Thread by @arijitchakrav

(🧵NO ONE COULD HAVE PREDICTED THIS): To answer the question "What does the future hold for 𝑆𝐀𝑅𝑆-𝐂𝑂𝑉-𝟐?" it's worth examining how predictable its evolutionary trajectory has been so far. Evolution is stochastic, but stochastic processes can still yield predictions. (1/)

Paradoxically, while evolution is highly unpredictable at a molecular level, predicting its consequences and anticipating its risks is actually quite easy. We'll dive a lot deeper into this idea in a later TT, as it's a crucial one for understanding our current situation. (2/)

While "expert" prognostications from the early pandemic were wildly off-base, it was possible to reason deductively. We (my collaborators & I, h/t in particular @madistod & @debravanegeren) called out many of the risks within the first year, in the peer-reviewed literature. (3/)

In the fall of '20, we used a combination of structure/function analysis & evolutionary theory to predict the rapid evolution of resistance to neutralizing antibodies (nAbs), which are critical for vaccines & monoclonals, as well as natural immunity. (4/)

journals.plos.org/plosone/articl…

In Jan '21, we predicted that vaccines alone wouldn’t allow a return to pre-pandemic conditions, predicting hundreds of thousands of deaths following rollout. At the time, this was a highly contrarian position, with "experts" predicting an end to the pandemic with vaccines. (5/)

In May '21, we predicted relaxing restrictions too soon would lead to a variant-driven rebound. This was the same week the WH said "If you're vaccinated, the pandemic is over for you", as they lifted mask restrictions. The rebound we predicted was the Delta wave of Sep '21 (7/)

(although we guessed it'd be a different variant). All of that fall, PH kept referring to a "pandemic of the unvaccinated", which was factually incorrect. It was a pandemic of the unmasked & unvaccinated. "Vax & relax" was destined to fail from the get-go, as we predicted. (8/)

In Apr '21, we predicted intrahost evolution during long-term infections would drive the emergence of resistance. This is well proven at this point- many of the jumps made by the virus have been punctuated equilibrium events, as predicted by this paper. Punc eq is bad news. (9/)

The Omicron wave was caused by a punctuated equilibrium (punc eq) event, similar to what we've seen for other pandemics. Punc eq events are particularly dangerous for managing a pandemic, because they lead to huge & unpredictable jumps in sequence space (more on this later) (10/)

So here we are today, with several variant-driven waves of infection/yr, at unpredictable intervals. The virus is evolving faster than ever before, and vaccines aren't slowing its evolution. We haven't reached the endemic state (see screenshots). It's a volatile situation. (11/

All of this is what we predicted. This is not a "we told you so", although we, in fact, did. This work was intended as warnings, not predictions. These papers, which took some heat for being "FUD" at the time, were pointing out worst-case scenarios & flaws in the strategy. (12/)

It gives us no joy that these things came to pass. In fact, if our predictions had been heeded, they'd have been wrong & our lives would've been far better for it today. Some predictions we've made since then haven't come to pass (& hopefully never will). Let's take a look. (13/)

Our modeling predicts the average person will be infected 1-2x/yr if they take no precautions. We now know that post-acute damage from 𝐂𝑂𝑉𝐈𝐃 is common, and reported for a wide range of organ systems. The health burden of 𝐂𝑂𝑉𝐈𝐃 is not shrinking (see screenshots) (14/)

We showed in a paper a couple of years ago that transmission is minimally impacted by fatal COVID-19 outcomes. Put simply, the virus could evolve to kill everyone it infects and not take a hit to transmission. Small changes in IFR can have big impacts (see screenshot). (15/)

The promises made about stable protection vs severe disease being provided by T cells are ...debatable. The aspirational statements made by T cell experts have not materialized - ~5yrs into the pandemic, there are no T cell treatments on the horizon. (18/)

We pointed out in a paper from last year that the risk of co-circulation of multiple strains (serotype formation) remains on the table. Such a development would further complicate vaccine development efforts, which are already struggling to keep up with viral evolution. (19/)

New variants emerge from prior lineages not widely circulating at the time of emergence. Our work suggests this is due to punctuated equilibrium, happening as a result of prolonged intrahost evolution during persistent infections (see screenshots, manuscript in progress). (20/)

This creates an engine of viral evo that's capable of indefinitely throwing us "curve balls". It's popular among experts to claim that the "worst is behind us". Our work suggests that's far from guaranteed. Each new variant is a fresh draw from the viral evolution lottery. (21/)

In addition to sudden reversions to early pandemic IFRs caused by immune evasion, unrestrained viral evolution brings the risk of altered viral pathology. We pointed out in a preprint from a couple of years ago that there are many evolutionary pathways to higher virulence (22/)

As with other viruses, CoV fatality rates can vary. It's far from clear that CoVs emerge into human populations with low IFRs. A competing hypothesis is that virulence falls over time with the evolution of host resistance. (Optimism is not a good basis for risk management). (23/)

There is, in fact,a genomic signature of selection from an ancient CoV pandemic in East Asia 25k yrs ago. Those who would argue "that'll never happen with 𝐂𝑂𝑉𝐈𝐃" should explain what makes them so confident in the trajectory of virulence evolution for 𝑆𝐀𝑅𝑆-𝐂𝑂𝑉-𝟐 (24/)

Five yrs in at this point & most of the early reassurances from experts were wrong. They were, in fact, inconsistent with what science predicted at the time. Failing to mitigate those risks has created a fresh set of downside risks that should be addressed, not dismissed.(25/25)

H/t again to my collaborators, @madistod & @DebraVanEgeren & many others for the work shown here. Also H/T to @TRyanGregory & @madistod for the discussions that led to this 🧵 & @0bj3ctivity & @gckirchoff for helpful feedback.

This is 🧵3 /5 in a series, earlier 🧵s below (1/2):

@madistod @DebraVanEgeren @TRyanGregory @0bj3ctivity @gckirchoff Part 0: foreword
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Part 1: pandemics
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Part 2: history
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