CME INDIA Presentation by Admin.

SARS-CoV-2 is the seventh coronavirus known to infect humans. UK new strain of SARS-CoV-2 is not a seventh wonder.

Recent news about new strain from UK, South Africa and some other countries have drawn media attention but in India, public is widely not concerned about it and looking at it as a gambling tactic. With significant decline in cases, palpable anxiety is not visible. Even suspension of flights to UK, is being seen as part of confused science. As known, new strain is known to occur since September, then suspension of flights has little to do in curbing fresh wave as many professionals feel, such strain has already entered…

How Unique is SARS-CoV-2?

• We know that adaptive process occurs in humans and how this virus came as zoonotic transfer is a mystery. Virus will be unable to take off without a series of mutations.
• We have not identified the closest viral relatives of SARS-CoV-2 circulating in animals.
• It is known that 40% of the new emerging diseases is caused by virus. RNA virus is most progressive in this regard. 
• The uniqueness of spike protein is crucial for the genetic isolation of SARS-CoV-2. It is responsible for its high affinity binding to human cells

Variability is life

Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease. –William Osler

• It is worth knowing that there is variability of SARS-CoV-2 viral genome in different species. It points about its animal origin and subsequent evolution of by jumping species in nature.
• Generation of new versions of viral diseases in humans is acquired due to the continuous molecular genetic operations inside host body. It happens by continuous species transmission.
• New disease may appear at any time, in any places, among any population which is unpredictable. Think for evolution as a collective action of genetic operation leading to environmental effect.

CME INDIA Discussion (22/12/2020)

Dr Atul Kalhan, Consultant Endocrinologist, Professor University of South Wales (USW); Director USW Post Grad Diploma & MSc Endocrine course:

• It was first detected in UK around September and by mid-December, two thirds of new cases of COVID-19 are due to this strain (also known as H69/V70 strain).
• It has a few mutations in spike protein (one of it is called N501Y in receptor binding domain) making its infectivity increase by about 2-fold (according to lab-based studies).
• The quoted figures for its infectivity being 70% more come from a presentation done in Imperial college, London.
• As the things stand, there is no evidence that this strain is leading to any changes in case fatality rate or severity of disease.
• It’s been noticed in Wales also and I will keep you informed about the case-fatality statistics locally in coming weeks.
• There is nothing to suggest at the moment that vaccine will be ineffective against this strain; so, no need to panic.
• Vaccination has started in full stream in UK with many of my colleagues getting the first dose (I had moderately severe COVID19 pneumonitis in October so delaying my first shot for another week at least).
• Let’s resist over reaction to this new mutant strain; being cautious is fair enough but avoid any kind of panic.
• Perhaps by March-April, a degree of normalcy will return.
• Economic implications and chronic conditions being not managed appropriately during pandemic will test healthcare systems across the globe in coming months. Jai Hind.

Dr Keyur Acharya – Intensivist, Critical Care Unit, Royal United Hospital, Bath, Somerset, UK:

• We know this since September and it is likely that this strain is everywhere. Genomic surveillance is better here and they picked it up earlier. I agree, it is undue panic.
• Genomics (Consortium of 12 public health bodies/academic institutions) have been sequencing genomics of viral sample since April. They have sequenced 140,000 odd viral samples so far. They identified this particular variant in September and they have been tracking this.
• London and Southeast saw sudden increase in rise in cases and this variant was found in 60% of patients. This was also found in other areas on England including Norfolk, Kent, Sussex, Suffolk. Specific mutation is VUI- 2012 12/01 N501Y.
• Essentially it means that in spike protein on 501st Amino acid there has been change of amino acid Asparagine(N) to Tyrosine(Y).  This mutation is now more than previous mutation D614G which was thought to be more transmissible.
• This has increased R value by 0.4 making it 60% to 70% more transmissible.
• It is certainly not more severe and does not carry more mortality.
• It does mean that we need to up our guard in terms of social distancing, masks and quarantine and speed up vaccination.
• So far it is not shown to reduce efficacy of vaccine. This particular mutation is confirmed in Denmark, Netherlands, Australia, Gibraltar. France and South Africa also are believed to be having this mutant. As it was found (though named in December) in September it is very likely that it has reached other countries.
• Is ban justified? Personally, I think yes as it will help slowing down spread. I do understand that this is medical thinking only and does not take into account economic and other consequences.

Dr Shashank Joshi, DM Endo., Mumbai:

• What to look for when a new virus strain arises:
  • Transmissibility
  • Pathogenicity (Ability to cause the disease)
  • Immunogenicity (To provoke the body immune response)
• 501 variants are more transmissible. It is yet to be proved weather they are more pathologic.
• Another thing to look is Antigenic Drift (minor mutation) or antigenic shift (major mutation).
• 614 mutation was a single gene mutation and 501 variants are three genes mutation.
• Antigenic Drift – One-way viruses change is called “antigenic drift.” These are small changes (or mutations) in the genes of the viruses that can lead to changes in the surface proteins of the virus. The surface proteins are “antigens,” which means they are recognized by the immune system and are capable of triggering an immune response, including production of antibodies that can block infection. The changes associated with antigenic drift happen continually over time as the virus replicates. Most vaccines are designed to target the spike proteins.
• The small changes that occur from antigenic drift usually produce viruses that are closely related to one another, which can be illustrated by their location close together on a phylogenetic tree. For example, Influenza viruses that are closely related to each other usually have similar antigenic properties. This means that antibodies your immune system creates against one influenza virus will likely recognize and respond to antigenically similar influenza viruses (this is called “cross-protection”).
• However, the small changes associated with antigenic drift can accumulate over time and result in viruses that are antigenically different (further away on the phylogenetic tree).
• It is also possible for a single (or small) change in a particularly important location on the protein to result in antigenic drift. When antigenic drift occurs, the body’s immune system may not recognize and prevent sickness caused by the newer viruses. As a result, a person becomes susceptible to infection again, as antigenic drift has changed the virus enough that a person’s existing antibodies won’t recognize and neutralize the newer viruses.
• In the case of flu antigenic drift is the main reason why people can get the flu more than one time, and it’s also a primary reason why the flu vaccine composition must be reviewed and updated each year (as needed) to keep up with evolving influenza viruses.
• Three major antigenic drifts in COVID-19:

1. D 614 G

Amino acid 614 on spike protein RBD part now contains G (Glycine) in place of aspartic acid (D)

2. UK Strain: Multiple gene mutations also called VUI 2020-12/01

N501Y: amino acid N (asparagine) replaced with Y tyrosine in this amino acid in spike RBD location

Deleted His69 Histidine at 69 location

Deleted Val70 Valine at 70 location

Deletion 144

A570D

D614G

P681H

T716I

S982A

D1118H

as well as mutations in other genomic regions.

3. South Africa drift: also 3 gene mutation

N501Y: amino acid N (asparagine) replaced with Y tyrosine in this amino acid in spike RBD location

Plus, two other gene mutations.

• Antigenic Shift

1. The other type of change is called “antigenic shift.” Antigenic shift is an abrupt, major change in a virus, resulting in new proteins in viruses that infect humans. Shift can result in a virus subtype in humans.
2. One-way shift can happen is when a virus from an animal population gains the ability to infect humans. Such animal-origin viruses can contain a protein that is so different from the same subtype in humans that most people do not have immunity to the new (e.g., novel) virus.
3. Such a “shift” occurred in the spring of 2009, when an H1N1 virus with genes from North American Swine, Eurasian Swine, humans and birds emerged to infect people and quickly spread, causing a pandemic. When shift happens, most people have little or no immunity against the new virus.
4. While influenza viruses change all the time due to antigenic drift, antigenic shift happens less frequently. Influenza pandemics occur very rarely; there have been four pandemics in the past 100 years. Type A influenza viruses undergo both antigenic drift and shift and are the only influenza viruses known to cause pandemics, while influenza type B viruses change only by the more gradual process of antigenic drift.

Important aspects of SARS-CoV-2 variant with multiple spike protein mutations in UK (Inputs posted by Dr Shashank Joshi)

1. A novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant has been identified in the United Kingdom.
2. Preliminary analysis suggests that the variant is significantly more transmissible than previously circulating variants, according to a Threat Assessment Brief issued by the European Centre for Disease Prevention and Control.
3. The new variant, referred to as SARS-CoV-2 VUI 202012/01 (Variant Under Investigation, year 2020, month 12, variant 01), shows an estimated potential to increase the reproductive number (R) by ≥0.4, with an estimated increased transmissibility of up to 70%.
4. There is no indication, as of now, of increased infection severity associated with the new variant.
5. SARS-CoV-2 VUI 202012/01 is defined by multiple spike protein mutations (deletion 69-70, deletion 144, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H), as well as mutations in other genomic regions.
6. The most affected region was in Kent/South East England, which saw an increase in the 14-day case notification rate from 100 cases per 100,000 population in week 41 of 2020 to over 400 per 100,000 in week 50 of 2020.
7. Analysis using viral genome sequence data identified a large proportion (>50%) of cases belonging to novel variant. As of December 13, 2020, a total of 1,108 individuals had been identified with the novel variant in England, with the earliest case identified on September 20, 2020.
8. Also seen in other countries, including Denmark and the Netherlands.
9. European Centre for Disease Prevention and Control is recommending the following:
   • Public health authorities and laboratories are urged to analyse and sequence virus isolates in a timely manner to identify cases of the new variant.
   • People with an epidemiological link to cases with the new variant or travel history to areas known to be affected should be identified immediately to test, isolate and follow up their contacts in order to stop the spread of the new variant.
   • If cases infected with this new SARS-CoV-2 variant or other new SARS-CoV-2 variants of potential concern are identified, countries should notify through the Early Warning and Response System of the European Union.
   • The importance of strict adherence to non-pharmaceutical interventions according to national policies needs to be communicated to the public, and in particular guidance on the avoidance of non-essential travel and social activities should be stressed.
   • Laboratories should review the PCR performance and drop-out of the S-gene. PCR could be used as an indicator for cases with the new variant for further sequencing and investigation.
   • Suspected cases of COVID-19 reinfection should be followed up, closely accompanied by sequencing respective virus isolates from these cases. Similarly, cases with treatment failures using convalescent plasma or monoclonal antibodies should be further studied.
   • With the implementation of vaccination, close monitoring of COVID-19-vaccinated individuals needs to be ensured to identify possible vaccination failure and breakthrough infections. Virus isolates from these cases should be sequenced and characterised genetically and antigenically.
   • The United Kingdom has an established SARS-CoV-2 genome sequencing consortium called COG-UK.
   • It consists of the national public health institutes, National Health Service organisations, academic institutions, and the Wellcome Sanger Institute. They are working to keep sequencing coverage high and geographically representative and to keep turnaround times low. This initiative increases the likelihood that emerging variants are identified and can be assessed in a timely fashion.
   • Reference: https://www.ecdc.europa.eu/sites/default/files/documents/SARS-CoV-2-variant-multiple-spike-protein-mutations-United-Kingdom.pdf ; European Centre for Disease Prevention and Control.

Dr A K Singh, Endocrinologist, Kolkata:

Dr Ambrish Mithal, DM Endo., Delhi: Terrible.

Dr N K Singh: Any data on mortality with this. Do you think, only this strain or defunct masking could be working?

Dr K N Manohar, Bengaluru: Good point as Antigenic drifts would be the likely cause and a variant with desire only shouldn’t cause higher mortality.

Dr A K Singh: No increase in death – thankfully.

Dr Jagdeeshan, Chennai: There are 2 variants of coronavirus that have caused alarm. The UK variant with higher transmission levels, and the South Africa variant that also has higher transmission levels, along with reports that it causes a more severe illness. Studies are on. UK one not fatal. African one just reported. They are doing research on it.

CDC says:

What implications could the emergence of new variants have?

Among the potential consequences of these mutations are the following:

• Ability to spread more quickly in humans. There is already evidence that one mutation, D614G, has this property to spread more quickly. In the lab, G614 variants propagate more quickly in human respiratory epithelial cells, out-competing D614 viruses. There also is evidence that the G614 variant spreads more quickly than viruses without the mutation.
• Ability to cause either milder or more severe disease in humans. There is no evidence that VOC 202012/01 produces more severe illness than other SARS-CoV-2 variants.
• Ability to evade detection by specific diagnostic tests. Most commercial polymerase chain reaction (PCR) tests have multiple targets to detect the virus, such that even if a mutation impacts one of the targets, the other PCR targets will still work.
• Decreased susceptibility to therapeutic agents such as monoclonal antibodies.
• Ability to evade vaccine-induced immunity. FDA-authorized vaccines are “polyclonal,” producing antibodies that target several parts of the spike protein. The virus would likely need to accumulate multiple mutations in the spike protein to evade immunity induced by vaccines or by natural infection.

CME INDIA Learning Points

• New strain of UK has been snappily named VUI-202012/01 (the first “Variant Under Investigation” in December 2020) and is defined by a set of 17 changes or mutations.
• One of the most significant is an N501Y mutation in the spike protein that the virus uses to bind to the human ACE2 receptor.
• Changes in this part of spike protein may, in theory, result in the virus becoming more infectious and spreading more easily between people.
• SARS-CoV-2 is an RNA virus, and mutations arise naturally as the virus replicates.
• Many thousands of mutations have already arisen, but only a very small minority are likely to be important and to change the virus in an appreciable way.
• Mutations that make viruses more infectious don’t necessarily make them more dangerous.
• There is currently no evidence that this strain causes more severe illness, although it is being detected in a wide geography, especially where there are increased cases being detected. The new variant has mutations to the spike protein that the three leading vaccines are targeting.
• However, vaccines produce antibodies against many regions in the spike protein, so it’s unlikely that a single change would make the vaccine less effective.

CME INDIA Tail Piece

• A new variant of the COVID-19 virus is driving a massive resurgence of the disease in South Africa, with experts warning the country is probably facing a much larger second wave.
• Now a new variant of the virus — known as 501.V2 — is driving a powerful second wave, making up about 80 to 90 per cent of new cases in Africa’s most industrialised nation. 
• The strain is different from Britain’s but is similar in the sense that it is spreading far.

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