CV. Humans 2, Omicron 1

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Eric Topol, Humans 2, Omicron 1 – by Eric Topol – Ground Truths (substack.com)
Recopilado por Carlos Cabrera Lozada. Miembro Correspondiente Nacional, ANM puesto 16. ORCID: 0000-0002-3133-5183. 10/01/2022

It’s pretty impressive that vaccines directed to the ancestral strain spike from 2 years ago, with the virus that’s evolved through nearly 300 million confirmed cases, and now to the hyper-mutated Omicron, have preserved efficacy of near 90% vs severe disease with a 3rd shot.

When you look at the marked “antigenic drift” of Omicron— how it appears so differently to our immune system—compared with the ancestral strain and the previous variants of concern or interest, as recently mapped by 2 new reports, it’s astounding how well we are holding up.

An adapted antigenic drift map from https://www.science.org/content/article/new-sars-cov-2-variants-have-changed-pandemic-what-will-virus-do-next using the 2 new cited reports

Why are we having an enormous number of new infections around the world, yet a relatively low severe disease toll as manifest by hospitalizations and deaths?

The first reason is that our T cells are not nearly as much affected as neutralizing antibodies for recognizing and responding to Omicron. There are 6 new studies, all reported in the last week, that consistently show fairly well preserved T cell function (both CD4+ and CD8+ cell types) that is durable versus Omicron 6 to 8 months out from vaccination (many types including Pfizer, Moderna, Astra-Zeneca, Novavax, J&J) and, in a few of these reports, after prior infection

Summary Table of 6 T cell studies for functionality vs Omicron

But there’s more than that. Our memory B cells, after a 3rd shot, adapt with a subset that has high Omicron reactivity. This adds another line of defense to our immunity wall, as nicely depicted in this recent review of memory B cells.

The “second wall” formed by memory B cells that have been adapted and specialized to the (in this case) Omicron variant (GC-germinal center)

The first line of defense induced by vaccination, neutralizing antibodies to Omicron, increase by 20-40 fold after the 3rd (booster) dose, which aligns with ~70% effectiveness vs symptomatic infection in 2 reports (South Africa and UK). Without the 3rd shot, there is minimal protection (<30% vaccine effectiveness point estimate).

Back to the initial sentence of this post, the latest UK report has shown us the vaccine effectiveness versus Omicron severe disease. i.e. hospitalizations with a 3rd shot (all brands vaccine) is 88%, which represents a marked increase from the waned 52% vaccine effectiveness vs hospitalization.

So the combination of a 3rd shot induced neutralizing antibodies that reduce infections. memory B cell sub-population that serve as specialists vs Omicron, and T-cells, our last line of defense, collectively provide a solid back-up immunity wall at the individual level. In short, the human immune response is pretty damn smart. And in case you’re wondering about durability of the near 90%? It ought to hold up pretty well against Omicron and prior variants since it is based on our on-demand memory B and T cells, not neutralizing antibodies.

I’ve modified the conceptual walls of defense from a prior post with what we’ve learned now that it’s become clear that 2-shot vaccines aren’t of much or any defense against Omicron infections, but some (~50%) vs severe disease, while 3-dose vaccination gets 2 additional layers built

The second reason why humans are winning is that Omicron, while hyper-transmissible, has lost some of the SARS-CoV-2 disease-causing capability (pathogenicity). Here are the now 7 reports, 5 in highly regarded animal models where Omicron was given, and 2 in vitro lab studies of lung cells. All are consistent in showing the reduced lung cell infectivity, lung organ reduced viral load , infectivity, and inflammation.

So between our immunity wall of defense versus Omicron and its decreased intrinsic virulence, why are people getting so sick, hospitalized, and dying? That’s the virus 1 score, because there are so many unvaccinated, vaccinated but waned (unboosted) people out there. Among the unvaccinated are people with prior Covid, but that only provides markedly reduced protection versus Omicron as compared with prior variants due to its antigenic drift. There’a also children who are less than age 5, not eligible to be vaccinated. The immunocompromised people represent a substantial group well over 7 million people in the United States, so that even with third shots they still have some vulnerability due to their incomplete immunity defense that can be built. That gets us to the variable immunity wall in any given place for how its population will respond to the Omicron challenge.

I’ve never heard the term “decoupling” as much as in the pandemic during its Delta and Omicron waves. It has essentially been used to describe a disproportionate relationship between cases as compared with hospitalizations or deaths. That is shown below for London’s Omicron wave

Graph by Paul Mainwood showing the decoupling of cases vs hospitalizations and deaths in London’t current Omicron wave in comparison to the prior Alpha wave

Indeed, clinical severity of Omicron has been shown to be 72% less in Gauteng ,South Africa (adjusted for multiple co-variates) and 60-70% reduced in the UK recent report cited above. This likely represents both the immunity wall and Omicron’s reduced virulence, but it isn’t possible to parse out how much of each. That these 2 very different populations have a similar reduction in clinical severity is notable: South Africa with only ~25% vaccination and very high prior Covid (with the Beta variant, with the most immune evasion prior to Omicron), in contrast to the UK with high vaccination and boosting, and high prior exposure.

Omicron will play out with considerable variability in decoupling by place and population. The United States is particularly vulnerable. There is a particularly low rate of fully vaccinated (62%, ranking below 66th for fully vaccinated in the world’s country list) and low rate of booster shots (21%, similarly raking well below the UK and Denmark at >50%; both of these countries have withstood marked increases in hospitalization and deaths to date, i.e maintained relative decoupling).

Hospitalizations have already exceeded 114,000 today and are increasing rapidly. The US had minimal decoupling in the Delta wave from cases to hospitalizations, reaching ~70% of its peak, unlike many countries that were well <40% of prior peaks. The same applied for deaths. The UK hit ~10% of its Alpha peak whereas the US was 60% of its fatality peak during the 1st Delta wave. So it remains to be seen in the US how much decoupling will take hold. We know that most people who get hospitalized or die are going to be unvaccinated, and to a lesser extent vaccinated and waned. As reviewed, the vaccine-induced immunity wall will largely protect from severe disease. We are clearly seeing this now via the substantial reduction of ICU need among those hospitalized with Covid in the United States.

The basic problem: while we have a very smart immune system that is vaccine- trained to defend surprisingly well against severe disease by a hyper-mutated, hyper -transmissible virus, too many humans have not gotten on board. We’ll nevertheless win this battle, fortunate to have 2 major points in our favor.

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