CME INDIA Presentation by Dr. Rajeev Jayadevan, MD, DNB, MRCP, ABIM (Med) ABIM (Gastro), NY. Vice Chairman, Kerala state IMA Research Cell. Member, National IMA Task Force on Corona Epidemic, Cochin.

Omicron is weaker in its stealth ability than delta.

Stealth refers to ability to infect large numbers of cells without awakening the body’s immune response. Somewhat like thieves operating in the dark after turning burglar alarms off. Omicron’s “ability to turn the cell’s burglar alarm off” is lower than that of Delta.

New study shows that the mutations in the Omicron variant do not cause substantial changes in the drug sensitivity profiles of the viruses.

Omicron is weaker in its stealth ability than delta.

Total Omicron cases in India: Tip of iceberg data only

Our labs did not test S gene in rt PCR.
Genomic sequencing done in limited cases.
Millions of home Rapid Antigen tests done (Not reported).
Millions not testes for very typical Omicron symptoms.

Scan this report of rt PCR

(Courtesy Dr Anoop Kumar, Chief Critical care BMH, Calicut)

  • PCR testing involves testing of more than one gene present on the genetic code of the virus. E.g., S, ORF 1ab, N, E. In Omicron, there are many mutations around the S gene. Therefore, on PCR testing, this will not light up. This is called S gene target failure (SGTF).
  • In the absence of other variants such as Alpha that cause a similar picture, S gene target failure can be considered a reliable surrogate (marker) of omicron.
  • Delta does not cause SGTF. Most PCR in India do not test for S gene. That’s why it is difficult to identify Omicron.
  • The other method of testing is whole genome sequencing, which is time consuming; done only in select centres.

One pilot series confirms Omicron is already widespread in the community

  • Omicron found in 75% of samples tested in Kerala. 38 out of 51 consecutive samples tested among inpatients at a Calicut Hospital have SGTF, a surrogate of Omicron. They did not have any connection with international travel.

What is the STEALTH STORY of Omicron vs Delta?

  • This study from Germany by @CiesekSandra and team shows that Omicron’s “ability to turn the cell’s burglar alarm off” is lower than that of Delta. (1)
  • Or that Omicron isn’t as smart as delta.
  • This suggests that our body can detect the presence of Omicron sooner than it could detect delta.
  • The cell’s burglar alarm system is interferon. Any cell that is infected by the virus is supposed to sound this alarm bell, alerting neighbouring cells about the invasion.
  • This enables neighbouring cells to scale up their defences and also attracts the body’s killer immune cells – that will arrive on site, and take out the offenders – before they cause greater damage.
  • Thus, stealth is an important ability – as far as the virus is concerned.
  • The researchers discovered this by using two types of cells which they infected with Omicron and with Delta.
  • The Vero cells that they used in the lab have defective alarm systems to start with. They found that both delta and omicron variants were able to invade this cell, with equal vigour.
  • However, when it came to infecting interferon-competent cells (Caco-2, Calu-3) Omicron fell behind delta.
  • This shows that these cells (which had intact burglar alarms) were able to ward off omicron, while delta could not be stopped.

Note: These are lab studies. Observations on cells in culture do not necessarily reflect what happens in the human body. Nevertheless, we need to look at such elegant research studies from such people of competence, but at the same time not to over-read or generalise. Evidence is like a painting, it is completed bit by bit.

CME INDIA Learning Points

  • Omicron (B.1.1.529), is a heavily mutated and highly contagious SARS-CoV-2 variant.
  • New study Ref-(1) (Not peer-reviewed) has given two very important insights
  1. Omicron isolates display similar sensitivity to eight of the most important anti-SARS-CoV-2 drugs and drug candidates. We have further confidence with these 3 most important drugs in Omicron management in specific situations), which is of timely relevance.
    1. Remdesivir.
    2. Molnupiravir.
    3. PF-07321332, the active compound in paxlovid.
Antiviral testing indicated a similar sensitivity of Omicron and Delta isolates to EIDD-1931, PF-07321332, remdesivir, favipiravir, ribavirin, nafamostat, camostat, and aprotinin and, hence, to a range of drugs representing different mechanisms of action.
This shows that the mutations in the Omicron variant do not cause substantial changes in the drug sensitivity profiles of the viruses.
  1. Most importantly, it was found that the Omicron variant displays a reduced capability of antagonising the host cell interferon response. This provides a potential mechanistic explanation for the clinically observed reduced pathogenicity of Omicron variant viruses compared to Delta variant viruses.

Input from Dr. Noni G. Singha, Consultant physician, Dibrugarh, Assam

Omicron has three lineages:

  • BA1
  • BA2
  • BA3

BA3 is less common lineage. Initially it was only BA1, lately BA2 is detected in many places including India. Approx. 80 % of Kolkata is of BA2 lineage. In upper Assam, also mainly BA2 as per ICMR Dibrugarh (they have a method to detect it, which is validated).

BA1 and BA3 has S gene drop or failure but BA2 has S gene many has expressed.

If S gene drop technique is used to detect Omicron, then it will not detect BA2, thereby making it difficult to distinguish from Alpha variant. So, need methods other than SGDT to detect Omicron perfectly.

CME INDIA Tail Piece

CME INDIA Discussion – 19/01/2022

Dr. Anand Malani, MD, Sangli: Some observations:

  1. Out of last 15 tests done over 2 days, S gene detected in 12 meaning Non-Omicron. Likely to be Delta.
  2. Even Delta behaving like a good boy. Complications much less. May be attributable to vaccination. No hospitalisation at large. CRP not exceeding 20. D dimer normal.
  3. Delta also having lot of upper resp. complaints especially throat pain. Wasn’t seen in last wave.

Questions based on above:

  1. Any chance of mixed infection Delta plus Omicron?
  2. Just like some Delta (about 20%) can have S gene target failure, can some Omicron have S gene presence (The Spike protein is mutated but not completely absent or changed). Just wondering. Difficult to believe that majority are still Delta. Any information available?
  3. Most important: Should an unvaccinated status be counted as high risk factor for proven Delta/ Non-Omicron and Monoclonal antibodies considered on the sole criterion of unvaccinated status?

Dr. Rajneesh Tyagi, Physician, Noida: Could be due to the fact that most of us were exposed to delta and many have partial immunity against it.

Dr. Sourav Maiti, Neurosciences, Kolkata: Yes, S gene target failure is not identification mark for omicron. A good number of omicron do have presence of S gene.

Dr. Chandrakar Tarke, Pulmonologist, Hyderabad: The BA.2 variant of Omicron will have S gene present. Majority being detected now are BA.2 as per data from Calcutta. S gene presence in the present scenario is mostly due to BA.2 variant of omicron rather than Delta. The recent GHMC Hyderabad data where gene sequencing was done showed 87 percent omicron.

Dr. P. R. Parthsarathy, Chest Physician, Chennai: May be one has to go by clinical judgement .in mild cases there will not be any problem even if S gene is present as long as the pt is being closely monitored for worsening of the symptoms.

Dr. Anand Malani, MD, Sangli: As per Government figures based on genetic sequencing 50-60 percent still Delta in Maharashtra. If S gene detected in Omicron too then there remains no way to differentiate. Gene sequencing takes time. Monoclonal decision cannot wait for that. Delta patients should not miss out the timeframe for monoclonal. Any other reliable way to differentiate? Clinically possible to some extent but accuracy will be low.

Dr. Sourav Maiti, Neurosciences, Kolkata: In Kolkata, we are getting mix up of Omicron and Delta in majority… along with a few cases (~15%) variants other than the VOCs. Majority cases seem mild to moderate.

Dr. Chandrakar Tarke, Pulmonologist, Hyderabad: Some kits can distinguish if it is ba 2.1 variant or not. Omisure is one such test. Some people are using it.

Dr. Anand Malani, MD, Sangli: BA.1 – In most of India. BA.2 – Stealth Variant of Omicron – No SGTF. In some parts. Not yet reported in Maharashtra. BA.3 – Not yet in India. One more question: If S gene target detected in BA.2 does it mean less mutated Spike protein? And is it amenable to Cocktail antibodies? At least theoretically. Unlikely that any trial or study is available. It’s confusing and clinically challenging!

References:

  1. Reduced interferon antagonism but similar drug sensitivity in Omicron variant compared to Delta variant SARS-CoV-isolates.Denisa Bojkova, Marek Widera, Sandra Ciesek, Mark N. Wass, Martin Michaelis, Jindrich Cinatl jr.bioRxiv 2022.01.03.474773; doi: https://doi.org/10.1101/2022.01.03.474773
  2. Planas P, Saunders N, Maes P, Guivel-et al.. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization. Nature. 2021 Dec 23. doi: 10.1038/d41586-021-03827-2



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