evidence virus is re-infecting the recovered cases in Pakistan or worldwide but may do this if some other superadded factors are there like sever immune deficiency

What should we do next?
There is reason for concern that we have a virus that seems to be spreading rapidly; but it is something we can deal with. 
Same prevention measures & treatment work for 501.V2. Similar 501 variants are in other countries e.g. Australia, UK . Inform key role-players & the public about the 501.V2 variant. Publish the data in a prominent journal. Urgently increase phylogenetic screening – need to sequence 100-200 viruses every month from across SA. Complete the studies to answer the 4 unknowns – fortunately, there are vaccine trials underway in SA e.g. J&J.

Have new mutant Variant reached in Pakistan?
The new coronavirus variant, which first emerged in the UK, has been detected in Sindh and the federal health authorities have been updated about it, it emerged on Tuesday, 29.12.2020

What the Pakistan is imposing travel restrictions?
Pakistan announced its updated standard operating procedures (SOPs) for travel restrictions imposed on inbound travelers from the United Kingdom, after cases of a highly new infectious strain of the coronavirus rose across the European country.9

What are the effects of this new B-117 virus and SA Varinat?
The virus is spreading rapidly and is affecting the other area in many ways.

  1. The rate of hospitalizations is increasing due to increased its transmissibility.
  2. The mortality rate has doubled, few days ago it was 1-2% of the infected people and now it is increased to 4% but statistically not significant.
  3. The likelihood of blindness has also been reported with this variant. The reason are unknown but Stroke may be a possibility.
  4. No re-infection has been reported so far
  5. Post-inoculation infection has not been reported
  6. Earlier concerns of children been disproportionately affected, has not been backed up by any data.

References

  1. Investigation of novel SARS-CoV-2 variant.Variant of Concern 202012/01. Technical briefing 2. URL: https://www.gov.uk/government/publications/investigation-of-novel-sars-cov-2-variant-variant-of-concern-20201201. Dated 31.12.2020.
  2. CDC. New variant’ of coronavirus identified in England. URL. https://www.cdc.gov/coronavirus/2019-ncov/more/scientific-brief-emerging-variant.html. Dated 28.12.2020
  3. Wroughton, Lesley; Bearak, Max (18 December 2020). “South Africa coronavirus: Second wave fueled by new strain, teen ‘rage festivals’”. The Washington Post. Archived from the original on 27 December 2020. Retrieved 20 December 2020.
  4. Mkhize, Dr Zwelini (18 December 2020). “Update on Covid-19 (18th December 2020)” (Press release). South Africa. COVID-19 South African Online Portal. Retrieved 23 December 2020. Our clinicians have also warned us that things have changed and that younger, previously healthy people are now becoming very sick.
  5. Abdool Karim, Salim (19 December 2020). “The 2nd Covid-19 wave in South Africa: Transmissibility & a 501.V2 variant”. Scribd. CAPRISA. p. 11. Retrieved 24 December 2020.
  6. BBC. The deadly viruses that vanished without trace. URL: https://www.bbc.com/future/article/20200918-why-some-deadly-viruses-vanish-and-go-extinct. Dated 28.12.2020
  7. WHO. Authorities investigating new COVID-19 variant in England. URL. https://www.bbc.com/news/health-55308211. Dated 28.12.2020
  8. Coronavirus cases in England’s cities and large towns. URL. https://www.centreforcities.org/data/coronavirus-cases-uk-cities-large-towns/ Dated 28.12.2020
  9. New coronavirus variant reaches Pakistan. URL. https://www.thenews.com.pk/latest/766187-new-coronavirus-variant-reaches-pakistan. Dated 30.12.2020
  10. Investigation of novel SARS-CoV-2 variant.Variant of Concern 202012/01. Technical briefing 2. URL: https://www.gov.uk/government/publications/investigation-of-novel-sars-cov-2-variant-variant-of-concern-20201201. Dated 31.12.2020.
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