Omicron has a lot of mutations – more so than previous VOCs. In the spike it has ~40 differences to the original Hu-1 virus (33 AA substitutions, 3 deletions, and 1 insertion). – Kristian G. Andersen
The key questions I’ll address in descending order of confidence in currently available evidence:
1. Mutation profile
2. Emergence
3. Immune escape properties
4. Transmission fitness
5. Virulence
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1⃣ Gut feeling:
Timing: recent, deep roots (high confidence)
Emergence: animals (very low confidence)
Immune escape: significant (medium-high confidence)
Transmission: increased (low confidence)
Virulence: similar (low confidence)
Details 🧵👇
3⃣ Emergence and reservoir
So where did Omicron come from? And when? We don’t know… But let’s take a look at some of the data and hypotheses. When it comes to age, we can answer two primary questions:
1. When did the lineage brach off?
2. How old is Omicron itself?
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We believe (a) the lineage leading to Omicron branched off a long time ago, (b) Omicron is young, but (c) is already widespread in parts of Africa. So what led to Omicron?
Three main hypotheses:
1. Undetected circulation
2. Immunocompromised patient(s)
3. Animal reservoir
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I don’t believe #1 is likely, leaving evolution in immunocompromised patient(s) or a reverse zoonosis, followed by a new zoonosis (human>animal>human) as the two hypotheses I find most plausible – although I have no confidence in either.
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I slightly favor reverse zoonosis for a few reasons:
1. The lineage is old and undetected circulation in immunocompromised patient(s) for this long seems unlikely
2. SARS-CoV-2 is a generalist virus and we have seen human>animal>human transmission happen in e.g., mink
..
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Many articles have already concluded that Omicron came from an immunocompromised person (“HIV” is often mentioned), but I disagree with that conclusion. While that’s certainly possible, we don’t have any data showing that’s the case.
Let’s keep all hypotheses open.
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Combine the rapid rise of Omicron with the observation from genetic data that it appears to be relatively young, what best explains that?
1. Increased immune evasion
2. Increased transmission
3. Combination of both
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Immunity will lower the fraction of susceptibles (x), leading to lower Rt. A more transmissible variant will increase R0, increasing Rt. But, Rt will also increase if a variant is capable of eroding immunity in the population – R0 stays the same, but x is now higher.
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Here lies the problem, because while we can reasonably estimate Rt, we don’t know whether an increase is due to R0 being higher (e.g., increased transmission) or x being higher (e.g., increased immune evasion).
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… all of this is also ignoring other factors that influence Rt, including contact patterns, duration of infectiousness, NPI usage, etc.
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This means that a more transmissible variant with no difference in immune escape properties *or* a variant with no difference in transmissibility, but with more immune escape properties could explain available evidence.
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Based on the mutations and early epi data, I expect Omicron will likely be more ‘escapy’ than previous VOCs, however, I don’t know by how much and whether it may be combined with increased transmission. Maybe – and mutations in e.g., the FCS (K679, H681) may suggest as much.
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To conclude this part, it’s important to remember that variants may have a localized ability to compete, but much less so outside a certain environment – we saw this with Beta, which was competitive in South Africa, but couldn’t compete with Alpha in most of the world.
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However, even if it’s true that previous VOCs had increased virulence, that correlation does not necessarily have to also hold up for Omicron.
There’s no selection for virulence (decreased or increased – despite what many may want you to believe)…
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But there are plausible mechanisms in which increased transmission could lead to decreased virulence – e.g., a virus that becomes primarily an upper respiratory virus, as opposed to what we have observed so far with SARS-CoV-2 being both upper and lower.
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SARS1, SARS2, and NL63 (an aCoV) all use ACE2 as their receptor, yet SARS1 primarily leads to lower respiratory infections (severe disease, but limited transmission) while NL63 is primarily upper respiratory (limited disease, relatively high transmission).
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So is it possible Omicron could have evolved to primarily lead to upper respiratory infections with higher transmission and less disease?
Sure, it’s possible – the increased transmission would quickly be selected for and the lower virulence would be a nice side effect.
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Finally, a HUGE thank of gratitude to amazing scientists in South Africa, Botswana, and elsewhere for alerting us to the presence of Omicron, as they did Beta. Without their work we’d be in a much worse spot – so let’s make sure this type of work is rewarded, not penalized.
fin/
