Thread by @vipintukur

The rise of #SARS2 variants & evidence of immunological interference (like OAS & weakened T-cell immunity) underscore the need for preemptive, next-gen vaccines that confer broad protection ag Covid

My piece in @theWireScience👇 @fitterhappierAJ

science.thewire.in/health/omicron…

What is common between Denmark, Israel, Austria, France, Switzerland, the UK, and the US? They all suffered an unprecedented severe wave of Omicron despite having some of the highest vaccination rates in the world. 2/ @1amnerd @thewire_in

@1amnerd @thewire_in Most of the Covid19 vaccines are based on spike-protein of SARS2. They have worked reasonably well so far. However, with the advent of #Omicron, one of the most mutated variants has exposed the limitations of these vaccines, particularly their ability to prevent infections 3/

For this reason, many countries and regions are rushing to grant booster vaccinations. However, repeated vaccinations may not be sustainable. 4/

media.nature.com/original/magaz…

There have also been concerns about the dangers of repeated booster doses. According to a report of European Medicines Agency, the repeat booster doses every four months could eventually weaken the immune response and tire out people. 5/

bloomberg.com/news/articles/…

I had earlier raised two very pertinent issues: the key overall objectives of the vaccination during a pandemic, and the role of booster doses in context with ongoing Covid19 pandemic 👇

science.thewire.in/health/covid-1…

science.thewire.in/health/covid-1…

For the first, it is stated that though prevention of severe disease and deaths has immense individual benefits – but as such contributes little to the virus’s transmission in the human population and ending the pandemic itself. 7/

science.thewire.in/health/covid-1…

In a pandemic, vaccines should stop the virus ongoing transmission. The current generation of COVID vaccines don’t provide significant protection on this front. And this is the reason why we are witnessing intense viral transmission even in the highly vaccinated countries 8/

New studies suggest that it may be less rewarding to vaccinate individuals with vaccines based on the ‘original’ Wuhan-spike. There may be an additional risk of non-updated vaccines generating a suboptimal immune response against the omicron variant. 9/

https://twitter.com/vipintukur/status/1486922123725897731?s=20&t=3fDkvY5c5bF-Dgv-yNvJkw

The study finds that prior vaccination with Wuhan like antigens followed by infection w/ Alpha/Delta gives rise to Ab responses with apparent Wuhan-specific imprinting manifesting as relatively decreased responses to the variant epitopes, compared to unvaxxed infected w/ variant

I had also earlier feared that the “Original Antigenic Sin” (older name for ‘Antigenic Imprinting’) could impact the performance of our Covid vaccine against the emerging SARS-CoV-2 variants. 11/
science.thewire.in/the-sciences/h…
tandfonline.com/doi/full/10.10…

This may have huge implications since the current vaccines/booster are still based on the Wuhan-like antigens & Omicron’s spike is highly mutated. No wonder, vaccine developers are now evaluating updated vaccines based on Omicron. Will they succeed? 12/

biorxiv.org/content/10.110…

Does it mean that the current Covid vaccines are useless?
No, the main merit of current vaccines is to provide protection against severe disease, hospitalization, & death. We know this protection is provided by our T cells—the last defence against the invading virus. 13/

But to generate adequate T cells immunity at least 2 doses of Covid vaccines is essential. We know that even in Omicron’s wave that led to great reduction in our NAbs, the T cells responses majorly preserved, & the virus couldn't escape our T cells 14/

science.org/doi/10.1126/sc…

As per the studies, 80% of epitopes in the spike protein recognized by CD8+ T cells are not affected by the mutations in the Omicron variant, two doses may still induce protection against severe disease 15/

nature.com/articles/s4159…

If we do a most dispassionate analysis, the current vaccines have been successful on two fronts:
1-providing protection against the severe disease, hospitalization, & death,
2-offering immune resistance to the mutating SARS2 virus 16/

In this process, the virus had to trade off its virulence to gain higher immune evasion--resulted in emergence of Omicron. CoV's virulence is a by-product of 2 factors : how inherently transmissible it is & how good it is at evading previous immunity 17/

theatlantic.com/health/archive…

But this is not the end of the story. The Omicron does not cease to amuse us. The recent @UKHSA report on vaccine effectiveness against death for Omicron variant showed significant waning of two-dose protection against severe disease and deaths. 18/

assets.publishing.service.gov.uk/government/upl…

The VE of two doses against death waned to only 59% that rose to 95% after the 3rd dose. Similar waning in protection against severe disease and deaths was also noted by the CDC and other US researchers. 19/

erictopol.substack.com/p/where-do-we-…

However, surprisingly, the protection accorded by the 3rd shot against hospitalization and death also waned after a few months and the 4th dose of the vaccine raised more than three-fold protection versus severe disease and hospitalization. 20/

nature.com/articles/d4158…

The waning in protection against severe disease has got far more sinister implications than mere waning in protection ag infection & symptomatic disease. We know that the memory T cell response has far more plasticity than NAbs for dealing with any new emerging variant 21/

This means our memory T cells responses are not performing as per the expectations. Acc to renowned T cell immunologist @fitterhappierAJ, the T-cells are damaged by Covid potentially undermining not just Covid immunity but immunity to other diseases 22/

https://twitter.com/fitterhappieraj/status/1487848130385268743?s=21

@fitterhappierAJ adds that much of the protection against Covid is not via ‘immunological memory’ or ‘T cell priming’ but rather through neutralizing antibodies. The ORF8 gene of the SARS-CoV-2 virus suppresses MHC that prevents activation of T cells 23/

https://twitter.com/fitterhappieraj/status/1487848130385268743?s=21

This is indeed the most disturbing aspect of the whole pathogenesis of Covid19 infection. If our T cells are not able to function properly, then our most robust wall against the severe disease is demolished. 24/

A recent study has also indicated that the T-cell reactivity to the Omicron variant is preserved in most but not all individuals and reduced by more than 50% in ∼20% of individuals. Even the booster dose was not able to restore this to 100%. 25/

cell.com/action/showPdf…

Taken together, while the ‘antigenic imprinting’ aka OAS decreasing our immunological response to the variant virus epitopes, on the other hand, the Omicron’s impact on our antibodies and T cells compartments have rendered our current Covid vaccines almost redundant. 26/

So, there is an urgent need to update our current Covid vaccines. Let us see what the options are available:
1-Continue to go for repeated boosting at regular intervals: But many believe that endless boosting might not be a practical or sustainable strategy 27/

2-Develop new vaccines: For new vaccines, we have two options,
1-‘Variant-specific vaccines’
2-A multi-antigenic, ‘Pan-coronavirus vaccine’.

On the first front, it is feared that by the time an Omicron-specific vaccine is tested, we wouldn’t have an Omicron wave anymore 28/

It makes a lot of sense to invest in a ‘universal’ or ‘pan-coronavirus’ vaccine that may not only be effective against the current variants but against future variants too. But this is a time-consuming process and not everybody is sure of its success 29/
tandfonline.com/doi/full/10.10…

3-Adopt a different vaccination strategy: Prime with a systemic (mRNA) vaccine and boost with a mucosal (intranasal) vaccine. Intranasal vaccines may prove most handy as a boosters. 30/

economictimes.indiatimes.com/industry/healt…

This is a very attractive approach & some researchers have shown that by using divergent spike proteins, Prime and Spike enable the induction of cross-reactive immunity ag sarbecoviruses w/out invoking OAS. But this vaccine is still in early phase 31/
biorxiv.org/content/10.110…

4-Animal adaptation of less pathogenic animal origin virus: another exciting option. The possibility of using animal-adapted variants to develop a multivalent SARS-CoV-2 vaccine, such as that for the vaccinia virus for smallpox can be explored. 32/
medrxiv.org/content/10.110…

Conclusions: To tackle this complex & unpredictable phase of the pandemic, the development of new covid-19 vaccines should be the global priority. 33/

The rise of #SARS2 variants, evidence of immunological interference like antigenic imprinting aka OAS & weakening of T cells immunity, underscore the continued need for next-generation pre-emptive vaccines that confer broad protection against coronavirus diseases. 34/end