Thread by @vipintukur

Last night, renowned Indian virologist, Dr T Jacob John predicted that the pandemic would end in the spring of 2022 & the #Omicron is probably the last VOC! Let’s see what are the other views on these issues. 1/

Making predictions is a risky thing. More so with the SARS2. Perhaps we know enough now to know we shouldn’t try to predict anything about this virus! 2/

No, the SARS2 has not stop evolving, and the #Omicron isn’t the last VOC. We are already witnessing its intense evolution in form of sister lineages like BA.2 & BA.1.1 which are quite distinct & distanced from the Omicron 3/

We know most viruses keep on mutating till they get the best ‘fit’! Most mutations will make a virus less fit (valleys) or have no effect at all (ridges), but a very small proportion will be peaks. We don’t know how high those peaks are or exactly how frequently they appear 4/

The SARS2’s VOCs keep surprising us because its evolutionary leaps look like nothing else we’ve seen before. Omicron racked up >50 mutations, w/ >30 in its spike alone. Of 4 seasonal CoVs, two accumulate only 0.3-0.5 mutations/year in their spike proteins 5/

The next variant may surprise us again. It could, by chance, become more virulent. It could become more transmissible. It will definitely alight upon new ways to escape the antibodies we’ve built up. The virus will keep finding those fitness peaks. 6/

Whether future variants will still cause huge numbers of infections will depend on how quickly the virus can keep evolving and how well our immunity holds up after repeated exposures. 7/

The coronavirus could indeed be an outlier that is inherently better than other viruses at exploring its fitness landscape. It helps to be an RNA virus, which acquires mutations more quickly than a DNA virus—and then it helps to be moving really fast 8/

Measles takes, on average, 11 or 12 days between infecting one person and that person infecting another; the coronavirus takes only 1.5 to 3. The more people it can infect, the more of the fitness landscape it can explore. 9/

It takes a while typically for a mutation to go from zero to even 5-10% of viruses in an infected person. That person then transmits only a tiny number of virus particles to the next person, so most of that diversity gets lost. 10/

Across millions of infections, some of those mutations are passed on, and they gradually accumulate into one viral lineage. This is the one traditional way of viral evolution. For ex. the #Delta VOC evolved through this pathway. 11/

Understanding the evolutionary forces that created Omicron can help us understand the realm of what is possible—even if it can’t tell us exactly what the next variant will look like. 12/

With Omicron, we got lucky. The set of mutations that makes the variant so good at infecting even vaccinated people just happens to also make it a little less inherently virulent. There’s no reason this will always be the case. 13/

cdc.gov/mmwr/volumes/7…

The coronavirus’s virulence is a by-product of two other factors under more direct evolutionary pressure: how inherently transmissible it is and how good it is at evading previous immunity. 14/

How deadly it is doesn’t matter so much, because the coronavirus is usually transmitted early on in an infection, long before it ever kills its host. 15/

A virus could replicate very, very fast, so that patients shed high levels of it. Omicron evolved in such a way that it replicates mostly in the upper airways, where it might be easier to transmit, rather than deep in the lungs. 16/

Delta, on the other hand, replicates more in the lungs than the Omicron, hence, was more virulent. The next variant could go either way—or it might chart an entirely new course. 17/

nature.com/articles/d4158…

Omicron doesn’t just have a lot of mutations; it has some really unusual ones. 13 of the mutations cluster in sites where scientists haven’t seen many changes before. That suggests mutations there normally make the virus less fit and get weeded out. 18/

biorxiv.org/content/10.110…

These 13 individually maladaptive changes might be adaptive when present all together. You can imagine a virus under pressure to escape from existing Abs. It acquires a series of mutations that make it less recognizable to Abs but perhaps worse at entering cells. 19/

In Omicron, this process remodeled key parts of the spike protein so that it both became less recognizable to existing antibodies and found a different strategy for entering cells. 20/

Coronavirus normally has 2 ways of infecting cells, either fusing directly w/ them or entering through a bubble. Omicron has become a specialist in the latter, which happens to work less well in lung cells than in upper airway cells & may explain its lower intrinsic severity 21/

So, to get around the immune system, the virus ended up changing one of its most basic functions! Do other sets of mutations interact in unknown ways to change key viral functions? Almost certainly. We just don’t know what they are yet. We’ll have to just wait & watch 22/

There are limits to how inherently transmissible the virus can get. Measles, the most transmissible virus, has an Ro of 12 to 18 (Delta’s 5). Omicron’s Ro is still unclear as a lot of its advantage seems to come from evading existing Abs rather than inherent transmissibility 23/

As the coronavirus has fewer & fewer non-immune people to infect, though, immune evasion will become a more & more important constraint on its evolution.
And here, the virus will never run out of new strategies, because what is optimal is always shifting. 24/

This #Omicron wave is generating a lot of Omicron immunity as it moves through the population, which has in effect made Omicron less fit than when it emerged. 25/

The next variant is more likely to be not Omicron, or something as antigenically distinct from Omicron as possible. But exactly what that looks like? Will it be more virulent? May be, yes. But it would definitely be more immune evasive than the Omicron! 26/

So, what is the conclusion? SARS2 virus’s evolution is still continued. Omicron is not the last VOC. There is a certainty that a new VOC will emerge. When? It is difficult to predict? Perhaps we know enough now to know we shouldn’t try to predict that. 27/

The above thread is based on the views of different virologists/evolutionary biologists that is very well conceptualized by @sarahzhang in her very well researched piece in @TheAtlantic 28/end

theatlantic.com/health/archive…