Thread by @arijitchakrav

Viral evolution is not our friend: a🧵 about the future of covid-19.

What does the future hold for us with COVID-19?

In a recent preprint (h/t @madistod), we continue to explore a question that's concerned us since the beginning of the pandemic: (1)

medrxiv.org/content/10.110…

Although the specifics of viral evolution are not predictable, its role in the trajectory of the pandemic has been very predictable, unfortunately. In the fall of '20, we posted a preprint predicting the virus would rapidly evolve to evade Abs: (2) journals.plos.org/plosone/articl…

In the spring of '21, we posted a preprint predicting that reopening after having partially vaccinated the population would lead to a massive variant-fueled rebound in cases (this was in the same week as the CDC said you can vax & relax): journals.plos.org/plosone/articl… (3)

Around the same time, we posted another preprint that said that long-term evolution in immunocompromised patients was likely to be an engine of viral evolution going forward & limiting onward transmission from these cases would be crucial: nature.com/articles/s4159… (4)

So yeah, while evolution is not predictable in the details, the consequences of evolution for the current pandemic have sadly been only too predictable. It's best to think of evolution in terms of risks to the future trajectory of the pandemic. (5)

When we say that there is a risk of something happening in our day-to-day lives, we mitigate against those risks instead of debating how certain those risks are to come to pass.  It's why we use fire extinguishers, condoms and seatbelts (hopefully not at the same time). (6)

Arguing that we might get lucky when it comes to viral evolution has been a hallmark of the public health response to the ongoing pandemic- it's the reason we've done so poorly. Anticipating what could go wrong is much more useful than anticipating what could go right.(7)

So what are the risks posed to us by viral evolution at this point? First, it's worth pointing out that the more the transmission, the greater the evolution. We & others have made this point in the literature (eg. the paper mentioned in tweet #2 of this thread). (8)

Large standing populations of virus help only the virus. And vaccines alone cannot slow viral evolution, because the transmission rate of intermediate SARS-CoV-2 mutants are what will impact the rate at which novel variants appear: medrxiv.org/content/10.110… (9)

As vaccines have only a limited impact on transmission, they aren't likely to be able to slow this evolutionary rate down. There's papers out there that show that the rate of viral evolution has increased after the rollout of vaccines, which is what you'd expect. (10)

Vaccines are still an important part of the overall solution, but vaccinating widely and then relaxing, in hopes of “hybrid immunity", only means more transmission, which means more evolution. (11)

There's no reason to expect this evolution to result in more benign outcomes- we showed in a recent paper that the virus could kill almost everyone it infects with minimal impact on its fitness (ability to succeed evolutionarily):  mdpi.com/2673-8112/2/12… (12)

The narrative that endemicity will lead to a more benign virus is provably false, with many counterexamples from real life. Endemicity is not a victory, a point made by others (h/t ariskatzourakis) as well. (13)

So what's going to happen next? A point made by us and others at this point (h/t @tvrb) is that cross-immunity (of one viral variant against the next) is likely to be a driving force for viral evolution at this point, which is bad news for vaccines: medrxiv.org/content/10.110… (14)

and therapeutics. Whatever we do to update the vaccines and mAbs, the virus will work to defeat quickly. And letting the population of the virus swell ("let er rip") means that there's a quadrillion monkeys on typewriters banging away at that problem at all times. (15)

It's not a winning strategy! Sure, we can't predict exactly when it will all go to hell in a handbasket, but playing chicken with a virus like this is quite certain to end badly. The house always wins with Russian Roulette, if you play enough times. (16)

And it's important to keep in mind that this virus may have other nasty "surprises" up its sleeve. Just because a certain thing hasn't happened already doesn't mean it's not a risk. By now it should be clear that a reactive strategy does very poorly in a situation like this. (17)

One such risk is the emergence of serotypes (groups of  sequences within a virus species that share a similar structure). Some diseases, such as dengue, have split into serotypes- meaning that these virus sequence families don't compete with each other and can coexist. (18)

o, for example, if you get infected by one serotype of dengue today, you can get infected by a different one *at the same time*. Serotypes are, at a minimum, a huge public health nuisance, because it means that you have 2+ pandemics running simultaneously. (19)

Serotypes for SARS-CoV-2 would increase disease burden, complicate control (need to match tests, vaccines & mAbs to serotypes). They also raise the potential for increases in viral virulence through antibody-dependent enhancement (ADE). (20)

ADE occurs in dengue, for example- when Abs from a 1st infection bind to an infecting viral particle during a 2nd infection with a different serotype, they can't neutralize the virus, but instead, help the virus infect immune cells more efficiently. Leads to severe disease. (21)

In a recent preprint, we examine the risk of serotype formation for SC2& show it's not off the table. We built a 2-strain epi model (SEIRS) to understand the role of immune evasion in inter-strain competition & dynamics under endemic conditions: medrxiv.org/content/10.110… (22)

Our modeling shows that there are a wide range of situations where strains can be expected to coexist. Basically, as long as the cross-immunity against the invading strain is low enough, we can expect coexistence. We haven't seen this yet in the pandemic, of course. (23)

But that's not to say we won't see it going forward. Serotype formation (and ADE) is one way in which the virus could access a dramatic increase in mortality rates. There are others (more on this later). That it hasn't happened yet doesn't mean the risk doesn't exist. (24)

The point being, viral evolution is proceeding at a rapid clip at this point, thanks to 'let er rip'. Even small changes in IFR could lead to really bad outcomes & there are multiple ways in which things could go sideways at this point. Hope is not a strategy. (25)

H/t my collaborators- @madistod, @lfwhite14 & @DebraVanEgeren, and all the others!

@trvrb *

@ArisKatzourakis