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.

Scenario is mindboggling and all looks maddening

Dr Eric Topol, UK:

(Founder and Director of the Scripps Research Translational Institute, Professor of Molecular Medicine, and Executive Vice-President of Scripps Research, UK.)

• New York State is a key bellwether for the US now, w/ the highest case/capita count, higher vaccinated (72 vs 62% US), much prior Covid, test positivity > 20%. Hospitalizations are steeply rising, mostly in people unvaccinated (through 12/20) Not a good look for other states to come.

Story of Peace and persistence (Dr Eric Topol)

• Vaccination induced T-cells vs Omicron well preserved compared with all variants and with 3 different vaccines.

• Here are VE (Vaccine effectiveness) for HOSPITALIZATION vs antibody titers relative to original variant (WT)  w/ all data from 4 vaccines & 4 variants on same graph; data spans 13.7-fold antibody titer range; predicted VE 89.6% (88.6-90.4) to 98.4% (98.2-98.7).
• VE for HOSPITALIZATION is very robust!

• This has been known for a long time. Unfortunately the world is obsessed with neutralising antibodies which are the easy thing to measure.
• If our immune response is a big dinner buffet neutralising antibody are like a single dish that everyone is talking about.
• Just because T cells are difficult to measure there are not enough papers or talk about it.
• All available evidence so far shows that 2 doses protect very well against severe disease. There is NO WANING.
• England study suggests that even one dose is protective against critical illness but I don’t have breakdown on how many are in the one dose cohort?
• Unfortunately, discussions on “decline in neutralising titres” have become so common. People who have limited knowledge of biology are often talking about it.
• It is only natural for them to feel anxious when they hear words like “40-fold decline” in titres against variants.
• There is limited correlation between levels of antibodies & immune protection from COVID-19.
• A 2-fold decline does NOT mean a 2-fold lower protection from infection.
• True that a GROUP of people who have highest levels of decline, will have more breakthrough infections VS. the lowest.
• Hospitalisation (specifically, serious disease or organ damage) is determined by whether the person is able to mount an immune response on time. That is whether it is a coordinated, proportionate response. Those with past infection or vaccination are able to do that.
• Since natural infection invites far more complications than vaccines do, it is much safer to take two doses of vaccine (or one dose, 3 months after natural infection). This ensures a B & T cell long term memory that is self-sustaining, and also continuously self-improving.
• This is called “affinity maturation” in our memory B cells which means the antibodies launched upon a future attack will gradually have been honed to perfection by our immune system, compared to relatively crude and blunt response during naive infection.
• This is the reason why the same vaccine, when given as 1st dose (as priming dose) and 2nd (as booster dose) protects against future variants.
• Unlike influenza, SARS-CoV2 virus is the same virus and it has not (yet) shown any ability to completely escape our immune response.
• Which means that even if a “breakthrough” infection occurs, people do not get seriously ill. Exceptions are very rare.
• That’s also the reason why a “low neutralising titre” does not mean we have lost our ability to fight off this virus.
• In summary, evidence so far has shown that deaths and critical illness continue to be reduced to near zero levels (see attached graphs) despite new variants appearing, by using vaccines based on the original Wuhan version of the virus.

CME INDIA Learning Points

• Vaccines have greatly reduced the impact of COVID-19, but vaccine protection against milder disease and infection have waned significantly, especially for the Delta variant (B.1.617.2).
• “A third vaccine dose could substantially reduce transmission of SARS-CoV-2 and prevent future surges, with the impact increasing with vaccine coverage and contact rates among individuals. Reducing transmission would reduce infection in both unvaccinated individuals and breakthrough infections in vaccinated individuals.” (3)
• There is emergence of numerous SARS-CoV-2 variants of interest (VOI) and of concern (VOC).
• This the is one of the most important developments in the COVID-19 pandemic.
• Medical science is still pondering over:
  1. Whether the different variants are more infectious?
  2. Whether more easily transmissible?
  3. Whether linked to more severe disease?
  4. Whether it escape immune responses induced by either vaccination or natural infection?
• A million-dollar question, what are the knowledge gaps in terms of our understanding of VOI/VOCs in relation to T and B cell immune reactivity.
• For Omicron, much less is available for memory T cells and memory B cells. Memory T cell and B cell recognition of variants are important issues.
• Regarding memory T cells, it has been demonstrated that for the early variants Alpha, Beta, Gamma and Epsilon the impact of mutations is limited and the majority of CD4⁺ and CD8⁺ T cell responses are preserved in both vaccinated and natural infection responses.
• New research (not peer reviewed) shows that adaptive immunity in vaccinated individuals to a comprehensive panel of SARS-CoV-2 variants, including Delta and Omicron, for multiple vaccines. It also demonstrates that the vast majority of T cell epitopes are fully conserved, not only in the “early” variants previously analysed but also in newer variants, suggesting that the continued evolution of variants has not been associated with increased escape from T cell responses at the population level.
• Vaccines and T cell recognition of several variants – It includes Delta and Omicron. It was experimentally measured in donors vaccinated with mRNA-1273, BNT162b2 or Ad26.COV2.S. Variant recognition relative to the ancestral sequence was similar in the three different vaccine platforms tested, which is reassuring in terms of the potential implications for protective effects being similar regardless of the vaccine platform considered.
• So, majority of memory T cells were not impacted by variants’ mutations, which is again reassuring in terms of the potential implications for T cell protective effects being similar regardless of the different vaccine cohorts considered.
• Memory T cell responses to the various variants, including Omicron,-Omicron responses were largely preserved in both CD4⁺ and CD8⁺ T cells. In depth epitope identification experiments revealed that both CD4⁺ and CD8⁺ T cell responses in vaccinated donors were broad, and the data further demonstrated that for each individual donor/variant combination the majority of responses recognized epitopes 100% conserved.
• These data provide a clear explanation for the limited impact of variant associated mutations on T cell responses.
• Reason for optimism – Most vaccine-elicited T cell responses remain capable of recognizing all known SARS-CoV-2 variants.

CME INDIA Tail Piece

References:

1. SARS-CoV-2 vaccination induces immunological memory able to cross-recognize variants from Alpha to Omicron. Alison Tarke, Camila H. Coelho, Zeli Zhang, Jennifer M. Dan, Esther Dawen Yu, Nils Methot, Nathaniel I. Bloom, Benjamin Goodwin, Elizabeth Phillips, Simon Mallal, John Sidney, Gilberto Filaci, Daniela Weiskopf, Ricardo da Silva Antunes, Shane Crotty, Alba Grifoni, Alessandro Sette. bioRxiv 2021.12.28.474333; doi: https://doi.org/10.1101/2021.12.28.474333
2. Melo-Gonzalez, F., Soto, J.A., Gonzalez, L.A., Fernandez, J., Duarte, L.F., Schultz, B.M., Galvez, N.M.S., Pacheco, G.A., Rios, M., Vazquez, Y., et al. (2021). Recognition of Variants of Concern by Antibodies and T Cells Induced by a SARS-CoV-2 Inactivated Vaccine. Front Immunol 12, 747830.
3. Third doses of COVID-19 vaccines reduce infection and transmission of SARS-CoV-2 and could prevent future surges in some populations: a modeling studynBilly J. Gardner, A. Marm Kilpatrick. medRxiv 2021.10.25.21265500; doi: https://doi.org/10.1101/2021.10.25.21265500

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